- Cancer > Lymphoma
Fellowship:Stanford University - Hematology and Oncology Fellowship (2011) CA
Residency:Stanford University Hospital -Clinical Excellence Research Center (2007) CA
Internship:Stanford University Hospital -Clinical Excellence Research Center (2006) CA
Board Certification: Internal Medicine, American Board of Internal Medicine (2008)
Medical Education:Stanford University School of Medicine (2005) CA
PhD, Stanford University, Clinical Trial Design & Tumor Immunology (2011)
Current Research and Scholarly Interests
Specific areas of active research include:
1. Immune Cell Allotransplantation for Curing Cancer: To develop novel vaccine strategies which induce tumor antigen specific immunity prior to infusing the donor inoculum and improve graft-versus-tumor reactions without exacerbation of graft-versus-host disease.
2. Augmenting Antibody Therapy for Curing Cancer: To identify and develop immunomodulatory antibodies targeting immune effector cells subsets, such as natural killer cells, which enhance the anti-tumor activity of tumor-targeting antibodies.
A Study Of PF-05082566 As A Single Agent And In Combination With Rituximab
A study of PF-05082566, a 4-1BB agonist monoclonal antibody (mAb), in patients with solid tumors or b-cell lymphomas, and in combination with rituximab in patients with CD20 positive Non-Hodgkin's Lymphoma (NHL).
Stanford is currently not accepting patients for this trial. For more information, please contact Ami Okada, (650) 725 - 4968.
Molecular Analysis of Thoracic Malignancies
A research study to learn about the biologic features of cancer development, growth, and spread. We are studying components of blood, tumor tissue, normal tissue, and other fluids, such as urine, cerebrospinal fluid, abdominal or chest fluid in patients with cancer. Our analyses of blood, tissue, and/or fluids may lead to improved diagnosis and treatment of cancer by the identification of markers that predict clinical outcome, markers that predict response to specific therapies, and the identification of targets for new therapies.
Clinical and Pathologic Studies in Non-Hodgkin's Lymphoma and Hodgkin's Disease
The purpose of this study is to characterize the molecular and cell biology of the tumor cells in lymphoma.
TLI & ATG for Non-Myeloablative Allogeneic Transplantation for MDS and MPD
To evaluate the feasibility and safety of TLI/ATG conditioning for allogeneic HCT for elderly patients with advanced stage MDS and MPD.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
Phase 1-2 of Azacitidine + Lenalidomide for Previously Untreated Elderly Patients With Acute Myeloid Leukemia (AML)
This study has a phase 1 and a phase 2 component. In phase 1, the objective is to determine the maximum tolerated dose (MTD) of lenalidomide when after azacitidine. In phase 2, the objective is to determine the efficacy of the combination treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.
A Study of CDX-1127 (Varlilumab) in Patients With Select Solid Tumor Types or Hematologic Cancers
This is a study of CDX-1127, a therapy that targets the immune system and may act to promote anti-cancer effects. The study enrolls patients with hematologic cancers (certain leukemias and lymphomas), as well as patients with select types of solid tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Vargas, 650-723-0371.
Safety, Tolerability, Pharmacokinetics, and Immunoregulatory Study of Urelumab (BMS-663513) in Subjects With Advanced and/or Metastatic Solid Tumors and Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma
The purpose of the study is to assess the safety, tolerability, pharmacokinetics and immunoregulatory activity of urelumab (BMS-663513) in cancer subjects with advanced and/or metastatic tumors and relapsed/refractory B-Cell Non-Hodgkin's Lymphoma
Stanford is currently not accepting patients for this trial. For more information, please contact Ami Okada, 650-725-4968.
Allogeneic Transplantation Using TL1 & ATG for Older Patients With Hematologic Malignancies
To measure how frequently and to what degree a complication of transplant cell acute graft versus host disease (GV/HD) occurs.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
A Study of PCI-32765 (Ibrutinib) in Patients With Refractory Follicular Lymphoma
The purpose of this study is to evaluate the efficacy and safety of PCI-32765 (ibrutinib) administered to patients with chemoimmunotherapy-resistant follicular lymphoma (FL).
Stanford is currently not accepting patients for this trial. For more information, please contact Lori Richards, 650-725-8589.
Phase I/II of a CpG-Activated Whole Cell Vaccine Followed by Autologous Immunotransplant for MCL
Mantle Cell Lymphoma is a sub-type of Non-Hodgkin's Lymphoma which is generally considered incurable with current therapy. Our goal is to accrue 59 patients who receive an autologous vaccine against their individual lymphoma after undergoing stem cell transplantation. Our hope is that vaccination will prolong the time which patients will stay in remission from their disease.
FNA Tumor Sampling for CD137 Modulation: A Pilot Study
The purpose of this study is to better understand the biology of the body's immune response to monoclonal antibody therapy for cancer. Your health information will be used to identify your tissues. The tissue we obtain may be useful for research or education, resulting in new drugs, therapies or diagnostic procedures.
Recombinant Interleukin-15 in Treating Patients With Advanced Melanoma, Kidney Cancer, Non-small Cell Lung Cancer, or Squamous Cell Head and Neck Cancer
This phase I trial studies the side effects and best dose of recombinant interleukin-15 in treating patients with melanoma, kidney cancer, non-small cell lung cancer, or head and neck cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. Recombinant interleukin-(IL)15 is a biological product, a protein, made naturally in the body and when made in the laboratory may help stimulate the immune system in different ways and stop tumor cells from growing.
Stanford is currently not accepting patients for this trial. For more information, please contact Brenda Hann, 650-723-0966.
Ipilimumab and Local Radiation Therapy in Treating Patients With Recurrent Melanoma, Non-Hodgkin Lymphoma, Colon, or Rectal Cancer
This pilot phase I/II trial studies the side effects and best of dose ipilimumab when given together with local radiation therapy and to see how well it works in treating patients with recurrent melanoma, non-Hodgkin lymphoma, colon, or rectal cancer. Monoclonal antibodies, such as ipilimumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Radiation therapy uses high energy x rays to kill cancer cells. Giving monoclonal antibody therapy together with radiation therapy may be an effective treatment for melanoma, non-Hodgkin lymphoma, colon, or rectal cancer
Stanford is currently not accepting patients for this trial. For more information, please contact Erin Waller, 650-725-0379.
A Phase 1 Study of Atezolizumab (an Engineered Anti-PDL1 Antibody) in Patients With Locally Advanced or Metastatic Solid Tumors
This Phase I, multicenter, first in human, open-label, dose escalation study will evaluate the safety, tolerability, and pharmacokinetics of Atezolizumab administered as single agent by intravenous (IV) infusion to patients with locally advanced or metastatic solid malignancies or hematologic malignancies.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, 650-721-6977.
Independent Studies (10)
- Directed Reading in Immunology
IMMUNOL 299 (Win, Spr)
- Directed Reading in Medicine
MED 299 (Aut, Win, Spr)
- Early Clinical Experience in Immunology
IMMUNOL 280 (Win, Spr)
- Early Clinical Experience in Medicine
MED 280 (Win, Spr)
- Graduate Research
IMMUNOL 399 (Win, Spr)
- Graduate Research
MED 399 (Aut, Win, Spr)
- Medical Scholars Research
MED 370 (Aut, Win, Spr)
- Teaching in Immunology
IMMUNOL 290 (Win, Spr)
- Undergraduate Research
IMMUNOL 199 (Win, Spr)
- Undergraduate Research
MED 199 (Aut, Win, Spr)
- Directed Reading in Immunology
- Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. journal of clinical investigation 2013; 123 (11): 4980-?
Intratumoral anti-CTLA-4 therapy: enhancing efficacy while avoiding toxicity.
Clinical cancer research
2013; 19 (19): 5261-5263
Systemic administration of the checkpoint blockade antibody anti-CTLA4 results in severe autoimmune toxicity, limiting its clinical efficacy. Fransen and colleagues show here that peritumoral delivery of low doses of this immunomodulatory drug can trigger a systemic antitumor immune response while preventing the toxicity against other organs.
View details for DOI 10.1158/1078-0432.CCR-13-1923
View details for PubMedID 23965900
Modulation of natural killer cell antitumor activity by the aryl hydrocarbon receptor
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2013; 110 (30): 12391-12396
The aryl hydrocarbon receptor (AhR) has become increasingly recognized for its role in the differentiation and activity of immune cell subsets; however, its role in regulating the activity of natural killer (NK) cells has not been described. Here, we show that AhR expression is induced in murine NK cells upon cytokine stimulation. We show that in the absence of AhR, NK cells have reduced cytolytic activity and reduced capacity to control RMA-S tumor formation in vivo, despite having normal development and maturation markers. Although AhR was first identified to bind the xenobiotic compound dioxin, AhR is now known to bind a variety of natural exogenous (e.g., dietary) and endogenous ligands. We show that activation of AhR with an endogenous tryptophan derivative, 6-formylindolo[3,2-b]carbazole, potentiates NK cell IFN-γ production and cytolytic activity. Further, administration of 6-formylindolo[3,2-b]carbazole in vivo enhances NK cell control of tumors in an NK cell- and AhR-dependent manner. Finally, similar effects on NK cell potency occur with AhR dietary ligands, potentially explaining the numerous associations that have been observed in the past between diet and NK cell function. Our studies introduce AhR as another regulator of NK cell activity in vivo.
