Alexander Isaac Salter

All Publications

• Novel immunotherapy combinations in neoadjuvant non-small cell lung cancer (NSCLC): a better chance at cure? Translational lung cancer research Salter, A. I., Das, M. 2024; 13 (3): 673-677

  View details for DOI 10.21037/tlcr-23-735

  View details for PubMedID 38601451

  View details for PubMedCentralID PMC11002516

• Synthetic receptors for logic gated T cell recognition and function CURRENT OPINION IN IMMUNOLOGY Simon, S., Bugos, G., Salter, A., Riddell, S. R. 2022; 74: 1-9

  Abstract

  Adoptive cell therapy with T cells engineered with customized receptors that redirect antigen specificity to cancer cells has emerged as an effective therapeutic approach for many malignancies. Toxicity due to on target or off target effects, antigen heterogeneity on cancer cells, and acquired T cell dysfunction have been identified as barriers that can hinder successful therapy. This review will discuss recent advances in T cell engineering that have enabled the application of logic gates in T cells that can mimic the integration of natural signaling pathways and act in a cell intrinsic or extrinsic fashion to precisely target tumor cells and regulate effector functions, potentially overcoming these barriers to effective therapy.

  View details for DOI 10.1016/j.coi.2021.09.003

  View details for Web of Science ID 000702481800001

  View details for PubMedID 34571290

  View details for PubMedCentralID PMC8901444

• Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function SCIENCE SIGNALING Salter, A., Rajan, A., Kennedy, J. J., Ivey, R. G., Shelby, S. A., Leung, I., Templeton, M. L., Muhunthan, V., Voillet, V., Sommermeyer, D., Whiteaker, J. R., Gottardo, R., Veatch, S. L., Paulovich, A. G., Riddell, S. R. 2021; 14 (697)

  Abstract

  Chimeric antigen receptor (CAR)-modified T cell therapy is effective in treating lymphomas, leukemias, and multiple myeloma in which the tumor cells express high amounts of target antigen. However, achieving durable remission for these hematological malignancies and extending CAR T cell therapy to patients with solid tumors will require receptors that can recognize and eliminate tumor cells with a low density of target antigen. Although CARs were designed to mimic T cell receptor (TCR) signaling, TCRs are at least 100-fold more sensitive to antigen. To design a CAR with improved antigen sensitivity, we directly compared TCR and CAR signaling in primary human T cells. Global phosphoproteomic analysis revealed that key T cell signaling proteins-such as CD3δ, CD3ε, and CD3γ, which comprise a portion of the T cell co-receptor, as well as the TCR adaptor protein LAT-were either not phosphorylated or were only weakly phosphorylated by CAR stimulation. Modifying a commonplace 4-1BB/CD3ζ CAR sequence to better engage CD3ε and LAT using embedded CD3ε or GRB2 domains resulted in enhanced T cell activation in vitro in settings of a low density of antigen, and improved efficacy in in vivo models of lymphoma, leukemia, and breast cancer. These CARs represent examples of alterations in receptor design that were guided by in-depth interrogation of T cell signaling.

  View details for DOI 10.1126/scisignal.abe2606

  View details for Web of Science ID 000688494900003

  View details for PubMedID 34429382

  View details for PubMedCentralID PMC8613804

• Designed protein logic to target cells with precise combinations of surface antigens SCIENCE Lajoie, M. J., Boyken, S. E., Salter, A., Bruffey, J., Rajan, A., Langan, R. A., Olshefsky, A., Muhunthan, V., Bick, M. J., Gewe, M., Quijano-Rubio, A., Johnson, J., Lenz, G., Nguyen, A., Pun, S., Correnti, C. E., Riddell, S. R., Baker, D. 2020; 369 (6511): 1637-+

  Abstract

  Precise cell targeting is challenging because most mammalian cell types lack a single surface marker that distinguishes them from other cells. A solution would be to target cells using specific combinations of proteins present on their surfaces. In this study, we design colocalization-dependent protein switches (Co-LOCKR) that perform AND, OR, and NOT Boolean logic operations. These switches activate through a conformational change only when all conditions are met, generating rapid, transcription-independent responses at single-cell resolution within complex cell populations. We implement AND gates to redirect T cell specificity against tumor cells expressing two surface antigens while avoiding off-target recognition of single-antigen cells, and three-input switches that add NOT or OR logic to avoid or include cells expressing a third antigen. Thus, de novo designed proteins can perform computations on the surface of cells, integrating multiple distinct binding interactions into a single output.

