Anusha Kalbasi, M.D.
Associate Professor of Radiation Oncology (Radiation Therapy)
Radiation Oncology - Radiation Therapy
Bio
Dr. Kalbasi is a board-certified radiation oncologist and physician-scientist at the Stanford Cancer Institute. He is also an associate professor of radiation oncology at Stanford Medicine and a project member of the Parker Institute for Cancer Immunotherapy.
In the clinic, Dr. Kalbasi specializes in the diagnosis and treatment of solid tumors, especially sarcoma and melanoma, with a focus on bringing new treatments to patients. This focus includes using advanced techniques in radiation oncology and cancer immunotherapy.
Dr. Kalbasi's NIH-funded laboratory studies the cancer-immune interface in various therapeutic contexts, including T cell therapy, cytokine therapy and innate immune agonism. The lab has described tumor cell-, T cell- and myeloid cell-intrinsic mechanisms of resistance to therapy and approaches to overcome therapy resistance. Dr. Kalbasi is also an experienced leader of clinical trials related to immunotherapy, T cell therapy and radiation therapy.
Prior to his arrival at Stanford Health Care, Dr. Kalbasi was assistant professor of radiation oncology in the David Geffen School of Medicine at UCLA and chief of sarcoma radiotherapy at the UCLA Jonsson Comprehensive Cancer Center. During his tenure, he was named a NextGen Star by the American Association of Cancer Research in recognition for excellence in cancer research.
Dr. Kalbasi’s work has been published in leading journals including Nature, Science Translational Medicine, JAMA Oncology, Lancet Oncology, Nature Cancer and Cancer Discovery. He has served as a peer reviewer for multiple prestigious journals, including the Proceedings of the National Academy of Sciences, Cell and the Journal of Clinical Investigation. He has also presented research to his peers at the American Association for Cancer Research and the American Institute of Chemical Engineers.
Clinical Focus
- Radiation Oncology
Academic Appointments
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Associate Professor, Radiation Oncology - Radiation Therapy
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Member, Bio-X
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Member, Stanford Cancer Institute
Honors & Awards
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Robert L. and Mary Ellenburg Endowed Faculty Scholar, Stanford University School of Medicine
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AACR NextGen Star Award, American Association for Cancer Research
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Joseph Drown Foundation Dean's Award in Research Excellence, UCLA
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Clinical Scientist Career Development Award (K08), National Cancer Institute
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Damon Runyon Clinical Investigator Award, Damon Runyon Cancer Research Foundation
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MRA Young Investigator Award, Melanoma Research Alliance
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SITC Young Investigator Award, Society for Immunotherapy of Cancer
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SARC Career Enhancement Award, Sarcoma Alliance for Research through Collaboration
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Tower Cancer Research Foundation Young Investigator Award, Tower Cancer Research Foundation
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ASCO Merit Award, Conquer Cancer Foundation
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ASCO Young Investigator Award, Conquer Cancer Foundation
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Alpha Omega Alpha, David Geffen School of Medicine at UCLA
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HHMI Research Scholar, Howard Hughes Medical Institute
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Geffen Scholar, David Geffen School of Medicine
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Phi Beta Kappa, UCLA
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Merck Index Award, UCLA Dept. of Chemistry & Biochemistry
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Robert C. Byrd Scholar, U.S. Dept. of Education
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Regents' Scholar, UCLA
Professional Education
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Board Certification: American Board of Radiology, Radiation Oncology (2017)
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Residency: University of Pennsylvania Radiation Oncology Program (2016) PA
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Internship: University of Pennsylvania Internal Medicine Residency (2012) PA
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Medical Education: UCLA David Geffen School Of Medicine Registrar (2011) CA
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B.S., UCLA, Biochemistry
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M.D., David Geffen School of Medicine at UCLA, Medicine
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Board Certification, American Board of Radiology, Radiation Oncology
Clinical Trials
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5-Day Preoperative Radiation for Soft Tissue Sarcoma
Recruiting
The purpose of this study is to examine the safety and efficacy of an abbreviated course of preoperative radiation, given over five days, for patients with soft tissue sarcoma of the extremity, trunk or retroperitoneum. This is in contrast to standard preoperative radiation, which is given over 25 days.