View details for DOI 10.1073/pnas.1302856110
View details for Web of Science ID 000322112300059
Identification of gene microarray expression profiles in patients with chronic graft-versus-host disease following allogeneic hematopoietic cell transplantation
2013; 148 (1): 124-135
Chronic graft-versus-host disease (GVHD) results in significant morbidity and mortality, limiting the benefit of allogeneic hematopoietic cell transplantation (HCT). Peripheral blood gene expression profiling of the donor immune repertoire following HCT may provide associated genes and pathways thereby improving the pathophysiologic understanding of chronic GVHD. We profiled 70 patients and identified candidate genes that provided mechanistic insight in the biologic pathways that underlie chronic GVHD. Our data revealed that the dominant gene signature in patients with chronic GVHD represented compensatory responses that control inflammation and included the interleukin-1 decoy receptor, IL-1 receptor type II, and genes that were profibrotic and associated with the IL-4, IL-6 and IL-10 signaling pathways. In addition, we identified three genes that were important regulators of extracellular matrix. Validation of this discovery phase study will determine if the identified genes have diagnostic, prognostic or therapeutic implications.
View details for DOI 10.1016/j.clim.2013.04.013
View details for Web of Science ID 000320427300015
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors
JOURNAL OF CLINICAL INVESTIGATION
2013; 123 (6): 2447-2463
Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.
View details for DOI 10.1172/JCI64859
View details for Web of Science ID 000320093100018
High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells
2013; 121 (8): 1367-1376
Defects in T-cell function in patients with cancer might influence their capacity to mount efficient antitumor immune responses. Here, we identified highly reduced IL-4-, IL-10-, and IL-21-induced phosphorylation of STAT6 and STAT3 in tumor-infiltrating T cells (TILs) in follicular lymphoma (FL) tumors, contrasting other non-Hodgkin lymphoma TILs. By combining phospho-protein-specific flow cytometry with several T-cell markers, we identified that CD4(+)CD45RO(+)CD62L(-) FL TILs were largely nonresponsive to cytokines, in contrast to the corresponding autologous peripheral blood subset. We observed differential expression of the inhibitory receptor PD-1 in FL TILs and peripheral blood T cells. Furthermore, CD4(+)PD-1(hi) FL TILs, containing T(FH) and non-T(FH) cells, had lost their cytokine responsiveness, whereas PD-1 TILs had normal cytokine signaling. However, this phenomenon was not tumor specific, because tonsil T cells were similar to FL TILs. FL tumor cells were negative for PD-1 ligands, but PD-L1(+) histiocytes were found within the T cell-rich zone of the neoplastic follicles. Disruption of the microenvironment and in vitro culture of FL TILs could restore cytokine signaling in the PD-1(hi) subset. Because FL TILs in vivo probably receive suppressive signals through PD-1, this provides a rationale for testing PD-1 Ab in combination with immunotherapy in patients with FL.
View details for DOI 10.1182/blood-2012-04-421826
View details for Web of Science ID 000321750000021
Outcomes After Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation with Total Lymphoid Irradiation and Anti-Thymocyte Globulin in Lymphoid Malignancies After Failed Autologous Transplantation
ELSEVIER SCIENCE INC. 2013: S154-S155
View details for Web of Science ID 000314441900082
TLI-ATG Conditioning and Allogeneic Transplantation for Patients with MDS and MPN
ELSEVIER SCIENCE INC. 2013: S113-S114
View details for Web of Science ID 000314441900010
- Cancer Vaccines and T Cell Therapy BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 2013; 19 (1): S97-S101
Breast Cancer Treatment with Imiquimod: Applying an Old Lotion to a New Disease
CLINICAL CANCER RESEARCH
2012; 18 (24): 6571-6573
Over the prior two decades, imiquimod, a toll-like receptor 7 agonist, has been applied to nearly 50 clinical settings. Because of its immunomodulatory role, the topical cream today, for the first time, is being applied to cutaneous breast cancer in preclinical models and in a phase II clinical trial.
View details for DOI 10.1158/1078-0432.CCR-12-3138
View details for Web of Science ID 000312580600001
View details for PubMedID 23172886
Non-Myeloablative Conditioning with Total Lymphoid Irradiation and ATG and Allogeneic Transplantation for Patients with Myelodysplastic Syndrome, Therapy-Related Myeloid Neoplasms, and Myeloproliferative Neoplasms.
AMER SOC HEMATOLOGY. 2012
View details for Web of Science ID 000314049601176
Targeting B-Cell Lymphoma with Idiotype-Specific Peptibodies: Toward a Personalized and Tumor-Specific Therapy
AMER SOC HEMATOLOGY. 2012
View details for Web of Science ID 000314049600205
Achieving Selective Graft-Versus-Leukemia without Graft-Versus-Host Effects by WT1 Peptide Vaccination of Donors and Stringent Engineering of the Allo-Graft
AMER SOC HEMATOLOGY. 2012
View details for Web of Science ID 000314049602377
in Situ Vaccination for Patients with Previously Untreated Follicular Lymphoma: Analysis of Immune Responses
AMER SOC HEMATOLOGY. 2012
View details for Web of Science ID 000314049600215
Immune Injury by Allogeneic CD4(+) T Cells Leads to Host Hematopoietic Stem Cell Dormancy and Prevents Engraftment of Donor Cells
AMER SOC HEMATOLOGY. 2012
View details for Web of Science ID 000314049601095
Identification of Candidate Transcriptional Biomarkers Associated with Chronic Graft-Versus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation
AMER SOC HEMATOLOGY. 2012
View details for Web of Science ID 000313838905099
Intratumoral Treg immunomodulation at a single site cures disseminated disease including in the brain
WILEY-BLACKWELL. 2012: 12-12
View details for Web of Science ID 000312889800022
Immune injury by allogeneic CD4(+) T cells leads to host hematopoietic stem cell dormancy and prevents engraftment of donor cells
KARGER. 2012: 102-102
View details for Web of Science ID 000310766700257
CD137 Is Expressed in Follicular Dendritic Cell Tumors and in Classical Hodgkin and T-Cell Lymphomas Diagnostic and Therapeutic Implications
AMERICAN JOURNAL OF PATHOLOGY
2012; 181 (3): 795-803
CD137 (also known as 4-1BB and TNFRSF9) is a member of the tumor necrosis factor receptor superfamily. Originally identified as a costimulatory molecule expressed by activated T cells and NK cells, CD137 is also expressed by follicular dendritic cells, monocytes, mast cells, granulocytes, and endothelial cells. Anti-CD137 immunotherapy has recently shown promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. We defined the expression of CD137 protein in both normal and neoplastic hematolymphoid tissue. CD137 protein is expressed by follicular dendritic cells in the germinal center and scattered paracortical T cells, but not by normal germinal-center B cells, bone marrow progenitor cells, or maturing thymocytes. CD137 protein is expressed by a select group of hematolymphoid tumors, including classical Hodgkin lymphoma, T-cell and NK/T-cell lymphomas, and follicular dendritic cells neoplasms. CD137 is a novel diagnostic marker of these tumors and suggests a possible target for tumor-directed antibody therapy.
View details for DOI 10.1016/j.ajpath.2012.05.015
View details for Web of Science ID 000309251100009
View details for PubMedID 22901750
The chemoattractant chemerin suppresses melanoma by recruiting natural killer cell antitumor defenses
JOURNAL OF EXPERIMENTAL MEDICINE
2012; 209 (8): 1427-1435
Infiltration of specialized immune cells regulates the growth and survival of neoplasia. Here, in a survey of public whole genome expression datasets we found that the gene for chemerin, a widely expressed endogenous chemoattractant protein, is down-regulated in melanoma as well as other human tumors. Moreover, high chemerin messenger RNA expression in tumors correlated with improved outcome in human melanoma. In experiments using the B16 transplantable mouse melanoma, tumor-expressed chemerin inhibited in vivo tumor growth without altering in vitro proliferation. Growth inhibition was associated with an altered profile of tumor-infiltrating cells with an increase in natural killer (NK) cells and a relative reduction in myeloid-derived suppressor cells and putative immune inhibitory plasmacytoid dendritic cells. Tumor inhibition required host expression of CMKLR1 (chemokine-like receptor 1), the chemoattractant receptor for chemerin, and was abrogated by NK cell depletion. Intratumoral injection of chemerin also inhibited tumor growth, suggesting the potential for therapeutic application. These results show that chemerin, whether expressed by tumor cells or within the tumor environment, can recruit host immune defenses that inhibit tumorigenesis and suggest that down-regulation of chemerin may be an important mechanism of tumor immune evasion.
View details for DOI 10.1084/jem.20112124
View details for Web of Science ID 000307016500006
View details for PubMedID 22753924
Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells
2012; 119 (24): 5758-5768
Natural killer (NK) cells are potent anti-viral and antitumor "first responders" endowed with natural cytotoxicity and cytokine production capabilities. To date, attempts to translate these promising biologic functions through the adoptive transfer of NK cells for the treatment of cancer have been of limited benefit. Here we trace the fate of adoptively transferred murine NK cells and make the surprising observation that NK cells traffic to tumor sites yet fail to control tumor growth or improve survival. This dysfunction is related to a rapid down-regulation of activating receptor expression and loss of important effector functions. Loss of interferon (IFN)? production occurs early after transfer, whereas loss of cytotoxicity progresses with homeostatic proliferation and tumor exposure. The dysfunctional phenotype is accompanied by down-regulation of the transcription factors Eomesodermin and T-bet, and can be partially reversed by the forced overexpression of Eomesodermin. These results provide the first demonstration of NK-cell exhaustion and suggest that the NK-cell first-response capability is intrinsically limited. Further, novel approaches may be required to circumvent the described dysfunctional phenotype.
View details for DOI 10.1182/blood-2012-03-415364
View details for Web of Science ID 000307396500028
View details for PubMedID 22544698
The chemoattractant chemerin as a natural tumor suppressive cytokine.