  View details for DOI 10.1126/science.aba6527

  View details for Web of Science ID 000574653300037

  View details for PubMedID 32820060

  View details for PubMedCentralID PMC8085813

• Visualization of human T lymphocyte-mediated eradication of cancer cells in vivo PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA He, X., Yin, X., Wu, J., Wickstrom, S. L., Duo, Y., Du, Q., Qin, S., Yao, S., Jing, X., Hosaka, K., Wu, J., Jensen, L. D., Lundqvist, A., Salter, A., Brautigam, L., Tao, W., Chen, Y., Kiessling, R., Cao, Y. 2020; 117 (37): 22910-22919

  Abstract

  Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.

  View details for DOI 10.1073/pnas.2009092117

  View details for Web of Science ID 000580028100049

  View details for PubMedID 32859758

  View details for PubMedCentralID PMC7502706

• Multispecific Targeting with Synthetic Ankyrin Repeat Motif Chimeric Antigen Receptors CLINICAL CANCER RESEARCH Balakrishnan, A., Rajan, A., Salter, A. I., Kosasih, P. L., Wu, Q., Voutsinas, J., Jensen, M. C., Pluckthun, A., Riddell, S. R. 2019; 25 (24): 7506-7516

  Abstract

  The outgrowth of antigen-negative variants is a significant challenge for adoptive therapy with T cells that target a single specificity. Chimeric antigen receptors (CAR) are typically designed with one or two scFvs that impart antigen specificity fused to activation and costimulation domains of T-cell signaling molecules. We designed and evaluated the function of CARs with up to three specificities for overcoming tumor escape using Designed Ankyrin Repeat Proteins (DARPins) rather than scFvs for tumor recognition.A monospecific CAR was designed with a DARPin binder (E01) specific for EGFR and compared with a CAR designed using an anti-EGFR scFv. CAR constructs in which DARPins specific for EGFR, EpCAM, and HER2 were linked together in a single CAR were then designed and optimized to achieve multispecific tumor recognition. The efficacy of CAR-T cells bearing a multispecific DARPin CAR for treating tumors with heterogeneous antigen expression was evaluated in vivo.The monospecific anti-EGFR E01 DARPin conferred potent tumor regression against EGFR+ targets that was comparable with an anti-EGFR scFv CAR. Linking three separate DARPins in tandem was feasible and in an optimized format generated a single tumor recognition domain that targeted a mixture of heterogeneous tumor cells, each expressing a single antigen, and displayed synergistic activity when tumor cells expressed more than one target antigen.DARPins can serve as high-affinity recognition motifs for CAR design, and their robust architecture enables linking of multiple binders against different antigens to achieve functional synergy and reduce antigen escape.

  View details for DOI 10.1158/1078-0432.CCR-19-1479

  View details for Web of Science ID 000509983400028

  View details for PubMedID 31548346

  View details for PubMedCentralID PMC6940018

• γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma BLOOD Pont, M. J., Hill, T., Cole, G. O., Abbott, J. J., Kelliher, J., Salter, A. I., Hudecek, M., Comstock, M. L., Rajan, A., Patel, B. R., Voutsinas, J. M., Wu, Q., Liu, L., Cowan, A. J., Wood, B. L., Green, D. J., Riddell, S. R. 2019; 134 (19): 1585-1597

  Abstract

  B-cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse, and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit γ-secretase (GS) complex, which reduces ligand density on tumor cells for CAR T-cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed adoptive T-cell therapy. We investigated whether blocking BCMA cleavage by small-molecule GS inhibitors (GSIs) could augment BCMA-targeted CAR T-cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR T cells in vitro. GSI treatment of MM tumor-bearing NOD/SCID/γc-/- mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR T-cell therapy. Importantly, short-term GSI administration to MM patients markedly increases the percentage of BCMA+ tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, a US Food and Drug Administration (FDA)-approved clinical trial has been initiated, combining GSI with concurrent BCMA CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT03502577.