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Gene Modified Immune Cells (IL13Ralpha2 CAR T Cells) After Conditioning Regimen for the Treatment of Stage IIIC or IV Melanoma or Metastatic Solid Tumors
Recruiting
This phase I trial studies the side effects and best dose of modified immune cells (IL13Ralpha2 CAR T cells) after a chemotherapy conditioning regimen for the treatment of patients with stage IIIC or IV melanoma or solid tumors that have spread to other places in the body (metastatic). The study agent is called IL13Ralpha2 CAR T cells. T cells are a special type of white blood cell (immune cells) that have the ability to kill tumor cells. The T cells are obtained from the patient's own blood, grown in a laboratory, and modified by adding the IL13Ralpha2 CAR gene. The IL13Ralpha2 CAR gene is inserted into T cells with a virus called a lentivirus. The lentivirus allows cells to make the IL13Ralpha2 CAR protein. This CAR has been designed to bind to a protein on the surface of tumor cells called IL13Ralpha2. This study is being done to determine the dose at which the gene-modified immune cells are safe, how long the cells stay in the body, and if the cells are able to attack the cancer.
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Nivolumab and BO-112 Before Surgery for the Treatment of Resectable Soft Tissue Sarcoma
Not Recruiting
This phase I trial studies the side effects of BO-112 when given together with nivolumab before surgery in treating patients with soft tissue sarcoma that can be removed by surgery (resectable). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with BO-112, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab and BO-112 before surgery may work better in treating patients with soft tissue sarcoma compared to nivolumab alone.
Stanford is currently not accepting patients for this trial.
2024-25 Courses
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Independent Studies (4)
- Graduate Research
CBIO 399 (Aut, Win, Spr, Sum) - Graduate Research
IMMUNOL 399 (Aut, Win, Spr, Sum) - Undergraduate Research
MED 199 (Aut, Win, Spr, Sum) - Undergraduate Research
RADO 199 (Aut, Win, Spr, Sum)
- Graduate Research
Stanford Advisees
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Doctoral Dissertation Reader (AC)
Cort Breuer, Grayson Rodriguez, Oliver Takacsi-Nagy -
Postdoctoral Faculty Sponsor
Ossama Labiad, Heather Ogana -
Doctoral Dissertation Advisor (AC)
Sarah Cavender, Kayla Kulhanek, Johnathon Soro
All Publications
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Gold-siRNA supraclusters enhance the anti-tumor immune response of stereotactic ablative radiotherapy at primary and metastatic tumors.
Nature biotechnology
2024
Abstract
Strategies to enhance the anti-tumor immune response of stereotactic ablative radiotherapy (SABR) at primary tumors and abscopal sites are under intensive investigation. Here we report a metabolizable binary supracluster (BSCgal) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSCgal comprises reversibly crosslinked cationic gold nanoclusters and siRNA complexes in a polymer matrix that biodegrades over weeks, facilitating clearance (90.3% in vivo clearance at 4 weeks) to reduce toxicity. The particle size well above the renal filtration threshold facilitates passive delivery to tumors. Using mouse models of head and neck cancer, we show that BSCgal augments the radiodynamic and immunotherapeutic effects of SABR at the primary and metastatic tumors by promoting tumor-inhibitory leukocytes, upregulating cytotoxic granzyme B and reducing immunosuppressive cell populations. It outperforms SABR plus Gal-1 antagonists, chemoradiation drug cisplatin or PD-1 inhibitor. This work presents a translatable strategy to converge focal radiosensitization with targeted immune checkpoint silencing for personalized radioimmunotherapy.
View details for DOI 10.1038/s41587-024-02448-0
View details for PubMedID 39448881
View details for PubMedCentralID 6053911
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Hypofractionated Preoperative Radiation Should Not Yet Be Used as Standard of Care for Extremity and Truncal Soft Tissue Sarcoma.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2024: JCO2400238
Abstract
Hypofractionated radiation therapy regimens should not be used as standard of care for localized soft tissue sarcoma.
View details for DOI 10.1200/JCO.24.00238
View details for PubMedID 39231372
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Effect of palliative radiation dose on symptom response in metastatic sarcomas.