AMER SOC CLINICAL ONCOLOGY. 2012
View details for Web of Science ID 000318009803142
Effect of stimulation of natural killer cells with an anti-CD137 mAb on the efficacy of trastuzumab, cetuximab, and rituximab
AMER SOC CLINICAL ONCOLOGY. 2012
View details for Web of Science ID 000318009801791
Combination strategies to enhance antitumor ADCC
2012; 4 (5): 511-527
The clinical efficacy of monoclonal antibodies as cancer therapeutics is largely dependent upon their ability to target the tumor and induce a functional antitumor immune response. This two-step process of ADCC utilizes the response of innate immune cells to provide antitumor cytotoxicity triggered by the interaction of the Fc portion of the antibody with the Fc receptor on the immune cell. Immunotherapeutics that target NK cells, ?? T cells, macrophages and dendritic cells can, by augmenting the function of the immune response, enhance the antitumor activity of the antibodies. Advantages of such combination strategies include: the application to multiple existing antibodies (even across multiple diseases), the feasibility (from a regulatory perspective) of combining with previously approved agents and the assurance (to physicians and trial participants) that one of the ingredients - the antitumor antibody - has proven efficacy on its own. Here we discuss current strategies, including biologic rationale and clinical results, which enhance ADCC in the following ways: strategies that increase total target-monoclonal antibody-effector binding, strategies that trigger effector cell 'activating' signals and strategies that block effector cell 'inhibitory' signals.
View details for DOI 10.2217/IMT.12.38
View details for Web of Science ID 000304733600018
View details for PubMedID 22642334
Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia
2012; 26 (5): 893-901
Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).
View details for DOI 10.1038/leu.2011.294
View details for Web of Science ID 000303883500005
View details for PubMedID 22033493
Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era
2012; 119 (17): 4083-4090
Tyrosine kinase inhibitors (TKIs) and reduced intensity conditioning (RIC)/nonmyeloablative (NMA) conditioning hematopoietic cell transplants (HCTs) have changed the therapeutic strategy for chronic myelogenous leukemia (CML) patients. We analyzed post-HCT outcomes of 306 CML patients reported to the Center for International Blood and Marrow Transplant Research aged 40 years and older undergoing RIC/NMA HCT from 2001 to 2007: 117 (38%) aged 40 to 49 years, 119 (39%) 50 to 59 years, and 70 (23%) 60 years or older. The majority (74%) had treatment with imatinib before HCT. At HCT, most patients aged 40 to 49 years were in chronic phase (CP) 1 (74%), compared with 31% aged 60 years or older. Siblings were donors for 56% aged 40 to 49 years; older cohorts had more unrelated donors. The majority received peripheral blood grafts and RIC across all age groups. 3 year overall survival (54%, 52%, and 41%), day + 100 grade II-IV acute GVHD (26%, 32%, and 32%), chronic GVHD (58%, 51%, and 43%), and 1-year treatment-related mortality (18%, 20%, and 13%) were similar across ages. The 3-year relapse incidence (36%, 43%, and 66%) and disease-free survival (35%, 32%, and 16%) were inferior in the oldest cohort. Importantly, for CP1 patients, relapse and disease-free survival were similar across age cohorts. Allogeneic RIC HCT for older patients with CML can control relapse with acceptable toxicity and survival in TKI-exposed CML, especially if still in CP1.
View details for DOI 10.1182/blood-2012-02-409763
View details for Web of Science ID 000305282900031
View details for PubMedID 22408257
Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2012; 109 (15): 5820-5825
Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8(+) memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.
View details for DOI 10.1073/pnas.1120237109
View details for Web of Science ID 000302533500055
View details for PubMedID 22440752
Adoptive Cell Therapy for Lymphoma with CD4 T Cells Depleted of CD137-Expressing Regulatory T Cells
2012; 72 (5): 1239-1247
Adoptive immunotherapy with antitumor T cells is a promising novel approach for the treatment of cancer. However, T-cell therapy may be limited by the cotransfer of regulatory T cells (T(reg)). Here, we explored this hypothesis by using 2 cell surface markers, CD44 and CD137, to isolate antitumor CD4 T cells while excluding T(regs). In a murine model of B-cell lymphoma, only CD137(neg)CD44(hi) CD4 T cells infiltrated tumor sites and provided protection. Conversely, the population of CD137(pos)CD44hi CD4 T cells consisted primarily of activated T(regs). Notably, this CD137(pos) T(reg) population persisted following adoptive transfer and maintained expression of FoxP3 as well as CD137. Moreover, in vitro these CD137(pos) cells suppressed the proliferation of effector cells in a contact-dependent manner, and in vivo adding the CD137(pos)CD44(hi) CD4 cells to CD137(neg)CD44(hi) CD4 cells suppressed the antitumor immune response. Thus, CD137 expression on CD4 T cells defined a population of activated T(regs) that greatly limited antitumor immune responses. Consistent with observations in the murine model, human lymphoma biopsies also contained a population of CD137(pos) CD4 T cells that were predominantly CD25(pos)FoxP3(pos) T(regs). In conclusion, our findings identify 2 surface markers that can be used to facilitate the enrichment of antitumor CD4 T cells while depleting an inhibitory T(reg) population.
View details for DOI 10.1158/0008-5472.CAN-11-3375
View details for Web of Science ID 000300989100023
View details for PubMedID 22232735
Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer
JOURNAL OF CLINICAL INVESTIGATION
2012; 122 (3): 1066-1075
Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2(+) breast cancer. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. CD137 activation, which was dependent on NK cell expression of the Fc?RIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors.
View details for DOI 10.1172/JCI61226
View details for Web of Science ID 000301021500029
View details for PubMedID 22326955
- What Happened to the Concept of the Physician-Scientist? ACADEMIC MEDICINE 2012; 87 (2): 132-133
SPACE AND TOLERANCE ARE CRITICAL FOR ENGRAFTMENT OF HEMATOPOIETIC ALLOGRAFTS IN RECIPIENTS CONDITIONED WITH TOTAL LYMPHOID IRRADIATION PLUS ATG
ELSEVIER SCIENCE INC. 2012: S326-S327
View details for Web of Science ID 000299398600328
Long-Term Outcome of Patients with Metastatic Breast Cancer Treated with High-Dose Chemotherapy and Transplantation of Purified Autologous Hematopoietic Stem Cells
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2012; 18 (1): 125-133
Metastatic breast cancer remains a major treatment challenge. The use of high-dose chemotherapy (HDCT) with rescue by autologous mobilized peripheral blood (MPB) is controversial, in part because of contamination of MPB by circulating tumor cells. CD34(+)Thy-1(+) selected hematopoietic stem cells (HSC) represent a graft source with a greater than 250,000-fold reduction in cancer cells. Here, we present the long-term outcome of a pilot study to determine feasibility and engraftment using HDCT and purified HSC in patients with metastatic breast cancer. Twenty-two patients who had been treated with standard chemotherapy were enrolled into a phase I/II trial between December 1996 and February 1998, and underwent HDCT followed by rescue with CD34(+)Thy-1(+) HSC isolated from autologous MPB. More than 12 years after the end of the study, 23% (5 of 22) of HSC recipients are alive, and 18% (4 of 22) are free of recurrence with normal hematopoietic function. Median progression-free survival (PFS) was 16 months, and median overall survival (OS) was 60 months. Retrospective comparison with 74 patients transplanted between February 1995 and June 1999 with the identical HDCT regimen but rescue with unmanipulated MPB indicated that 9% of patients are alive, and 7% are without disease. Median PFS was 10 months, and median OS was 28 months. In conclusion, cancer-depleted HSC following HDCT resulted in better than expected 12- to 14-year PFS and OS in a cohort of metastatic breast cancer patients. These data prompt us to look once again at purified HSC transplantation in a protocol powered to test for efficacy in advanced-stage breast cancer patients.
View details for DOI 10.1016/j.bbmt.2011.07.009
View details for Web of Science ID 000303140200015
View details for PubMedID 21767515
Treatment advances have not improved the early death rate in acute promyelocytic leukemia
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
2012; 97 (1): 133-136
Early mortality in acute promyelocytic leukemia has been reported to occur in less than 10% of patients treated in clinical trials. This study reports the incidence and clinical features of acute promyelocytic leukemia patients treated at Stanford Hospital, CA, USA since March 1997, focusing on early mortality. We show that the risk of early death in acute promyelocytic leukemia patients is higher than previously reported. In a cohort of 70 patients who received induction therapy at Stanford Hospital, 19% and 26% died within seven and 30 days of admission, respectively. High early mortality was not limited to our institution as evaluation of the Surveillance, Epidemiology and End Results Database demonstrated that 30-day mortality for acute promyelocytic leukemia averaged 20% from 1977-2007 and did not improve significantly over this interval. Our findings show that early death is now the greatest contributor to treatment failure in this otherwise highly curable form of leukemia.
