Anusha Kalbasi, MD

All Publications

• Decoding the evolutionary landscape of soft tissue sarcomas: From multiregion origins to therapy-driven adaptation Soudi, S., Silvia, N., Subramanian, A., Nouth, S., Ryu, F., Kaneko, T., New, C., Kenney, D., Avedian, R., Steffner, R., Mohler, D., Kalbasi, A., Van De Rijn, M., Charville, G., Moding, E. AMER ASSOC CANCER RESEARCH. 2025: B18

  View details for DOI 10.1158/1538-7445.CANEVOL25-B018

  View details for Web of Science ID 001652158200008

• Five-Day Preoperative Radiation Therapy for Patients With High-Risk Soft Tissue Sarcoma: A Nonrandomized Clinical Trial. JAMA network open Nikitas, J., Kendal, J. K., Savjani, R. R., Jackson, N., Peterson, N., Deng, J., Hernandez, J., Chong, N., Singh, A. S., Chmielowski, B., Federman, N. C., Crompton, J. G., Kadera, B. E., Wessel, L. E., Christ, A. B., Nelson, S. D., Dry, S. M., Weidhaas, J. B., Steinberg, M. L., Bernthal, N. M., Eilber, F. C., Kalbasi, A., Reddy, V. K. 2025; 8 (12): e2550195

  Abstract

  Standard preoperative radiotherapy (RT) for high-risk soft tissue sarcoma (STS) is delivered over 5 weeks, which can be a logistical challenge for patients.To evaluate the long-term toxic effects and clinical outcomes associated with a shorter 5-day, dose-equivalent preoperative RT regimen.Phase 2, single-group nonrandomized trial with an initial cohort (April 2016 to May 2018) and expansion cohort (October 2018 to May 2023) at a single academic center in the US. Participants were patients with histologically confirmed extremity or trunk STS recommended to undergo standard preoperative RT and surgery. Patients with planned neoadjuvant systemic therapy who were enrolled in the expansion group were excluded from this analysis. Analysis was conducted September 2024 to August 2025.A total of 30 Gy in 5 fractions were delivered preoperatively.The primary end point was 2-year grade 2 or higher radiation toxic effects. Secondary end points included major wound complications (MWC), local failure, distant progression, and overall survival.A total of 110 patients were treated with preoperative RT and surgery (42 patients [38%] were aged 65-79 years; 64 [58%] were male; 75 had tumors of the lower extremity [68%], and 64 patients [58%] had high-grade disease). The initial cohort accrued 50 patients who underwent surgery. The expansion cohort accrued 83 patients; 60 of 83 were treated without neoadjuvant chemotherapy and were included. Median (IQR) follow-up was 37.3 (20.1-60.6) months, including 64.2 (36.3-74.1) months for the initial cohort and 30.0 (13.5-40.2) months for the expansion cohort. At 2 years, 14 of 74 evaluable patients (18.9%) developed grade 2 or higher toxic effects (10 patients [25.0%] for the initial cohort and 4 patients [11.8%] for the expansion cohort). MWCs occurred in 33 of 110 patients (30.0%); (17 [34.0%] for the initial cohort and 16 [26.7%] for the expansion cohort). Time to wound closure exceeded 6 months for 15 patients (13.6%), including 12 of 29 patients (41.4%) who underwent local tissue advancement flaps. Two-year local control adjusting for competing risk of death was 92.4% (95% CI, 86.3%-96.5%). There were 3 (2.7%) bone fractures and 5 (4.5%) amputations.This nonrandomized clinical trial of ultrahypofractionated preoperative RT identified durable local control with MWC and favorable late grade 2 or higher toxic effects rates. Randomized data are necessary to differentiate the safety profiles of various fractionation regimens, especially duration of wound healing.ClinicalTrials.gov Identifier: NCT02701153.