Clinical and translational radiation oncology
2024; 48: 100803
Abstract
Palliative radiotherapy (RT) plays a crucial role in alleviating symptoms associated with metastatic sarcoma. However, there is a lack of consensus on the optimal palliative radiation dose and fractionation for metastatic sarcomas. We analyzed the association between biologically effective radiation dose and symptom response for patients who underwent palliative RT for metastatic sarcomas.We retrospectively identified patients with metastatic sarcoma treated with palliative RT between 1999 and 2021 at our institution. We assessed the association between equivalent dose in 2 Gy fractions (EQD2) with an α/β of three and symptom relief or overall survival (OS) using univariable and multivariable analyses.Of the 198 metastatic sites treated, the most common indications for palliative radiation were pain (n = 181, 91 %) and compression of adjacent structures (n = 16, 8 %). In our analysis, an EQD2 of > 20 Gy was associated with greater rates of short-term symptom relief (n = 143, 85 %) at the RT site compared to an EQD2 of ≤ 20 Gy (n = 14, 54 %, P = 0.001) with no reports of grade 3 or higher toxicity. However, there was no significant improvement in short-term symptom relief for higher radiation doses. Patients treated with an EQD2 of ≤ 20 Gy had a significantly worse performance status, but there was no significant difference in overall survival based on EQD2 on multivariable analysis.An EQD2 ≤ 20 Gy (e.g., 8 Gy in 1 fraction) provided inadequate palliative benefit in this series. An EQD2 > 20 Gy resulted in greater rates of symptom palliation in metastatic sarcomas, but further dose escalation did not improve symptom response or durability. These findings suggest standard palliative regimens such as 20 Gy in 5 fractions (EQD2 of 28 Gy) are effective for patients with metastatic sarcomas.
View details for DOI 10.1016/j.ctro.2024.100803
View details for PubMedID 38988806
View details for PubMedCentralID PMC11231649
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Targeted Bias: The Next Swing at IL2 Therapy.
Cancer discovery
2024; 14 (7): 1145-1146
Abstract
Despite its long history of toxicity and limited efficacy, IL2 has re-entered the clinic as a companion to the recently FDA-approved tumor infiltrating lymphocyte therapy. In back-to-back articles, Moynihan and Kaptein introduce a new fusion protein that delivers a biased IL2 mutein to CD8 T cells. See related article by Moynihan et al., p. 1206 (6). See related article by Kaptein et al., p. 1226 (7).
View details for DOI 10.1158/2159-8290.CD-24-0558
View details for PubMedID 38946323
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Letting Radiation Therapy "Make Its Bones".
International journal of radiation oncology, biology, physics
2024; 118 (5): 1161
View details for DOI 10.1016/j.ijrobp.2023.10.021
View details for PubMedID 38492964
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Antitumor Immune Responses in B2M-Deficient Cancers.
Cancer immunology research
2023
Abstract
beta2-microglobulin (B2M) is a critical component of the MHC class I molecule and is required to present tumor antigens to T cells. Its loss results in acquired resistance to immune checkpoint blockade (ICB) therapies. However, there have been well-documented cases of B2M-inactivated tumors responding to ICB, justifying investigation of how an antitumor immune response can be generated to tumors without surface MHC class I. We knocked-out B2M in three murine models with varying baseline MHC class I expression and sensitivity to anti-programmed death receptor (PD-1) therapy and analyzed the immune responses. MC38 and YUMMER2.1 without B2M responded to anti-PD-1 alone or with an IL2 agonist, and this was mediated by CD4+ T cells and natural killer (NK) cells. The more aggressive B16 without B2M expression only partially responded to the IL2 agonist, and this was dependent on NK cells. When analyzing nearly 300 pretreatment biopsies from patients with melanoma receiving PD-1 blockade-based therapies, we found infrequent B2M mutations or homozygous loss but more frequent loss of heterozygosity (LOH) or copy number gains. B2M LOH was enriched in biopsies from patients without response to therapy, and these biopsies were more frequently infiltrated by activated NK cells. We conclude that in the absence of B2M, activation of CD4+ T cells and NK cells can mediate responses to murine models of PD-1 blockade therapy. Additionally, in human melanoma the intratumoral presence of activated NK cells upon partial B2M loss likely selects against tumor escape through low surface MHC class I expression.