  View details for DOI 10.1182/blood.2019000050

  View details for Web of Science ID 000495894200007

  View details for PubMedID 31558469

  View details for PubMedCentralID PMC6871311

• Tinkering in the garage - tuning CARs for safety NATURE REVIEWS CLINICAL ONCOLOGY Salter, A. I., Riddell, S. R. 2019; 16 (9): 530-532

  View details for DOI 10.1038/s41571-019-0240-2

  View details for Web of Science ID 000482189100009

  View details for PubMedID 31209340

• Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables Selective Tumor Targeting CANCER CELL Srivastava, S., Salter, A., Liggitt, D., Yechan-Gunja, S., Sarvothama, M., Cooper, K., Smythe, K. S., Dudakov, J. A., Pierce, R. H., Rader, C., Ridde, S. R. 2019; 35 (3): 489-+

  Abstract

  Many potential targets for CAR-T cells in solid tumors are expressed in some normal tissues, raising concern for off-tumor toxicity. Following lymphodepletion, CAR-T cells targeting the tumor-associated antigen ROR1 lysed tumors in mice but induced lethal bone marrow failure due to recognition of ROR1+ stromal cells. To improve selectivity, we engineered T cells with synthetic Notch (synNotch) receptors specific for EpCAM or B7-H3, which are expressed on ROR1+ tumor cells but not ROR1+ stromal cells. SynNotch receptors induced ROR1 CAR expression selectively within the tumor, resulting in tumor regression without toxicity when tumor cells were segregated from, but not when co-localized with, normal ROR1+ cells. This strategy, thus, permits safe targeting of tumors that are sufficiently separated from normal cells.

  View details for DOI 10.1016/j.ccell.2019.02.003

  View details for Web of Science ID 000461697400014

  View details for PubMedID 30889382

  View details for PubMedCentralID PMC6450658

• Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function SCIENCE SIGNALING Salter, A. I., Ivey, R. G., Kennedy, J. J., Voillet, V., Rajan, A., Alderman, E. J., Voytovich, U. J., Lin, C., Sommermeyer, D., Liu, L., Whiteaker, J. R., Gottardo, R., Paulovich, A. G., Riddell, S. R. 2018; 11 (544)

  Abstract

  Chimeric antigen receptors (CARs) link an antigen recognition domain to intracellular signaling domains to redirect T cell specificity and function. T cells expressing CARs with CD28/CD3ζ or 4-1BB/CD3ζ signaling domains are effective at treating refractory B cell malignancies but exhibit differences in effector function, clinical efficacy, and toxicity that are assumed to result from the activation of divergent signaling cascades. We analyzed stimulation-induced phosphorylation events in primary human CD8+ CD28/CD3ζ and 4-1BB/CD3ζ CAR T cells by mass spectrometry and found that both CAR constructs activated similar signaling intermediates. Stimulation of CD28/CD3ζ CARs activated faster and larger-magnitude changes in protein phosphorylation, which correlated with an effector T cell-like phenotype and function. In contrast, 4-1BB/CD3ζ CAR T cells preferentially expressed T cell memory-associated genes and exhibited sustained antitumor activity against established tumors in vivo. Mutagenesis of the CAR CD28 signaling domain demonstrated that the increased CD28/CD3ζ CAR signal intensity was partly related to constitutive association of Lck with this domain in CAR complexes. Our data show that CAR signaling pathways cannot be predicted solely by the domains used to construct the receptor and that signal strength is a key determinant of T cell fate. Thus, tailoring CAR design based on signal strength may lead to improved clinical efficacy and reduced toxicity.

  View details for DOI 10.1126/scisignal.aat6753

  View details for Web of Science ID 000442311300004

  View details for PubMedID 30131370

  View details for PubMedCentralID PMC6186424

• Chimeric antigen receptor-modified T cells: CD19 and the road beyond BLOOD Salter, A. I., Pont, M. J., Riddell, S. R. 2018; 131 (24): 2621-2629

  Abstract

  The ability to harness a patient's immune system to target malignant cells is now transforming the treatment of many cancers, including hematologic malignancies. The adoptive transfer of T cells selected for tumor reactivity or engineered with natural or synthetic receptors has emerged as an effective modality, even for patients with tumors that are refractory to conventional therapies. The most notable example of adoptive cell therapy is with T cells engineered to express synthetic chimeric antigen receptors (CARs) that reprogram their specificity to target CD19. CAR T cells have shown remarkable antitumor activity in patients with refractory B-cell malignancies. Ongoing research is focused on understanding the mechanisms of incomplete tumor elimination, reducing toxicities, preventing antigen escape, and identifying suitable targets and strategies based on established and emerging principles of synthetic biology for extending this approach to other hematologic malignancies. This review will discuss the current status, challenges, and potential future applications of CAR T-cell therapy in hematologic malignancies.