  View details for DOI 10.1001/jamanetworkopen.2025.50195

  View details for PubMedID 41405883

• IL-9 as a naturally orthogonal cytokine with optimal JAK/STAT signaling for engineered T cell therapy. Immunity Jiang, H., Limsuwannarot, S., Kulhanek, K. R., Pal, A., Labiad, O., Rysavy, L. W., Wong, A., Su, L., Cavender, S., Soro, J., Testa, S., Ogana, H., Waghray, D., Tao, P., Jude, K. M., Seet, C. S., Crooks, G. M., Moding, E. J., Garcia, K. C., Kalbasi, A. 2025

  Abstract

  Cytokines and their receptors enable precise tuning of T cell function. Leveraging this biology holds tremendous promise for optimizing antitumor immunity. Arming T cells with a synthetically orthogonal interleukin (IL)-9 receptor (o9R), for instance, permits facile engraftment and potent anti-tumor functions. Exploiting the paucity of wild-type IL-9R expression and the safety of high doses of IL-9, here, we showed that, compared with o9R, T cells engineered with wild-type IL-9R exhibited superior tissue infiltration, stemness, and anti-tumor activity. These qualities were consistent with a stronger Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal, which included canonically IL-12-driven STAT4 in addition to STAT1/3/5. IL-9R T cells were exquisitely sensitive to perturbations of proximal signaling, including structure-guided attenuation, amplification, and rebalancing of JAK/STAT signals. Biased IL-9R mutants showed that STAT1 acts as a rheostat between stem-like and effector states. In summary, we identify IL-9/IL-9R as a naturally orthogonal cytokine-receptor pair with an optimal JAK/STAT signaling profile for engineered T cell therapy.

  View details for DOI 10.1016/j.immuni.2025.10.024

  View details for PubMedID 41274289

  View details for PubMedCentralID PMC12643178

• Dedicated review of sarcoma pathology is necessary for corroborative diagnosis in nearly one half of referred patients. Surgery Eckardt, M. A., Siena, N. M., Copeland, A. R., McCaw, T. R., Shehata, M. S., Lofftus, S. Y., Graham, D. S., Dao, H. B., Singh, A. S., Chmielowski, B., Federman, N., Kadera, B. E., Kalbasi, A., Bernthal, N. M., Eilber, F. R., Dry, S. M., Nelson, S. D., Eilber, F. C., Crompton, J. G. 2025; 188: 109610

  Abstract

  BACKGROUND: Specialized centers have been shown to improve survival and functional outcomes in patients with sarcoma. The objective of this study was to determine the rate and clinical impact of changes in pathologic diagnosis between high- and low-volume sarcoma centers.METHODS: We performed a retrospective review of patients discussed at UCLA Multidisciplinary Sarcoma Conference over 1 year. Patients with a pathology report from an outside facility and subsequent formal UCLA pathology review were included. Of 1,350 cases and 877 unique patients presented, 196 patients were identified for analysis. The primary outcome was to assess concordance between pathologic diagnosis at high- and low-volume sarcoma centers. Concordance was defined as either full concordance, minor discordance, or major discordance between the original diagnosis and review by a sarcoma pathology specialist.RESULTS: Of the 196 patients who were included in this study, 44% had full concordance on review of their pathology, 12% had minor discordance, and 44% had major discordance. Major discordance included benign/malignant mismatch (n = 23/87, 26%), discrepancy in histologic subtype (n = 25/87, 29%), change from nondiagnostic to diagnostic (n = 34/87, 39%) and major grading discrepancy (n = 5/87, 6%). After excluding other high-volume centers (n = 18), the major discordance rate increased to 48% (n = 85/178).CONCLUSION: Nearly one half (44%) of patients had a major change to their diagnosis that would affect prognosis or treatment plan after referral to a high-volume sarcoma center. A coordinated system for pathologic re-review for all potential sarcoma diagnoses could facilitate optimal management of patients with these rare malignancies.

  View details for DOI 10.1016/j.surg.2025.109610

  View details for PubMedID 41072121

• Distinct cell state ecosystems for nodular lymphocyte-predominant Hodgkin lymphoma. Nature communications Subramanian, A., Su, S., Flerlage, J., Alig, S., Younes, S., Marks, L. J., Pinnix, C., Vega, F., Steiner, R., Kumar, P., Mocikova, H., Sykorova, A., Prochazka, V., Milito, C., Allen, P., Paulino, D., Ramsay, A., Flerlage, T., Palese, M., West, R., Zhu, C., Noordenbos, T., Schroers-Martin, J., Zhao, S., Park, N. J., Kalbasi, A., Moding, E. J., Newman, A. M., Advani, R. H., Hoppe, R. T., Diehn, M., Natkunam, Y., Alizadeh, A. A., Binkley, M. S. 2025; 16 (1): 8473