View details for DOI 10.1158/2326-6066.CIR-23-0139
View details for PubMedID 37801341
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Patterns of local recurrence and risk of skin recurrence in soft tissue sarcomas after surgical resection.
Practical radiation oncology
2023
Abstract
Although there is a theoretical risk of skin seeding during surgical resection of soft tissues sarcomas (STSs), current consensus guidelines recommend against routine use of bolus during RT. However, the risk of skin recurrence has not been systematically assessed. We aimed to assess the patterns of local recurrence (LR) in patients with STS treated with surgery with or without RT.We performed a retrospective analysis of adults with STSs evaluated at our institution between 2007-2021. For patients who developed LR, the depth was evaluated. Progression free survival (PFS) and overall survival (OS) were analyzed from time of first LR using Kaplan-Meier method. Cumulative incidence of distant metastasis (CIDM) was calculated with competing risk analysis from date of LR.Of the 206 patients evaluated, 20 had LR (9.7%). Among patients with LR, five patients (25.0%) were treated with surgery alone and 15 patients (75.0%) with surgery and RT. In patients treated with RT, 46.7% had pre-operative RT, 53.3% had post operative RT, and bolus was used in 46.7%. Surgical margins were close (<1mm) in 4 patients (20.0%) and positive in 10 patients (50.0%). LR occurred in the deep subfascial tissue in 9 patients (45%), subcutaneous tissue in 10 patients (50.0%), and skin in 1 patient (5.0%). The patient with a skin recurrence was treated with surgery alone and the tumor involved the skin at presentation. In patients treated with RT, LR occurred within RT field in 13 patients (86.7%). At 1 year after LR, PFS was 70.3%, OS was 81.7%, and CIDM was 5.9%.Skin recurrences were rare after surgical resection of STSs, and only occurred in a tumor that involved the skin at initial presentation. These findings support current recommendations against routine use of bolus in STSs not involving the skin at presentation.
View details for DOI 10.1016/j.prro.2023.09.006
View details for PubMedID 37804883
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IGF2BP3 as a Prognostic Biomarker in Well-Differentiated/Dedifferentiated Liposarcoma.
Cancers
2023; 15 (18)
Abstract
BACKGROUND: Although IGF2BP3 has been implicated in tumorigenesis and poor outcomes in multiple cancers, its role in soft-tissue sarcoma (STS) remains unknown. Preliminary data have suggested an association with IGF2BP3 expression among patients with well-differentiated/dedifferentiated liposarcoma (WD/DD LPS), a disease where molecular risk stratification is lacking.METHODS: We examined the survival associations of IGF2BP3 via univariate and multivariate Cox regression in three unique datasets: (1) the Cancer Genome Atlas (TCGA), (2) an in-house gene microarray, and (3) an in-house tissue microarray (TMA). A fourth dataset, representing an independent in-house TMA, was used for validation.RESULTS: Within the TCGA dataset, IGF2BP3 expression was a poor prognostic factor uniquely in DD LPS (OS 1.6 vs. 5.0 years, p = 0.009). Within the microarray dataset, IGF2BP3 expression in WD/DD LPS was associated with worse survival (OS 7.7 vs. 21.5 years, p = 0.02). IGF2BP3 protein expression also portended worse survival in WD/DD LPS (OS 3.7 vs. 13.8 years, p < 0.001), which was confirmed in our validation cohort (OS 2.7 vs. 14.9 years, p < 0.001). In the multivariate model, IGF2BP3 was an independent risk factor for OS, (HR 2.55, p = 0.034).CONCLUSION: IGF2BP3 is highly expressed in a subset of WD/DD LPS. Across independent datasets, IGF2BP3 is also a biomarker of disease progression and worse survival.
View details for DOI 10.3390/cancers15184489
View details for PubMedID 37760460
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Adopting shorter radiation regimens: rules of engagement for sarcoma.