View details for DOI 10.3324/haematol.2011.046490
View details for Web of Science ID 000299870500022
View details for PubMedID 21993679
Tailored temozolomide therapy according to MGMT methylation status for elderly patients with acute myeloid leukemia
AMERICAN JOURNAL OF HEMATOLOGY
2012; 87 (1): 45-50
Temozolomide sensitivity is determined by methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter. This study assessed whether the temozolomide dose can be tailored by MGMT promoter status and whether protracted, low-dose temozolomide can "prime" blasts in patients with unmethylated MGMT (unMGMT). Elderly patients with high-risk AML were stratified by MGMT methylation. Patients with methylated MGMT (mMGMT) received temozolomide 200 mg/m(2) orally for 7 days every 4 weeks, while patients with unMGMT received temozolomide 100 mg/m(2) orally for 14 days followed by 200 mg/m(2) orally for 7 days every 6weeks. Of 36 patients (median age, 75 years), 31 (86%) had an unMGMT promoter. Overall response rate for the entire cohort was 36%. Patients with mMGMT and unMGMT had similar response rates (40% vs. 29%). Median duration of response and overall survival (OS) among responders were 29 and 35 weeks, respectively. Induction deaths (ID) occurred in 25% of patients, mostly caused by disease progression. Hematological toxicities were the most common adverse event. Toxicities were similar between patients on conventional versus protracted schedules. High HCT-CI scores were predictive of lower CR rate, higher ID, and shorter OS, while bone marrow blast count <50% at screening predicted for improved responses. Temozolomide, dosed according to MGMT methylation status, demonstrated modest clinical activity in elderly patients with AML, especially in those presenting with fewer comorbidities and low disease burden. The trial was registered on www.ClinicalTrials.gov as #NCT00611247.
View details for DOI 10.1002/ajh.22191
View details for Web of Science ID 000298257700010
View details for PubMedID 22052619
Immunotransplant for Mantle Cell Lymphoma: Phase I/II Study Preliminary Results
AMER SOC HEMATOLOGY. 2011: 1323-1323
View details for Web of Science ID 000299597104419
Donor Immunization with WT1 Peptide Augments Anti-Leukemic Activity After MHC-Matched Bone Marrow Transplantation
AMER SOC HEMATOLOGY. 2011: 827-828
View details for Web of Science ID 000299597102491
Natural Killer Cell Adoptive Immunotherapy Is Hampered by A Rapid Development of NK Cell Dysfunction Characterized by Loss of Effector Mechanisms and Downregulation of the Transcription Factors T-Bet and Eomesodermin; Definition and Possible Mechanism of NK Cell Exhaustion
AMER SOC HEMATOLOGY. 2011: 457-457
View details for Web of Science ID 000299597101271
Graft T Cells Retard Stem Cell Derived Lymphoid Organ Reconstitution and Immune Function After Allogeneic Transplantation
AMER SOC HEMATOLOGY. 2011: 1722-1722
View details for Web of Science ID 000299597106199
Donor immunization with WT1 peptide augments antileukemic activity after MHC-matched bone marrow transplantation
2011; 118 (19): 5319-5329
The curative potential of MHC-matched allogeneic bone marrow transplantation (BMT) is in part because of immunologic graft-versus-tumor (GvT) reactions mediated by donor T cells that recognize host minor histocompatibility antigens. Immunization with leukemia-associated antigens, such as Wilms Tumor 1 (WT1) peptides, induces a T-cell population that is tumor antigen specific. We determined whether allogeneic BMT combined with immunotherapy using WT1 peptide vaccination of donors induced more potent antitumor activity than either therapy alone. WT1 peptide vaccinations of healthy donor mice induced CD8(+) T cells that were specifically reactive to WT1-expressing FBL3 leukemia cells. We found that peptide immunization was effective as a prophylactic vaccination before tumor challenge, yet was ineffective as a therapeutic vaccination in tumor-bearing mice. BMT from vaccinated healthy MHC-matched donors, but not syngeneic donors, into recipient tumor-bearing mice was effective as a therapeutic maneuver and resulted in eradication of FBL3 leukemia. The transfer of total CD8(+) T cells from immunized donors was more effective than the transfer of WT1-tetramer(+)CD8(+) T cells and both required CD4(+) T-cell help for maximal antitumor activity. These findings show that WT1 peptide vaccination of donor mice can dramatically enhance GvT activity after MHC-matched allogeneic BMT.
View details for DOI 10.1182/blood-2011-05-356238
View details for Web of Science ID 000296867100035
SYSTEMIC ANTITUMOR IMMUNITY TRIGGERED BY INTRATUMORAL IMMUNOMODULATION CURES DISTANT METASTATIC CNS LYMPHOMA
OXFORD UNIV PRESS INC. 2011: 38-38
View details for Web of Science ID 000297026600155
Targeting immune effector cells to promote antibody-induced cytotoxicity in cancer immunotherapy
TRENDS IN IMMUNOLOGY
2011; 32 (11): 510-516
Monoclonal antibodies (mAbs) are in widespread use for the treatment of cancer. Their success as cancer therapeutics relies substantially on their ability to engage the immune system. Specifically, Fc-receptor-expressing immune cells mediate the killing of tumor cells by mAbs. Stimulation of these immune effector cells might therefore represent a promising strategy to enhance the therapeutic potential of mAbs. For instance, stimulation of natural killer cells, ?? T cells, macrophages, or dendritic cells can be used to enhance antibody-dependent cellular cytotoxicity, phagocytosis or even tumor vaccine effects. Here, we review several ways to improve the antitumor efficacy of mAbs by combining them with therapies that are directed against immune effector cells.
View details for DOI 10.1016/j.it.2011.07.003
View details for Web of Science ID 000296828400002
View details for PubMedID 21907000
Selective Resistance of CD44(hi) T Cells to p53-Dependent Cell Death Results in Persistence of Immunologic Memory after Total Body Irradiation
JOURNAL OF IMMUNOLOGY
2011; 187 (8): 4100-4108
Our previous studies showed that treatment of mice with total body irradiation (TBI) or total lymphoid tissue irradiation markedly changes the balance of residual T cell subsets to favor CD4(+)CD44(hi) NKT cells because of the differential resistance of the latter subset to cell death. The object of the current study was to further elucidate the changed balance and mechanisms of differential radioresistance of T cell subsets after graded doses of TBI. The experimental results showed that CD4(+) T cells were markedly more resistant than CD8(+) T cells, and CD44(hi) T cells, including NKT cells and memory T cells, were markedly more resistant than CD44(lo) (naive) T cells. The memory T cells immunized to alloantigens persisted even after myeloablative (1000 cGy) TBI and were able to prevent engraftment of bone marrow transplants. Although T cell death after 1000 cGy was prevented in p53(-/-) mice, there was progressive T cell death in p53(-/-) mice at higher doses. Although p53-dependent T cell death changed the balance of subsets, p53-independent T cell death did not. In conclusion, resistance of CD44(hi) T cells to p53-dependent cell death results in the persistence of immunological memory after TBI and can explain the immune-mediated rejection of marrow transplants in sensitized recipients.
View details for DOI 10.4049/jimmunol.1101141
View details for Web of Science ID 000295623100022
View details for PubMedID 21930972
Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment
2011; 118 (5): 1350-1358
Several gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the "germinal center B cell-like" subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of "cell-of-origin" classification, "stromal signatures," IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL.
View details for DOI 10.1182/blood-2011-03-345272
View details for Web of Science ID 000293510000028
View details for PubMedID 21670469
Cytotoxic T lymphocyte responses against melanocytes and melanoma
JOURNAL OF TRANSLATIONAL MEDICINE
Vitiligo is a common toxicity associated with immunotherapy for melanoma. Cytotoxic T lymphocytes (CTLs) against melanoma commonly target melanoma-associated antigens (MAAs) which are also expressed by melanocytes. To uncouple vitiligo from melanoma destruction, it is important to understand if CTLs can respond against melanoma and melanocytes at different levels.To understand the dichotomous role of MAA-specific CTL, we characterized the functional reactivities of established CTL clones directed to MAAs against melanoma and melanocyte cell lines.CTL clones generated from melanoma patients were capable of eliciting MHC-restricted, MAA-specific lysis against melanocyte cell lines as well as melanoma cells. Among the tested HLA-A*0201-restricted CTL clones, melanocytes evoked equal to slightly higher degranulation and cytolytic responses as compared to melanoma cells. Moreover, MAA-specific T cells from vaccinated patients responded directly ex vivo to melanoma and melanocytes. Melanoma cells express slightly higher levels of MART-1 and gp100 than melanocytes as measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry.Our data suggest that CTLs respond to melanoma and melanocytes equally in vitro and directly ex vivo.
View details for DOI 10.1186/1479-5876-9-122
View details for Web of Science ID 000294153500001
View details for PubMedID 21794122
- Prolonged disease-free survival and overall survival with CVP alternating with fludarabine in advanced follicular lymphoma AMERICAN JOURNAL OF HEMATOLOGY 2011; 86 (6): 515-518
Active and Passive Immunotherapy for Lymphoma: Proving Principles and Improving Results
JOURNAL OF CLINICAL ONCOLOGY
2011; 29 (14): 1864-1875
Conventional chemotherapy for lymphoma has advanced greatly over the past 50 years, changing some lymphoma subtypes from uniformly lethal to curable; however, the majority of lymphomas in patients remain incurable, and there is a need for novel therapies with less toxicity and more specific targeting of tumor cells. The vertebrate immune system has evolved the capacity for such specific targeting through the B-cell and T-cell receptors; passive immunotherapies utilizing these receptors, such as monoclonal antibodies (mAbs) or T cells, have shown efficacy in treating lymphomas. The first generation of mAb-based therapies has transformed the standard of care for lymphoma, and newer antibodies may improve on this approach. Clinical activity has been shown by T cells bearing receptors that target viral antigens as well as T cells bearing re-engineered receptors that target antigens recognized by antibodies. Active immunotherapies, such as vaccines and immune checkpoint blockades, have prolonged survival in certain solid tumors and are being actively pursued to treat lymphoma. A variety of vaccines (eg, protein- and cell-based vaccines) are being tested in ongoing trials, and the most recent iterations show therapeutic activity. Newer trials are addressing the problem of tumor-induced immunosuppression by the use of antibodies against immunologic checkpoints or by the reinfusion of primed T cells after lymphodepletion, a process we refer to as immunotransplantation. Herein, we discuss results of the various immunotherapy strategies applied to lymphoma and the ongoing approaches for their improvement.