  View details for DOI 10.1182/blood-2018-01-785840

  View details for Web of Science ID 000435552600006

  View details for PubMedID 29728402

  View details for PubMedCentralID PMC6032892

• <i>Ptpn11</i> Deletion in cD4<SUP>+</SUP> cells Does not affect T cell Development and Functions but causes cartilage Tumors in a T cell-independent Manner FRONTIERS IN IMMUNOLOGY Miah, S., Jayasuriya, C. T., Salter, A. I., Reilly, E. C., Fugere, C., Yang, W., Chen, Q., Brossay, L. 2017; 8: 1326

  Abstract

  The ubiquitously expressed tyrosine phosphatase Src homology region 2 domain-containing phosphatase-2 (SHP-2, encoded by Ptpn11) is required for constitutive cellular processes including proliferation, differentiation, and the regulation of immune responses. During development and maturation, subsets of T cells express a variety of inhibitory receptors known to associate with phosphatases, which in turn, dephosphorylate key players of activating receptor signaling pathways. We hypothesized that SHP-2 deletion would have major effects on T cell development by altering the thresholds for activation, as well as positive and negative selection. Surprisingly, using mice conditionally deficient for SHP-2 in the T cell lineage, we show that the development of these lymphocytes is globally intact. In addition, our data demonstrate that SHP-2 absence does not compromise T cell effector functions, suggesting that SHP-2 is dispensable in these cells. Unexpectedly, in aging mice, Ptpn11 gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in wrist bones in a T cell-independent manner. These tumors resemble miniature cartilaginous growth plates and contain CD4-lineage positive chondrocyte-like cells. Altogether these results indicate that SHP-2 is a cartilage tumor suppressor during aging.

  View details for DOI 10.3389/fimmu.2017.01326

  View details for Web of Science ID 000412952700001

  View details for PubMedID 29085371

  View details for PubMedCentralID PMC5650614

• Fully human CD19-specific chimeric antigen receptors for T-cell therapy LEUKEMIA Sommermeyer, D., Hill, T., Shamah, S. M., Salter, A. I., Chen, Y., Mohler, K. M., Riddell, S. R. 2017; 31 (10): 2191-2199

  Abstract

  Impressive results have been achieved by adoptively transferring T-cells expressing CD19-specific CARs with binding domains from murine mAbs to treat B-cell malignancies. T-cell mediated immune responses specific for peptides from the murine scFv antigen-binding domain of the CAR can develop in patients and result in premature elimination of CAR T-cells increasing the risk of tumor relapse. As fully human scFv might reduce immunogenicity, we generated CD19-specific human scFvs with similar binding characteristics as the murine FMC63-derived scFv using human Ab/DNA libraries. CARs were constructed in various formats from several scFvs and used to transduce primary human T-cells. The resulting CD19-CAR T-cells were specifically activated by CD19-positive tumor cell lines and primary chronic lymphocytic leukemia cells, and eliminated human lymphoma xenografts in immunodeficient mice. Certain fully human CAR constructs were superior to the FMC63-CAR, which is widely used in clinical trials. Imaging of cell surface distribution of the human CARs revealed no evidence of clustering without target cell engagement, and tonic signaling was not observed. To further reduce potential immunogenicity of the CARs, we also modified the fusion sites between different CAR components. The described fully human CARs for a validated clinical target may reduce immune rejection compared with murine-based CARs.

  View details for DOI 10.1038/leu.2017.57

  View details for Web of Science ID 000412179600020

  View details for PubMedID 28202953

  View details for PubMedCentralID PMC5608623

• A BiTE from cancer's intracellular menu NATURE BIOTECHNOLOGY Salter, A. I., Riddell, S. R. 2015; 33 (10): 1040-1041

  View details for Web of Science ID 000362555700020

  View details for PubMedID 26448086

• Role of SHIP1 in Invariant NKT Cell Development and Functions JOURNAL OF IMMUNOLOGY Anderson, C. K., Salter, A. I., Toussaint, L. E., Reilly, E. C., Fugere, C., Srivastava, N., Kerr, W. G., Brossay, L. 2015; 195 (5): 2149-2156

  Abstract

  SHIP1 is a 5'-inositol phosphatase known to negatively regulate the signaling product of the PI3K pathway, phosphatidylinositol (3-5)-trisphosphate. SHIP1 is recruited to a large number of inhibitory receptors expressed on invariant NK (iNKT) cells. We hypothesized that SHIP1 deletion would have major effects on iNKT cell development by altering the thresholds for positive and negative selection. Germline SHIP1 deletion has been shown to affect T cells as well as other immune cell populations. However, the role of SHIP1 on T cell function has been controversial, and its participation on iNKT cell development and function has not been examined. We evaluated the consequences of SHIP1 deletion on iNKT cells using germline-deficient mice, chimeric mice, and conditionally deficient mice. We found that T cell and iNKT cell development are impaired in germline-deficient animals. However, this phenotype can be rescued by extrinsic expression of SHIP1. In contrast, SHIP1 is required cell autonomously for optimal iNKT cell cytokine secretion. This suggests that SHIP1 calibrates the threshold of iNKT cell reactivity. These data further our understanding of how iNKT cell activation is regulated and provide insights into the biology of this unique cell lineage.