The Lancet. Oncology
2023; 24 (2): e70
View details for DOI 10.1016/S1470-2045(23)00008-6
View details for PubMedID 36725150
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Lifelong Imaging Surveillance is Indicated for Patients with Primary Retroperitoneal Liposarcoma.
Annals of surgical oncology
2022
Abstract
Surveillance imaging of patients with retroperitoneal liposarcoma (RP-LPS) after surgical resection is based on a projected risk of locoregional and distant recurrence. The duration of surveillance is not well defined because the natural history of RP-LPS after treatment is poorly understood. This study evaluated the long-term risk of recurrence and disease-specific survival (DSS) for a cohort of patients with at least 10 years of progression-free survival (10yr-PFS) from their primary resection.The prospective University of California, Los Angeles (UCLA) Sarcoma Database identified RP-LPS patients with 10yr-PFS after initial resection. The patients in the 10yr-PFS cohort were subsequently evaluated for recurrence and DSS. The time intervals start at date of initial surgical resection. Cox proportional hazards models were used to determine factors associated with recurrence and DSS.From 1972 to 2010, 76 patients with RP-LPS had at least 10 years of follow-up evaluation. Of these 76 patients, 39 (51%) demonstrated 10yr-PFS. The median follow-up period was 15 years (range 10-33 years). Among the 10yr-PFS patients, 49% (19/39) experienced a recurrence at least 10 years after surgery. Of those who experienced recurrence, 42% (8/19) died of disease. Neither long-term recurrence nor DSS were significantly associated with age, sex, tumor size, LPS subtype, surgical margin, or perioperative treatment with radiation or chemotherapy.Patients who have primary RP-LPS treated with surgical resection ± multimodality therapy face a long-term risk of recurrence and disease-specific death unacknowledged by current surveillance imaging guidelines. Among the patients with 10yr-PFS, 49% experienced a recurrence, and 42% of those died of disease. These findings suggest a need for lifelong surveillance imaging for patients with RP-LPS.
View details for DOI 10.1245/s10434-022-12977-0
View details for PubMedID 36581724
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Engineered IL13 variants direct specificity of IL13Rα2-targeted CAR T cell therapy.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (33): e2112006119
Abstract
IL13Rα2 is an attractive target due to its overexpression in a variety of cancers and rare expression in healthy tissue, motivating expansion of interleukin 13 (IL13)-based chimeric antigen receptor (CAR) T cell therapy from glioblastoma into systemic malignancies. IL13Rα1, the other binding partner of IL13, is ubiquitously expressed in healthy tissue, raising concerns about the therapeutic window of systemic administration. IL13 mutants with diminished binding affinity to IL13Rα1 were previously generated by structure-guided protein engineering. In this study, two such variants, termed C4 and D7, are characterized for their ability to mediate IL13Rα2-specific response as binding domains for CAR T cells. Despite IL13Rα1 and IL13Rα2 sharing similar binding interfaces on IL13, mutations to IL13 that decrease binding affinity for IL13Rα1 did not drastically change binding affinity for IL13Rα2. Micromolar affinity to IL13Rα1 was sufficient to pacify IL13-mutein CAR T cells in the presence of IL13Rα1-overexpressing cells in vitro. Interestingly, effector activity of D7 CAR T cells, but not C4 CAR T cells, was demonstrated when cocultured with IL13Rα1/IL4Rα-coexpressing cancer cells. While low-affinity interactions with IL13Rα1 did not result in observable toxicities in mice, in vivo biodistribution studies demonstrated that C4 and D7 CAR T cells were better able to traffic away from IL13Rα1+ lung tissue than were wild-type (WT) CAR T cells. These results demonstrate the utility of structure-guided engineering of ligand-based binding domains with appropriate selectivity while validating IL13-mutein CARs with improved selectivity for application to systemic IL13Rα2-expressing malignancies.
View details for DOI 10.1073/pnas.2112006119
View details for PubMedID 35939683
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Infrequent chromosomal loss and recurrent gains lead to imbalanced expression of HLA genes in melanoma
AMER ASSOC CANCER RESEARCH. 2022
View details for Web of Science ID 000892509509177
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Human chimeric orthogonal IL9 receptor signaling promotes stemness and polyfunctionality for adoptive T cell therapy of cancer
AMER ASSOC CANCER RESEARCH. 2022
View details for Web of Science ID 000892509507393
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Potentiating adoptive cell therapy using synthetic IL-9 receptors.