View details for DOI 10.1200/JCO.2010.33.4623
View details for Web of Science ID 000290382300020
View details for PubMedID 21482977
CD8(+)CD44(hi) but not CD4(+)CD44(hi) memory T cells mediate potent graft antilymphoma activity without GVHD
2011; 117 (11): 3230-3239
Allogeneic hematopoietic cell transplantation can be curative in patients with leukemia and lymphoma. However, progressive growth of malignant cells, relapse after transplantation, and graft-versus-host disease (GVHD) remain important problems. The goal of the current murine study was to select a freshly isolated donor T-cell subset for infusion that separates antilymphoma activity from GVHD, and to determine whether the selected subset could effectively prevent or treat progressive growth of a naturally occurring B-cell lymphoma (BCL(1)) without GVHD after recipients were given T cell-depleted bone marrow transplantations from major histocompatibility complex-mismatched donors. Lethal GVHD was observed when total T cells, naive CD4(+) T cells, or naive CD8(+) T cells were used. Memory CD4(+)CD44(hi) and CD8(+)CD44(hi) T cells containing both central and effector memory cells did not induce lethal GVHD, but only memory CD8(+) T cells had potent antilymphoma activity and promoted complete chimerism. Infusion of CD8(+) memory T cells after transplantation was able to eradicate the BCL(1) lymphoma even after progressive growth without inducing severe GVHD. In conclusion, the memory CD8(+) T-cell subset separated graft antilymphoma activity from GVHD more effectively than naive T cells, memory CD4(+) T cells, or memory total T cells.
View details for DOI 10.1182/blood-2010-10-312751
View details for Web of Science ID 000288496300035
View details for PubMedID 21239702
Acute myeloid leukaemia in the elderly: a review
BRITISH JOURNAL OF HAEMATOLOGY
2011; 152 (5): 524-542
The majority of patients with acute myeloid leukaemia (AML) are elderly. Advancements in supportive care and regimen intensification have resulted in improvements in clinical outcomes for younger AML patients, but analogous improvements in older patients have not been realized. While outcomes are compromised by increased comorbidities and susceptibility to toxicity from therapy, it is now recognized that elderly AML represents a biologically distinct disease that is more aggressive and less responsive to therapy. Some patients tolerate and benefit from intensive remission-induction approaches, while others are best managed with less aggressive strategies. The challenge is to differentiate these groups based on host-related and biological features, in order to maximize the therapeutic benefit and minimize toxicity. As more is understood about the complicated pathogenesis and molecular basis of AML, there are more opportunities to develop and test targeted therapies. Elderly patients, with their narrow therapeutic window, are well positioned to derive a benefit from these novel agents, and therefore, despite a difficult past, there are reasons to be optimistic about the future of elderly AML.
View details for DOI 10.1111/j.1365-2141.2010.08470.x
View details for Web of Science ID 000287315600003
View details for PubMedID 21314823
Immunomodulating antibodies and drugs for the treatment of hematological malignancies
CANCER AND METASTASIS REVIEWS
2011; 30 (1): 97-109
The aim of cancer immunotherapy is to induce immune cells to kill tumor and promote immunological memory that protects against tumor recurrence. Most current immunotherapies, such as monoclonal antibodies (mAb), target the tumor cells directly. Advances in our understanding of the immune system such as the role of co-stimulatory and co-inhibitory receptors, and the advent of new immunomodulatory agents provide new opportunities to target the immune system and enhance anti-tumor immune responses. These promising agents include immunomodulating mAbs, Toll-like receptor agonists, IMiDs, and cytokines. In this review, we discuss the current results of immunomodulating agents in the treatment of hematological malignancies and propose applications that include targeting of the innate and adaptive immune systems as well as combinations with tumor-specific mAbs.
View details for DOI 10.1007/s10555-011-9274-3
View details for Web of Science ID 000288769700009
View details for PubMedID 21271352
CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies
2011; 117 (8): 2423-2432
Antibody-dependent cell-mediated cytotoxicity (ADCC), which is largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. CD137 is a costimulatory molecule expressed on a variety of immune cells after activation, including NK cells. In the present study, we show that an anti-CD137 agonistic mAb enhances the antilymphoma activity of rituximab by enhancing ADCC. Human NK cells up-regulate CD137 after encountering rituximab-coated tumor B cells, and subsequent stimulation of these NK cells with anti-CD137 mAb enhances rituximab-dependent cytotoxicity against the lymphoma cells. In a syngeneic murine lymphoma model and in a xenotransplanted human lymphoma model, sequential administration of anti-CD20 mAb followed by anti-CD137 mAb had potent antilymphoma activity in vivo. These results support a novel, sequential antibody approach against B-cell malignancies by targeting first the tumor and then the host immune system.
View details for DOI 10.1182/blood-2010-08-301945
View details for Web of Science ID 000287698800023
View details for PubMedID 21193697
LONG-TERM FOLLOW-UP OF METASTATIC BREAST CANCER PATIENTS RECEIVING HIGHLY PURIFIED AUTOLOGOUS CD34+THY-1+HEMATOPOIETIC STEM CELLS AFTER HIGH-DOSE CHEMOTHERAPY
ELSEVIER SCIENCE INC. 2011: S198-S198
View details for Web of Science ID 000287350500123
A CpG-loaded tumor cell vaccine induces antitumor CD4(+) T cells that are effective in adoptive therapy for large and established tumors
AMER SOC HEMATOLOGY. 2011: 118-127
We designed a whole tumor cell vaccine by "loading" lymphoma tumor cells with CG-enriched oligodeoxynucleotide (CpG), a ligand for the Toll-like receptor 9 (TLR9). CpG-loaded tumor cells were phagocytosed, delivering both tumor antigen(s) and the immunostimulatory CpG molecule to antigen-presenting cells (APCs). These APCs then expressed increased levels of costimulatory molecules and induced T-cell immunity. TLR9 was required in the APCs but not in the CpG-loaded tumor cell. We demonstrate that T cells induced by this vaccine are effective in adoptive cellular therapy for lymphoma. T cells from vaccinated mice transferred into irradiated, syngeneic recipients protected against subsequent lymphoma challenge and, remarkably, led to regression of large and established tumors. This therapeutic effect could be transferred by CD4(+) but not by CD8(+) T cells. A CpG-loaded whole-cell vaccination is practical and has strong potential for translation to the clinical setting. It is currently being tested in a clinical trial of adoptive immunotherapy for mantle-cell lymphoma.
View details for DOI 10.1182/blood-2010-06-288456
View details for Web of Science ID 000285963900021
View details for PubMedID 20876455
Noninvasive Prediction of Graft-Verus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation by Gene Expression Profiling
AMER SOC HEMATOLOGY. 2010: 393-394
View details for Web of Science ID 000289662200897
Immunomodulation of NK Cells through 4-1BB (CD137) to Improve the Anti-Lymphoma Activity of Rituximab: Antibody-Based Anti-Lymphoma
AMER SOC HEMATOLOGY. 2010: 188-189
View details for Web of Science ID 000289662200423
CD137 Identifies a Population of Regulatory T Cells That Inhibit Anti-Tumor Immune Responses In Adoptive Immunotherapy
AMER SOC HEMATOLOGY. 2010: 868-868
View details for Web of Science ID 000289662202316
Temozolomide In Acute Myeloid Leukemia: A MGMT Promoter Methylation Status-Based Treatment Stratification
AMER SOC HEMATOLOGY. 2010: 1357-1358
View details for Web of Science ID 000289662203644
Clinical and Pathological Features of Non-Hodgkin Lymphomas Harboring Concurrent t(14;18) and 8q24 Anomalies
AMER SOC HEMATOLOGY. 2010: 1291-1292
View details for Web of Science ID 000289662203465
Prediction of Survival In Diffuse Large B-Cell Lymphoma Based On the Expression of Two Genes Reflecting Tumor and Microenvironment
AMER SOC HEMATOLOGY. 2010: 836-837
View details for Web of Science ID 000289662202229
A Phase I Study of Sequential Azacitidine and Lenalidomide for Elderly Patients with Acute Myeloid Leukemia (AML)
AMER SOC HEMATOLOGY. 2010: 1347-1347
View details for Web of Science ID 000289662203619
NF-kappa B Signaling In Response to CpG Stratifies Mantle Cell Lymphoma Patient Outcome
AMER SOC HEMATOLOGY. 2010: 67-68
View details for Web of Science ID 000289662200145
Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: A single-center experience
AMERICAN JOURNAL OF HEMATOLOGY
2010; 85 (11): 877-881
The majority of patients with acute myeloid leukemia (AML) will require second-line chemotherapy for either relapsed or refractory disease. Currently, only allogeneic hematopoietic cell transplantation (HCT) offers a curative option in this setting and no preferred regimen has been established. The reported efficacy of second-line regimens is widely disparate, thus limiting informed clinical decision making. A retrospective review of 77 patients receiving therapy between 2001 and 2008 with relapsed, 42, and refractory, 35, AML was performed to determine overall response rate and survival following mitoxantrone (8 mg/m(2)/day), etoposide (100 mg/m(2)/day), and cytarabine (1,000 mg/m(2)/day) chemotherapy administered over 5 days. Among 77 patients (median age of 54 years and 64% intermediate risk karyotype) with median follow-up of 153 days, 18% achieved a complete response and 8% a morphologic leukemia-free state. Fifty-seven (74%) experienced treatment failure, 10 of whom achieved a remission after additional therapy. Median overall survival (OS) was 6.8 months. Among patients achieving a response, 50% received consolidation with allogeneic HCT, autologous HCT (5%), or consolidation chemotherapy alone (45%). A nonsignificant trend in overall response (50%, 27%, and 23.8%) and median OS (8.3, 6.8, and 4.7 months) was observed by cytogenetic stratification into favorable, intermediate, and unfavorable risk. Patients with refractory versus relapsed disease had similar overall responses (20% and 31%, P = 0.41) and median OS (5.3 and 7.6 months, P = 0.36). Despite risk stratification by the European Prognostic Index, our series demonstrates inferior rates of response and survival, illustrating the limited activity of this regimen in our cohort.