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and few studies have comprehensively investigated the immune microenvironment and rare lymphocyte-predominant (LP) cells. Here we develop a NLPHL specific lymphocyte-predominant ecotype (LPE) model to identify 34 distinct cell states across 14 cell types that co-occur within 3 LPEs for 171 cases. LPE1 and LPE2 were characterized by immunosuppressive microenvironments with high expression of B2M on LP cells, CD8 T-cell exhaustion, immune checkpoint genes expressed by follicular T-cells, and an improved freedom from progression compared to LPE3 in training (n = 109, with 65% LPE1/2) and validation cohorts (n = 62, with 61% LPE1/2). We validate the co-occurrence and co-localization of cell states using spatial transcriptomics. Protein expression of HLA-I and HLA-II on LP cells and SSTR2 on dendritic cells was predictive of LPE1 (C-statistic=0.69), LPE2 (C-statistic=0.79), and LPE3 (C-statistic=0.60). This study establishes a clinically relevant biologic categorization for NLPHL.

  View details for DOI 10.1038/s41467-025-63339-9

  View details for PubMedID 41006203

  View details for PubMedCentralID PMC12475200

• LIFE-THREATENING MALIGNANCY IN PREGNANCY: A CASE SERIES OF THREE PATIENTS TREATED WITH PROTON RADIOTHERAPY WITH LONG TERM FOLLOW-UP Kurtz, G., Kalbasi, A., Hartl, B., Bieda, B., Amit, U., Alonso-Basanta, M., LaRiviere, M., Hill-Kayser, C. ELSEVIER IRELAND LTD. 2025

  View details for Web of Science ID 001588640400091

• SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics. Genome medicine Testa, S., Pal, A., Subramanian, A., Varma, S., Tang, J. P., Graham, D., Arfan, S., Pan, M., Bui, N. Q., Ganjoo, K. N., Dry, S., Huang, P., van de Rijn, M., Jiang, W., Kalbasi, A., Moding, E. J. 2025; 17 (1): 89

  Abstract

  The FDA approval of T cell receptor-engineered T cells (TCR-T) for synovial sarcoma demonstrates the potential for adoptive T cell therapies (ACTs) in solid tumors. However, the paucity of tumor-associated targets without expression in normal tissues remains a major bottleneck, especially in rare cancer subtypes.We developed a comprehensive computational pipeline called SCAN-ACT that leverages single-cell RNA sequencing and multi-omics data from tumor and normal tissues to nominate and prioritize putative targets for both chimeric antigen receptor (CAR)- and TCR-T cells. For surface membrane targets, SCAN-ACT proposes monospecific targets and potential target pairs for bispecific Boolean logic-gated CAR T cells. For peptide-MHC targets, SCAN-ACT proposes intracellular peptides bound to a diverse set of human leukocyte antigens. Selected targets were validated experimentally by protein expression and for peptide-MHC binding.We applied the SCAN-ACT pipeline to soft tissue sarcoma (STS), analyzing 986,749 single cells to identify and prioritize 395 monospecific CAR-T targets, 14,192 bispecific CAR-T targets, and 5020 peptide-MHC targets for TCR-T cells. Proposed targets and target pairs reflected the mesenchymal, neuronal, and hematopoietic ontogeny of STS. We further validated SCAN-ACT in glioblastoma revealing its versatility.This work provides a robust data repository along with a web-based and user-friendly set of analysis tools to accelerate ACT development for solid tumors ( https://scanact.stanford.edu/ ).

  View details for DOI 10.1186/s13073-025-01514-9

  View details for PubMedID 40814001

  View details for PubMedCentralID PMC12351953

• Expanding the cytokine receptor alphabet reprograms T cells into diverse states. Nature Zhao, Y., Ogishi, M., Pal, A., Su, L. L., Tao, P., Jiang, H., Rodriguez, G. E., Chen, X., Sun, Q., Rysavy, L. W., Limsuwannarot, S., Waghray, D., Kalbasi, A., Garcia, K. C. 2025