Nature
2022
Abstract
Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common gamma-chain (gammac) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding gammac cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rbeta-ECD-IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells,o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.
View details for DOI 10.1038/s41586-022-04801-2
View details for PubMedID 35676488
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Orthogonal IL-9 receptor signaling reprograms T cells to obviate conditioning chemotherapy before adoptive cell therapy.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000680263500048
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Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma.
Science translational medicine
2020; 12 (565)
Abstract
Defects in tumor-intrinsic interferon (IFN) signaling result in failure of immune checkpoint blockade (ICB) against cancer, but these tumors may still maintain sensitivity to T cell-based adoptive cell therapy (ACT). We generated models of IFN signaling defects in B16 murine melanoma observed in patients with acquired resistance to ICB. Tumors lacking Jak1 or Jak2 did not respond to ICB, whereas ACT was effective against Jak2 KO tumors, but not Jak1 KO tumors, where both type I and II tumor IFN signaling were defective. This was a direct result of low baseline class I major histocompatibility complex (MHC I) expression in B16 and the dependency of MHC I expression on either type I or type II IFN signaling. We used genetic and pharmacologic approaches to uncouple this dependency and restore MHC I expression. Through independent mechanisms, overexpression of NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) and intratumoral delivery of BO-112, a potent nanoplexed version of polyinosinic:polycytidylic acid (poly I:C), each restored the efficacy of ACT against B16-Jak1 KO tumors. BO-112 activated double-stranded RNA (dsRNA) sensing (via protein kinase R and Toll-like receptor 3) and induced MHC I expression via nuclear factor κB, independent of both IFN signaling and NLRC5. In summary, we demonstrated that in the absence of tumor IFN signaling, MHC I expression is essential and sufficient for the efficacy of ACT. For tumors lacking MHC I expression due to deficient IFN signaling, activation of dsRNA sensors by BO-112 affords an alternative approach to restore the efficacy of ACT.
View details for DOI 10.1126/scitranslmed.abb0152
View details for PubMedID 33055240
View details for PubMedCentralID PMC8053376
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Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma.
Cancer cell
2020; 38 (4): 500-515.e3
Abstract
We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.
View details for DOI 10.1016/j.ccell.2020.08.005
View details for PubMedID 32916126
View details for PubMedCentralID PMC7872287
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Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade.
Cancer discovery
2020; 10 (8): 1140-1157
Abstract
Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti-PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti-PD-1, mediated by natural killer (NK) and CD8 T cells. B2M-knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. SIGNIFICANCE: The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy.This article is highlighted in the In This Issue feature, p. 1079.
View details for DOI 10.1158/2159-8290.CD-19-1409
View details for PubMedID 32467343
View details for PubMedCentralID PMC7416458
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A Phase II Trial of 5-Day Neoadjuvant Radiotherapy for Patients with High-Risk Primary Soft Tissue Sarcoma.
Clinical cancer research : an official journal of the American Association for Cancer Research
2020; 26 (8): 1829-1836
Abstract
In a single-institution phase II study, we evaluated the safety of a 5-day dose-equivalent neoadjuvant radiotherapy (RT) regimen for high-risk primary soft tissue sarcoma.Patients received neoadjuvant RT alone (30 Gy in five fractions) to the primary tumor with standard margins. The primary endpoint was grade ≥2 late-radiation toxicity. Major wound complications, local recurrences, and distant metastases were also examined. In exploratory analysis, we evaluated germline biomarkers for wound toxicity and the effects of the study on treatment utilization.Over 2 years, 52 patients were enrolled with median follow-up of 29 months. Seven of 44 evaluable patients (16%) developed grade ≥2 late toxicity. Major wound complications occurred in 16 of 50 patients (32%); a signature defined by 19 germline SNPs in miRNA-binding sites of immune and DNA damage response genes, in addition to lower extremity tumor location, demonstrated strong predictive performance for major wound complications. Compared with the preceding 2-year period, the number of patients treated with neoadjuvant RT alone at our institution increased 3-fold, with a concomitant increase in the catchment area.A shorter 5-day neoadjuvant RT regimen results in favorable rates of wound complications and grade ≥2 toxicity after 2-year follow-up. Five-day RT significantly increased utilization of neoadjuvant RT at our high-volume sarcoma center. With further validation, a putative germline biomarker for wound complications may guide safer RT utilization.