View details for DOI 10.1002/ajh.21857
View details for Web of Science ID 000283568200010
View details for PubMedID 20872554
Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma
2010; 142 (5): 699-713
Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.
View details for DOI 10.1016/j.cell.2010.07.044
View details for Web of Science ID 000281523200014
View details for PubMedID 20813259
Risk stratification in extranodal natural killer/T-cell lymphoma
EXPERT REVIEW OF ANTICANCER THERAPY
2010; 10 (9): 1395-1405
Extranodal natural killer/T-cell lymphoma (ENKL), a subtype of natural killer/T-cell malignancies, is a rare subset of lymphomas with significant biological and clinical heterogeneity. The prognosis of ENKL is variable and therapeutic approaches are not well established. The optimal dose, combination, and sequence of radiotherapy and chemotherapy are evolving, as is the role of stem cell transplantation. Radiotherapy is an essential component of therapy for early-stage disease. The clinical course of advanced disease is highly aggressive, with frequent chemotherapy resistance and a poor prognosis. For relapsed disease, asparaginase-based regimens have provided encouraging results and are currently under investigation in the frontline setting. Our article discusses the key aspects of biology, pathogenesis and clinical presentation that contribute to the heterogeneity, and proposes a stratified approach to the treatment of ENKL based on clinical, pathologic and biologic risk factors. Although considerable advances have been made in our understanding of the biology and prognosis of this lymphoma, it remains critical that all patients with a diagnosis of ENKL are enrolled and treated in clinical trials so that optimal therapies can be identified.
View details for DOI 10.1586/ERA.10.130
View details for Web of Science ID 000282259800012
View details for PubMedID 20836675
Quantitative, Architectural Analysis of Immune Cell Subsets in Tumor-Draining Lymph Nodes from Breast Cancer Patients and Healthy Lymph Nodes
2010; 5 (8)
To date, pathological examination of specimens remains largely qualitative. Quantitative measures of tissue spatial features are generally not captured. To gain additional mechanistic and prognostic insights, a need for quantitative architectural analysis arises in studying immune cell-cancer interactions within the tumor microenvironment and tumor-draining lymph nodes (TDLNs).We present a novel, quantitative image analysis approach incorporating 1) multi-color tissue staining, 2) high-resolution, automated whole-section imaging, 3) custom image analysis software that identifies cell types and locations, and 4) spatial statistical analysis. As a proof of concept, we applied this approach to study the architectural patterns of T and B cells within tumor-draining lymph nodes from breast cancer patients versus healthy lymph nodes. We found that the spatial grouping patterns of T and B cells differed between healthy and breast cancer lymph nodes, and this could be attributed to the lack of B cell localization in the extrafollicular region of the TDLNs.Our integrative approach has made quantitative analysis of complex visual data possible. Our results highlight spatial alterations of immune cells within lymph nodes from breast cancer patients as an independent variable from numerical changes. This opens up new areas of investigations in research and medicine. Future application of this approach will lead to a better understanding of immune changes in the tumor microenvironment and TDLNs, and how they affect clinical outcomes.
View details for DOI 10.1371/journal.pone.0012420
View details for Web of Science ID 000281234700034
View details for PubMedID 20811638
NKT cells, Treg, and their interactions in bone marrow transplantation
EUROPEAN JOURNAL OF IMMUNOLOGY
2010; 40 (7): 1862-1869
Bone marrow transplantation (BMT) is a potentially curative treatment for patients with leukemia and lymphoma. Tumor eradication is promoted by the anti-tumor activity of donor T cells contained in the transplant; however, donor T cells also mediate the serious side effect of graft-versus-host disease (GVHD). Separation of GVHD from graft anti-tumor activity is an important goal of research in improving transplant outcome. One approach is to take advantage of the immunomodulatory activity of regulatory NKT cells and CD4(+)CD25(+) Treg of host and/or donor origin. Both host and donor NKT cells and donor Treg are able to prevent GVHD in murine models. In this review, we summarize the mechanisms of NKT cell- and Treg-mediated protection against GVHD in mice while maintaining graft anti-tumor activity. In addition, we also examine the interactions between NKT cells and Treg in the context of BMT, and integrate the data from murine experimental models with the observations made in humans.
View details for DOI 10.1002/eji.201040394
View details for Web of Science ID 000280220600014
View details for PubMedID 20583031
Immunophenotypic features of acute myeloid leukemia with inv(3)(q21q26.2)/t(3;3)(q21;q26.2)
2010; 34 (5): 594-597
Immunophenotypic identification of myeloid specific antigens is an important diagnostic tool in the management of patients with acute myeloid leukemia (AML). These antigens allow determination of cell of origin and degree of differentiation of leukemia blasts. AML with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a relatively rare subtype of AML. The immunophenotypic characteristics of inv(3) AML patients are somewhat limited. We identified 14 new cases of hematological disorders with increased myeloid blasts carrying inv(3)(q21q26.2)/t(3;3)(q21;q26.2). Also, we identified another 13 cases previously published in the literature, where the immunophenotype of inv(3)(q21q26.2) was documented. As a group, patients with AML with inv(3)(q21q26.2) had high levels of early myeloid (CD13, CD33, CD117 and MPO) and uncommitted markers (CD34, HLA-DR and CD56) and a high rate of monosomy 7 in addition to the inv(3)(q21q26.2). Differential karyotype and expression of certain antigens were noted in patients with de novo AML with inv(3)(q21q26.2) vs. those with inv(3)(q21q26.2)-containing blasts.
View details for DOI 10.1016/j.leukres.2009.08.029
View details for Web of Science ID 000276945300009
View details for PubMedID 19781775
Noninvasive Prediction of Graft-Versus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation by Gene Expression Profiling.
WILEY-BLACKWELL. 2010: 483-483
View details for Web of Science ID 000275921703258
Adoptive Therapy for Lymphoma with CD4 Memory T Cells Depleted of CD137-Expressing Tregs.
AMER SOC HEMATOLOGY. 2009: 674-675
View details for Web of Science ID 000272725802061
Early Mortality in Acute Promyelocytic Leukemia May Be Higher Than Previously Reported.
AMER SOC HEMATOLOGY. 2009: 420-421
View details for Web of Science ID 000272725801195
Therapeutic Potential of Anti-CD137 Antibody in Lymphoma
AMER SOC HEMATOLOGY. 2009: 301-302
View details for Web of Science ID 000272725800723
Is Time of the Essence in Adult Acute Myeloid Leukemia (AML)? Time to Blast Clearance and Time to Induction Therapy Fail to Predict Overall Survival (OS).
AMER SOC HEMATOLOGY. 2009: 646-647
View details for Web of Science ID 000272725801797
Prediction of Survival in Diffuse Large B-Cell Lymphoma Based On the Expression of Two Genes: Integration of Tumor and Microenvironment Contributions
AMER SOC HEMATOLOGY. 2009: 258-258
View details for Web of Science ID 000272725800623
Nonmyeloablative conditioning with total lymphoid irradiation and antithymocyte globulin: an update
CURRENT OPINION IN HEMATOLOGY
2009; 16 (6): 460-465
The immune modulatory effects of total lymphoid irradiation (TLI) for graft-versus-host disease (GVHD) protection and transplantation tolerance following allogeneic bone marrow and organ transplantation have been studied for years in animal models. In preclinical models nonmyeloablative TLI conditioning alters residual host T cell subsets to favor regulatory natural killer T cells that suppress GVHD and prevent organ allograft rejection. These preclinical models have been recently adapted to human transplantation.Patients receiving allogeneic hematopoietic cell transplantation for hematological malignancies conditioned with TLI and depletive T cell antibodies showed sustained donor chimerism, a reduced incidence of acute GVHD yet retained graft antitumor activity. As in the preclinical models, nonmyeloablative TLI conditioning significantly altered residual host T cell subsets favoring natural killer T cells, and the low incidence of GVHD was associated with increased IL-4 secretion by chimeric donor T cells. The TLI regimen used in cancer patients was modified to determine conditions for stable mixed chimerism and tolerance induction following combined hematopoietic cell and kidney transplantation.This review summarizes the evolution of the preclinical TLI protocols and their recent translation to clinical trials, and discusses the mechanisms involved in protection from GVHD and the induction of tolerance following mixed chimerism.
View details for DOI 10.1097/MOH.0b013e3283319e8f
View details for Web of Science ID 000271559200007
View details for PubMedID 19812489
Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by T-reg depletion
2009; 114 (16): 3431-3438
Despite the success of passive immunotherapy with monoclonal antibodies (mAbs), many lymphoma patients eventually relapse. Induction of an adaptive immune response may elicit active and long-lasting antitumor immunity, thereby preventing or delaying recurrence. Immunomodulating mAbs directed against immune cell targets can be used to enhance the immune response to achieve efficient antitumor immunity. Anti-CD137 agonistic mAb has demonstrated antitumor efficacy in various tumor models and has now entered clinical trials for the treatment of solid tumors. Here, we investigate the therapeutic potential of anti-CD137 mAb in lymphoma. We found that human primary lymphoma tumors are infiltrated with CD137+ T cells. We therefore hypothesized that lymphoma would be susceptible to treatment with anti-CD137 agonistic mAb. Using a mouse model, we demonstrate that anti-CD137 therapy has potent antilymphoma activity in vivo. The antitumor effect of anti-CD137 therapy was mediated by both natural killer (NK) and CD8 T cells and induced long-lasting immunity. Moreover, the antitumor activity of anti-CD137 mAb could be further enhanced by depletion of regulatory T cell (T(regs)). These results support the evaluation of anti-CD137 therapy in clinical trials for patients with lymphoma.