  View details for DOI 10.4049/jimmunol.1500567

  View details for Web of Science ID 000360014200027

  View details for PubMedID 26232432

  View details for PubMedCentralID PMC4546909

• Genome Sequencing of Idiopathic Pulmonary Fibrosis in Conjunction with a Medical School Human Anatomy Course PLOS ONE Kumar, A., Dougherty, M., Findlay, G. M., Geisheker, M., Klein, J., Lazar, J., Machkovech, H., Resnick, J., Resnick, R., Salter, A. I., Talebi-Liasi, F., Arakawa, C., Baudin, J., Bogaard, A., Salesky, R., Zhou, Q., Smith, K., Clark, J. I., Shendure, J., Horwitz, M. S. 2014; 9 (9)

  Abstract

  Even in cases where there is no obvious family history of disease, genome sequencing may contribute to clinical diagnosis and management. Clinical application of the genome has not yet become routine, however, in part because physicians are still learning how best to utilize such information. As an educational research exercise performed in conjunction with our medical school human anatomy course, we explored the potential utility of determining the whole genome sequence of a patient who had died following a clinical diagnosis of idiopathic pulmonary fibrosis (IPF). Medical students performed dissection and whole genome sequencing of the cadaver. Gross and microscopic findings were more consistent with the fibrosing variant of nonspecific interstitial pneumonia (NSIP), as opposed to IPF per se. Variants in genes causing Mendelian disorders predisposing to IPF were not detected. However, whole genome sequencing identified several common variants associated with IPF, including a single nucleotide polymorphism (SNP), rs35705950, located in the promoter region of the gene encoding mucin glycoprotein MUC5B. The MUC5B promoter polymorphism was recently found to markedly elevate risk for IPF, though a particular association with NSIP has not been previously reported, nor has its contribution to disease risk previously been evaluated in the genome-wide context of all genetic variants. We did not identify additional predicted functional variants in a region of linkage disequilibrium (LD) adjacent to MUC5B, nor did we discover other likely risk-contributing variants elsewhere in the genome. Whole genome sequencing thus corroborates the association of rs35705950 with MUC5B dysregulation and interstitial lung disease. This novel exercise additionally served a unique mission in bridging clinical and basic science education.

  View details for DOI 10.1371/journal.pone.0106744

  View details for Web of Science ID 000347993600058

  View details for PubMedID 25192356

  View details for PubMedCentralID PMC4156421

• Adoptive Therapy With Chimeric Antigen Receptor-Modified T Cells of Defined Subset Composition CANCER JOURNAL Riddell, S. R., Sommermeyer, D., Berger, C., Liu, L., Balakrishnan, A., Salter, A., Hudecek, M., Maloney, D. G., Turtle, C. J. 2014; 20 (2): 141-144

  Abstract

  The ability to engineer T cells to recognize tumor cells through genetic modification with a synthetic chimeric antigen receptor has ushered in a new era in cancer immunotherapy. The most advanced clinical applications are in targeting CD19 on B-cell malignancies. The clinical trials of CD19 chimeric antigen receptor therapy have thus far not attempted to select defined subsets before transduction or imposed uniformity of the CD4 and CD8 cell composition of the cell products. This review will discuss the rationale for and challenges to using adoptive therapy with genetically modified T cells of defined subset and phenotypic composition.

  View details for DOI 10.1097/PPO.0000000000000036

  View details for Web of Science ID 000337688200009

  View details for PubMedID 24667960

  View details for PubMedCentralID PMC4149222

• Merck Ad5/HIV induces broad innate immune activation that predicts CD8<SUP>+</SUP> T-cell responses but is attenuated by preexisting Ad5 immunity PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zak, D. E., Andersen-Nissen, E., Peterson, E. R., Sato, A., Hamilton, M., Borgerding, J., Krishnamurty, A. T., Chang, J. T., Adams, D. J., Hensley, T. R., Salter, A. I., Morgan, C. A., Duerr, A. C., De Rosa, S. C., Aderem, A., McElrath, M. 2012; 109 (50): E3503-E3512

  Abstract

  To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8(+) T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity.