View details for DOI 10.1158/1078-0432.CCR-19-3524
View details for PubMedID 32054730
View details for PubMedCentralID PMC7189949
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Adopting shorter radiation regimens: rules of engagement for sarcoma
LANCET ONCOLOGY
2020; 24 (2): E70
View details for Web of Science ID 000931567800001
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Tumour-intrinsic resistance to immune checkpoint blockade.
Nature reviews. Immunology
2020; 20 (1): 25-39
Abstract
'Immune checkpoint blockade' for cancer describes the use of therapeutic antibodies that disrupt negative immune regulatory checkpoints and unleash pre-existing antitumour immune responses. Antibodies targeting the checkpoint molecules cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and PD1 ligand 1 (PD-L1) have had early success in the clinic, which has led to approval by the US Food and Drug Administration of multiple agents in several cancer types. Yet, clinicians still have very limited tools to discriminate a priori patients who will and will not respond to treatment. This has fuelled a wave of research into the molecular mechanisms of tumour-intrinsic resistance to immune checkpoint blockade, leading to the rediscovery of biological processes critical to antitumour immunity, namely interferon signalling and antigen presentation. Other efforts have shed light on the immunological implications of canonical cancer signalling pathways, such as WNT-β-catenin signalling, cell cycle regulatory signalling, mitogen-activated protein kinase signalling and pathways activated by loss of the tumour suppressor phosphoinositide phosphatase PTEN. Here we review each of these molecular mechanisms of resistance and explore ongoing approaches to overcome resistance to immune checkpoint blockade and expand the spectrum of patients who can benefit from immune checkpoint blockade.
View details for DOI 10.1038/s41577-019-0218-4
View details for PubMedID 31570880
View details for PubMedCentralID PMC8499690
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SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study
CANCER DISCOVERY
2018; 8 (10): 1250–57
Abstract
PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate "flu-like" symptoms. Among the 9 patients naïve to anti-PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti-PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.Significance: These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone. Cancer Discov; 8(10); 1250-7. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1195.
View details for PubMedID 30154193
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(99)mTc-phytate as a diagnostic probe for assessing inflammatory reaction in malignant tumors
NUCLEAR MEDICINE COMMUNICATIONS
2015; 36 (10): 1042-1048
Abstract
Once administered intravenously, technetium-99m (99mTc)-labeled phytate binds to calcium in the serum and behaves as a nanoparticle. On the basis of the high permeability of the tumor vasculature, 99mTc-phytate is expected to leak and accumulate specifically in inflammatory cells. The aim of this study was to evaluate the potential of 99mTc-phytate in assessing the degree of inflammation in Ehrlich solid tumors in mice.99mTc-phytate was prepared by adding pertechnetate to a solution containing phytic acid and stannous chloride. The blood half-life of this particle following intravenous injection was determined using blood samples from healthy animals, whereas its size was measured by photon correlation spectroscopy. Scintigraphic imaging and biodistribution studies were carried out in tumor-bearing mice at 30 min and 2 h after injection.The average size of the particles was in the range of 200 nm, suggesting that they are capable of passively passing through fenestrations in tumor vessels, which are 200-2000 nm in size. The blood half-life for 99mTc-phytate was found to be 2.1 min, a result that is in agreement with previous studies. Data from tumor-bearing mice showed high tumor uptake at 2 h after 99mTc-phytate administration. As a result, a high tumor-to-muscle ratio was achieved (T/M = 25.9 ± 7.54).These findings indicate that 99mTc-sodium phytate has promising properties for identifying the type of tumor. This approach will have significant implications for characterizing tumor biology and treatment of malignant lesions.
View details for DOI 10.1097/MNM.0000000000000358
View details for Web of Science ID 000360658300010
View details for PubMedID 26147941