View details for DOI 10.1182/blood-2009-05-223958
View details for Web of Science ID 000270834500013
View details for PubMedID 19641184
TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors
2009; 114 (5): 1099-1109
A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.
View details for DOI 10.1182/blood-2009-03-211441
View details for Web of Science ID 000268491100025
View details for PubMedID 19423725
Total lymphoid irradiation for graft-versus-host disease protection.
Current opinion in oncology
2009; 21: S23-6
The immunosuppressive effects of total lymphoid irradiation (TLI) for protection against graft-versus-host disease (GvHD) after allogeneic bone marrow transplantation have been studied for years in animal models. In preclinical models of bone marrow transplantation non-myeloablative TLI conditioning protects against GvHD by skewing host T-cell subsets to favor regulatory natural killer T cells that suppress GvHD by polarizing donor T cells towards secretion of non-inflammatory cytokines such as IL-4. These preclinical models have recently been adapted to human transplantation.Patients receiving allogeneic hematopoietic cell transplantation for hematological malignancies conditioned with TLI and depletive T-cell antibodies showed sustained donor chimerism, a reduced incidence of acute GvHD yet retained anti-tumor activity. As in the preclinical models, the low incidence of GvHD is associated with increased IL-4 secretion by chimeric donor T cells.This review summarizes the evolution of the preclinical TLI protocols and their recent translation to clinical trials, and discusses the mechanisms involved in protection from GvHD and the induction of tolerance following mixed chimerism.
View details for DOI 10.1097/01.cco.0000357471.68713.35
View details for PubMedID 19561409
Dynamic CD8 T-cell responses to tumor-associated Epstein-Barr virus (EBV) antigens in patients with EBV-negative Hodgkin's disease
AMER SOC CLINICAL ONCOLOGY. 2009
View details for Web of Science ID 000276606605482
Extranodal natural killer/T-cell lymphoma: current concepts in biology and treatment
LEUKEMIA & LYMPHOMA
2009; 50 (11): 1773-1784
Natural killer/T-cell (NK/T) lymphomas represent a group of rare tumors of NK and NK-T cells. The World Health Organization classifies NK-cell tumors into three types, extranodal NK/T-cell lymphomas (ENKL, nasal and non-nasal), NK-cell leukemias, and a blastic variant (CD4-positive, CD56-positive hematodermic neoplasms). We focus our review to the current concepts in biology and treatment of ENKL. Though considerable advances have been made in our understanding of NK-cell biology, malignant transformation including the role of Epstein-Barr virus, and prognosis, the rare nature of ENKL and its heterogeneity limit the ability to standardize therapy. Radiotherapy is fundamental to treatment of early-stage disease with a role for chemoradiotherapy among high-risk patients. The clinical course of advanced disease is highly aggressive with frequent chemotherapy resistance and a poor prognosis. Therapeutic approaches to advanced-stage or relapsed and refractory disease, including the appropriate sequence of chemotherapy, combined modality therapy, and stem cell transplantation is not well-established. International and multicenter clinical trials are needed for this rare and aggressive disease.
View details for DOI 10.3109/10428190903186502
View details for Web of Science ID 000272145000014
View details for PubMedID 19883307
Dynamic CD8 T-Cell Responses to Tumor-Associated Epstein-Barr Virus Antigens in Patients With Epstein-Barr Virus-Negative Hodgkin's Disease
2009; 18 (5-6): 287-292
In almost half of patients diagnosed with Hodgkin's disease (HD), the malignant Reed-Sternberg (RS) cells express Epstein-Barr virus (EBV) antigens. Multiple translational efforts are actively investigating antitumor immune strategies by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. In an effort to explore the EBV-specific immune response, here we characterize EBV-specific CTL responses to lytic and latent EBV antigens in 12 consecutive EBV carriers with EBV-negative HD. Compared to healthy donors, we detected weak, baseline EBV-specific responses to both lytic and latent antigens by IFN-gamma ELISPOT in patients with EBV-negative HD at diagnosis. Chemoradiotherapy was associated temporally with a decrease EBV-specific responses. At final follow-up (24 months), recovery of EBV-specific CTL responses was observed with robustness of lytic-specific response equivalent to healthy controls. We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment. Our observation challenges prior belief that patients with HD remain immunodeficient following therapy and argues that the clinical significance of the EBV-specific immune response in EBV-negative HD should be further investigated.
View details for DOI 10.3727/096504009X12596189659169
View details for Web of Science ID 000274459900010
View details for PubMedID 20225766
Outcomes Following Allogeneic Hematopoietic Cell Transplantation (HCT) Using Non-Myeloablative Conditioning with Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) Confirm a Low Incidence of Graft Versus Host Disease (GVHD) with Retained Anti-Tumor Activity.
AMER SOC HEMATOLOGY. 2008: 1136-1137
View details for Web of Science ID 000262104703746
Optimizing therapy for acute myeloid leukemia.
Journal of the National Comprehensive Cancer Network
2008; 6 (10): 1003-1016
The 10-year overall survival for younger patients with newly diagnosed acute myeloid leukemia has improved threefold in the past 2 decades. This improvement has occurred in large part because of advances in supportive care and efforts to optimize standard induction and consolidation therapies applied in a stratified approach based on predictors of individual patient risk. Innovations in diagnostic technologies have broadened the understanding of key prognostic factors, including cytogenetic and molecular status, which define the extensive interpatient heterogeneity of this clonal disease. Despite this progress, only approximately 25% of patients who experience a complete remission with cytotoxic chemotherapy (50%-70% of patients with newly diagnosed disease) remain disease-free. Efforts to develop novel agents are actively ongoing, particularly for older patients (age > or = 60), and targeted therapies, for specific subsets of patients are being based on a better understanding of the biology of the disease.
View details for PubMedID 19176198
Renal failure and rhabdomyolysis associated with sitagliptin and simvastatin use
2008; 25 (10): 1229-1230
Sitagliptin is a new oral glucose-lowering medication that acts via the incretin hormone system. The most common side-effects are headache and pharyngitis, and few serious adverse events were observed during clinical trials. Dose adjustment is recommended in renal insufficiency, but long-term safety experience is limited.We present a patient with chronic renal insufficiency who developed leg pain, weakness and tenderness after starting treatment with high-dose sitagliptin while on simvastatin. The patient had acute renal failure and rhabdomyolysis that resolved with cessation of sitagliptin, simvastatin, ezetimibe, diuretics and olmesartan. All drugs except sitagliptin, ezetimibe and simvastatin were resumed, and the patient was subsequently started on lovastatin without recurrence of rhabdomyolysis.High doses of sitagliptin may have worsened this patient's renal failure and precipitated rhabdomyolysis by increasing circulating levels of simvastatin. Given the high likelihood that sitagliptin will be co-administered with statins and renally active medications, further study of long-term safety of sitagliptin in renal sufficiency may be warranted.
View details for DOI 10.1111/j.1464-5491.2008.02536.x
View details for Web of Science ID 000259814600013
View details for PubMedID 19046202
New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients
SPRINGER. 2008: 588-588
View details for Web of Science ID 000255851900029
New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients
Current practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer patients with tumor-involved sentinel lymph nodes (SLNs), although fewer than half will have non-sentinel node (NSLN) metastasis. Our goal was to develop new models to quantify the risk of NSLN metastasis in SLN-positive patients and to compare predictive capabilities to another widely used model.We constructed three models to predict NSLN status: recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted Classification and Regression Trees (CART), and multivariate logistic regression (MLR) informed by CART. Data were compiled from a multicenter Northern California and Oregon database of 784 patients who prospectively underwent SLN biopsy and completion ALND. We compared the predictive abilities of our best model and the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram) in our dataset and an independent dataset from Northwestern University.285 patients had positive SLNs, of which 213 had known angiolymphatic invasion status and 171 had complete pathologic data including hormone receptor status. 264 (93%) patients had limited SLN disease (micrometastasis, 70%, or isolated tumor cells, 23%). 101 (35%) of all SLN-positive patients had tumor-involved NSLNs. Three variables (tumor size, angiolymphatic invasion, and SLN metastasis size) predicted risk in all our models. RP-ROC and boosted CART stratified patients into four risk levels. MLR informed by CART was most accurate. Using two composite predictors calculated from three variables, MLR informed by CART was more accurate than the Nomogram computed using eight predictors. In our dataset, area under ROC curve (AUC) was 0.83/0.85 for MLR (n = 213/n = 171) and 0.77 for Nomogram (n = 171). When applied to an independent dataset (n = 77), AUC was 0.74 for our model and 0.62 for Nomogram. The composite predictors in our model were the product of angiolymphatic invasion and size of SLN metastasis, and the product of tumor size and square of SLN metastasis size.We present a new model developed from a community-based SLN database that uses only three rather than eight variables to achieve higher accuracy than the Nomogram for predicting NSLN status in two different datasets.