  View details for DOI 10.1073/pnas.1208972109

  View details for Web of Science ID 000312605600018

  View details for PubMedID 23151505

  View details for PubMedCentralID PMC3528489

• Impact of Pretransplantation Minimal Residual Disease, As Detected by Multiparametric Flow Cytometry, on Outcome of Myeloablative Hematopoietic Cell Transplantation for Acute Myeloid Leukemia JOURNAL OF CLINICAL ONCOLOGY Walter, R. B., Gooley, T. A., Wood, B. L., Milano, F., Fang, M., Sorror, M. L., Estey, E. H., Salter, A. I., Lansverk, E., Chien, J. W., Gopal, A. K., Appelbaum, F. R., Pagel, J. M. 2011; 29 (9): 1190-1197

  Abstract

  Allogeneic hematopoietic cell transplantation (HCT) benefits many patients with acute myeloid leukemia (AML) in first remission. Hitherto, little attention has been given to the prognostic impact of pretransplantation minimal residual disease (MRD).We retrospectively studied 99 consecutive patients receiving myeloablative HCT for AML in first morphologic remission. Ten-color multiparametric flow cytometry (MFC) was performed on bone marrow aspirates before HCT. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRD positive.Before HCT, 88 patients met morphologic criteria for complete remission (CR), whereas 11 had CR with incomplete blood count recovery (CRi). Twenty-four had MRD before HCT as determined by MFC. Two-year estimates of overall survival were 30.2% (range, 13.1% to 49.3%) and 76.6% (range, 64.4% to 85.1%) for MRD-positive and MRD-negative patients; 2-year estimates of relapse were 64.9% (range, 42.0% to 80.6%) and 17.6% (range, 9.5% to 27.9%). After adjustment for all or a subset of cytogenetic risk, secondary disease, incomplete blood count recovery, and abnormal karyotype pre-HCT, MRD-positive HCT was associated with increased overall mortality (hazard ratio [HR], 4.05; 95% CI, 1.90 to 8.62; P < .001) and relapse (HR, 8.49; 95% CI, 3.67 to 19.65; P < .001) relative to MRD-negative HCT.These data suggest that pre-HCT MRD is associated with increased risk of relapse and death after myeloablative HCT for AML in first morphologic CR, even after controlling for other risk factors.

  View details for DOI 10.1200/JCO.2010.31.8121

  View details for Web of Science ID 000288532500033

  View details for PubMedID 21282535

  View details for PubMedCentralID PMC3083874

• Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission LEUKEMIA Walter, R. B., Pagel, J. M., Gooley, T. A., Petersdorf, E. W., Sorror, M. L., Woolfrey, A. E., Hansen, J. A., Salter, A. I., Lansverk, E., Stewart, F. M., O'Donnell, P. V., Appelbaum, F. R. 2010; 24 (7): 1276-1282

  Abstract

  Hematopoietic cell transplantation (HCT) from a matched related donor (MRD) benefits many adults with acute myeloid leukemia (AML) in first complete remission (CR1). The majority of patients does not have such a donor and will require an alternative donor if HCT is to be undertaken. We retrospectively analyzed 226 adult AML CR1 patients undergoing myeloablative unrelated donor (URD) (10/10 match, n=62; 9/10, n=29) or MRD (n=135) HCT from 1996 to 2007. The 5-year estimates of overall survival, relapse and nonrelapse mortality (NRM) were 57.9, 29.7 and 16.0%, respectively. Failure for each of these outcomes was slightly higher for 10/10 URD than MRD HCT, although statistical significance was not reached for any end point. The adjusted hazard ratios (HRs) were 1.43 (0.89-2.30, P=0.14) for overall mortality, 1.17 (0.66-2.08, P=0.60) for relapse and 1.79 (0.86-3.74, P=0.12) for NRM, respectively, and the adjusted odds ratio for grades 2-4 acute graft-versus-host disease was 1.50 (0.70-3.24, P=0.30). Overall mortality among 9/10 and 10/10 URD recipients was similar (adjusted HR 1.16 (0.52-2.61), P=0.71). These data indicate that URD HCT can provide long-term survival for CR1 AML; outcomes for 10/10 URD HCT, and possibly 9/10 URD HCT, suggest that this modality should be considered in the absence of a suitable MRD.

  View details for DOI 10.1038/leu.2010.102

  View details for Web of Science ID 000279892900005

  View details for PubMedID 20485378

  View details for PubMedCentralID PMC3001162