View details for DOI 10.1186/1471-2407-8-66
View details for Web of Science ID 000255935500001
View details for PubMedID 18315887
- Massive splenic infarct in a collegiate football player with hemoglobin SC disease CLINICAL JOURNAL OF SPORT MEDICINE 2008; 18 (1): 89-91
Antiviral prophylaxis for chemotherapy-induced reactivation of chronic hepatitis B virus infection.
Clinics in liver disease
2007; 11 (4): 965-?
Chronic hepatitis B virus (HBV) carriers are at considerable risk of reactivation of HBV infection when undergoing chemotherapy or immunosuppressive therapy. Complications of HBV reactivation, including asymptomatic elevation of HBV DNA levels, acute hepatitis, acute liver failure, and delays or dose reductions in chemotherapy, are avoidable with appropriate prophylactic oral antiviral therapy. This article reviews evidence for and presents a grade A recommendation supporting primary prophylaxis among HBV carriers with lamivudine. The dose and duration of prophylaxis, risk of lamivudine resistance, and future directions of prophylactic therapy for HBV reactivation during chemotherapy are discussed. Recommendations are suggested based on expert opinion for prophylaxis with the combination of lamivudine plus adefovir or with entecavir as alternative antiviral strategies that substantially reduce or avoid the risk of HBV antiviral drug resistance.
View details for PubMedID 17981237
Systematic review: lamivudine prophylaxis for chemotherapy-induced reactivation of chronic hepatitis B virus infection
ALIMENTARY PHARMACOLOGY & THERAPEUTICS
2006; 24 (7): 1003-1016
Reactivation of hepatitis B virus infection in asymptomatic hepatitis B surface antigen carriers undergoing chemotherapy or immunosuppressive therapy is a well-documented and potentially fatal complication. Data supporting the use of lamivudine for primary prophylaxis have emerged, but its use remains controversial and is not standardized.To review current randomized-controlled trials, randomized trials and prospective case series to provide a clinically applicable, evidence-based recommendation.The published literature was identified using a MEDLINE/PubMed search with secondary review of cited publications, and inclusion of all prospective studies.In nine prospective trials and one randomized-controlled trial, the rate of hepatitis among subjects receiving lamivudine prophylaxis ranged from 0% to 20% (16 of 173, 9.2%), compared with 33-67% among controls. Of patients receiving prophylaxis, 0-24% (15 of 173, 8.7%) developed hepatitis B virus reactivation, compared with 29-56% of controls. Three reactivation-related mortalities were reported (one receiving prophylaxis, two controls). No patients withdrew secondary to toxicity or development of lamivudine-resistant mutations.The available data show a four- to sevenfold decrease in the rate of hepatitis and hepatitis B virus reactivation in patients who receive lamivudine prophylaxis. It is thus recommended that all hepatitis B surface antigen carriers receive lamivudine, or a comparable anti-viral agent, as prophylaxis from the initiation of chemotherapy until at least 1 year following its completion.
View details for DOI 10.1111/j.1365-2036.2006.03081.x
View details for Web of Science ID 000240441300002
View details for PubMedID 16984494
Predicting non-sentinel lymph node involvement in breast cancer patients.
AMER SOC CLINICAL ONCOLOGY. 2006: 10S-10S
View details for Web of Science ID 000239009400039
Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer
2005; 2 (9): 904-919
While lymph node metastasis is among the strongest predictors of disease-free and overall survival for patients with breast cancer, the immunological nature of tumor-draining lymph nodes is often ignored, and may provide additional prognostic information on clinical outcome.We performed immunohistochemical analysis of 47 sentinel and 104 axillary (nonsentinel) nodes from 77 breast cancer patients with 5 y of follow-up to determine if alterations in CD4, CD8, and CD1a cell populations predict nodal metastasis or disease-free survival. Sentinel and axillary node CD4 and CD8 T cells were decreased in breast cancer patients compared to control nodes. CD1a dendritic cells were also diminished in sentinel and tumor-involved axillary nodes, but increased in tumor-free axillary nodes. Axillary node, but not sentinel node, CD4 T cell and dendritic cell populations were highly correlated with disease-free survival, independent of axillary metastasis. Immune profiling of ALN from a test set of 48 patients, applying CD4 T cell and CD1a dendritic cell population thresholds of CD4 > or = 7.0% and CD1a > or = 0.6%, determined from analysis of a learning set of 29 patients, provided significant risk stratification into favorable and unfavorable prognostic groups superior to clinicopathologic characteristics including tumor size, extent or size of nodal metastasis (CD4, p < 0.001 and CD1a, p < 0.001). Moreover, axillary node CD4 T cell and CD1a dendritic cell populations allowed more significant stratification of disease-free survival of patients with T1 (primary tumor size 2 cm or less) and T2 (5 cm or larger) tumors than all other patient characteristics. Finally, sentinel node immune profiles correlated primarily with the presence of infiltrating tumor cells, while axillary node immune profiles appeared largely independent of nodal metastases, raising the possibility that, within axillary lymph nodes, immune profile changes and nodal metastases represent independent processes.These findings demonstrate that the immune profile of tumor-draining lymph nodes is of novel biologic and clinical importance for patients with early stage breast cancer.
View details for DOI 10.1371/journal.pmed.0020284
View details for Web of Science ID 000232433600019
View details for PubMedID 16124834
Rapid assessment of recognition efficiency and functional capacity of antigen-specific T-cell responses
JOURNAL OF IMMUNOTHERAPY
2005; 28 (4): 297-305
It is increasingly recognized that cells within an antigen-specific CD8 T-cell population may be diverse in recognition efficiency for target, which may significantly affect the overall efficacy of the response in clinical settings such as viral infections and cancer. CD8 T cells with seemingly identical antigen specificity, particularly those elicited by cancer vaccines, may be heterogeneous for sensitivity and recognition efficiency for the cognate peptide and functional state in vivo. Analysis of individual T-cell clones derived from an antigen-specific T-cell population would provide an accurate assessment of the overall response; however, this is time- and labor-intensive, preventing rapid and routine assessment of patient samples from clinical trials. By stimulating antigen-specific T cells that otherwise appear homogeneous on tetramer staining with graded amounts of cognate peptides, the authors show that individual cells downmodulate surface T-cell receptors (TCR) and thus lose tetramer reactivity with variable dynamics within the T-cell population. The dynamics of TCR downregulation represent an accurate assessment of an individual cell's antigen sensitivity, recognition efficiency, and relative functional state within an antigen-specific population and have direct correlation to killing capacity by chromium release as well as degranulation by CD107 mobilization. Furthermore, despite correlation of average T-cell function by all three techniques, TCR downregulation uncovered heterogeneity in T-cell responses after vaccination among patient samples directly ex vivo. When examined using this novel technique, antigen-specific T cells elicited by vaccination with heteroclitic peptides exhibited significantly different recognition efficiencies for the heteroclitic versus native peptides, translating into differences in functional responses. With advancing cancer vaccine trials, the capacity to detect and functionally characterize antigen-specific T-cell responses in detail is critical. Techniques, as presented here, that rapidly assess the overall antigen sensitivity, recognition efficiency, and functional status of patients' T-cell responses will guide future vaccine trials and immunotherapies.
View details for Web of Science ID 000230219200004
View details for PubMedID 16000947
Distribution of distress in post-socialist Mongolia: a cultural epidemiology of yadargaa
SOCIAL SCIENCE & MEDICINE
2004; 58 (3): 471-485
This study discusses quality of life in post-socialist Mongolia. Yadargaa, a fatigue-related illness in traditional Mongolian medicine, results from lifestyle imbalance. We examine the distribution of yadargaa and its association to socioeconomic changes under capitalism. Ethnographic interviews concerning yadargaa were conducted with health professionals, yadargaa patients, and laypersons. Epidemiological methods were used to identify risk groups, to estimate the point prevalence, and to assess the distribution of meanings and interpretations of yadargaa. The epidemiological sample included 194 individuals, half urban and half rural. Nearly half of the epidemiological sample suffered from yadargaa (49%). These yadargaa sufferers felt that they benefited less than non-yadargaa subjects from the current socioeconomic changes. Among these, perceived change in employment opportunities was one of the best predictors of yadargaa. Additionally, yadargaa sufferers were predominantly women, the elderly, and urban residents. Yadargaa varies greatly in presentation; Western psychiatric categories are only able to explain half of yadargaa cases. In conclusion, yadargaa strongly associates with disenfranchised groups in the capitalist economy. As a culturally constructed indicator of quality of life, yadargaa is a window into the lives of women and men in post-socialist Mongolia.
View details for DOI 10.1016/S0277-9536(03)00216-8
View details for Web of Science ID 000187743300003
View details for PubMedID 14652045
An ecological-transactional model of significant risk factors for child psychopathology in outer Mongolia
CHILD PSYCHIATRY & HUMAN DEVELOPMENT
2004; 35 (2): 163-181
The present study examined significant risk factors, including child maltreatment, for child psychopathology in a cross-cultural setting. Ninety-nine Mongolian boys, ages 3-10 years, were assessed. Primary caregivers (PCG) completed structured interviews including the Emory Combined Rating Scale (ECRS) and the Mood and Feelings Questionnaire (MFQ). Structural equation modeling identifies eight risk factors affecting child psychopathology: Three with direct effects (severity of physical punishment, PCG's MFQ score, and PCG's education), three with indirect effects (cultural acceptance of violence as discipline, presence of community violence, and contact with extended family), and two with direct and indirect effects (quality of marriage/presence of spousal abuse, and household size). Results support the ecological-transactional theory of developmental psychopathology in a cross-cultural setting. Structural equation modeling provides a useful technique to isolate specific sites for intervention, while maintaining a comprehensive perspective of risk factor interaction.
View details for Web of Science ID 000226068300005
View details for PubMedID 15577280