  Abstract

  T cells respond to cytokines through receptor dimers that have been selected over the course of evolution to activate canonical JAK-STAT signalling and gene expression programs1. However, the potential combinatorial diversity of JAK-STAT receptor pairings can be expanded by exploring the untapped biology of alternative non-natural pairings. Here we exploited the common γ chain (γc) receptor as a shared signalling hub on T cells and enforced the expression of both natural and non-natural heterodimeric JAK-STAT receptor pairings using an orthogonal cytokine receptor platform2-4 to expand the γc signalling code. We tested receptors from γc cytokines as well as interferon, IL-10 and homodimeric receptor families that do not normally pair with γc or are not naturally expressed on T cells. These receptors simulated their natural counterparts but also induced contextually unique transcriptional programs. This led to distinct T cell fates in tumours, including myeloid-like T cells with phagocytic capacity driven by orthogonal GSCFR (oGCSFR), and type 2 cytotoxic T (TC2) and helper T (TH2) cell differentiation driven by orthogonal IL-4R (o4R). T cells with orthogonal IL-22R (o22R) and oGCSFR, neither of which are natively expressed on T cells, exhibited stem-like and exhaustion-resistant transcriptional and chromatin landscapes, enhancing anti-tumour properties. Non-native receptor pairings and their resultant JAK-STAT signals open a path to diversifying T cell states beyond those induced by natural cytokines.

  View details for DOI 10.1038/s41586-025-09393-1

  View details for PubMedID 40804519

  View details for PubMedCentralID 5947856

• Incomplete Cancer Surgery Correlates With Loss of Immune Surveillance and Hyper-Progression of Disease. Journal of surgical oncology Fine, S. A., Lim, S. Y., Siena, N. M., de Jesus, A. B., Goh, T., Markus, L., Russell, T. A., Kendal, J. K., Lofftus, S. Y., Shehata, M. S., Dao, H. B., Lee, A., Klingbeil, K. D., Kadera, B. E., Chmielowski, B., Nelson, S. D., Dry, S. M., Bernthal, N. M., Singh, A. S., Reddy, V. K., Kalbasi, A., Wessel, L. E., Prins, R. M., Eilber, F. R., Eilber, F. C., McCaw, T. R., Crompton, J. G. 2025

  Abstract

  BACKGROUND: Surgery is potentially curative for solid cancers; however, in cases of incomplete surgery, the impact of surgery on immune surveillance in the residual tumor microenvironment is not known. We sought to understand how surgery impacts immune populations in a residual tumor and correlates with overall survival in patients with primary pleomorphic liposarcoma.METHODS: This retrospective cohort study was conducted by searching the UCLA Sarcoma Program database for all patients with a histologic diagnosis of primary pleomorphic liposarcoma from 1995 to 2015. Patient follow-up was carried out through 2021. Patients were stratified by completeness of initial surgery: microscopically complete (R0), microscopically incomplete (R1), and grossly incomplete (R2). Six out of seven patients with an initial R2 resection underwent short-interval re-resection to negative margins within 120 days (R2-to-R0). We used immunofluorescence microscopy to characterize changes in immune populations of the tumor microenvironment.RESULTS: On multivariate analysis of this 32-patient cohort, age, tumor size, and R2-to-R0 resection were significantly associated with mortality. The hazard ratio for mortality after R2-to-R0 resection was 109 (p value<0.01). The median overall survival for patients with R2-to-R0 resection was 2.0 years compared to 8.5 years for an upfront R0 resection (p value<0.001). Immunofluorescence on four pairs of initial and re-resected tumors revealed a postoperative accumulation of suppressive myeloid and T regulatory immune populations in the residual microenvironment.DISCUSSION: We found that an initial incomplete surgery correlated with the accumulation of suppressive immune populations in the residual tumor microenvironment and mortality-a phenomenon we call hyper-progression of disease. Our findings have implications for therapeutically targeting immunosuppressive populations in the perioperative period to improve patient survival.

  View details for DOI 10.1002/jso.70023

  View details for PubMedID 40631605

• Association of Histologic Subtype With Radiation Response and Survival Outcomes in Synovial Sarcoma. Advances in radiation oncology Matsui, J. K., Jackson, S., Fang, J., Mohler, D. G., Steffner, R. J., Avedian, R. S., Charville, G. W., Rijn, M. v., Million, L., Chin, A. L., Hiniker, S. M., Kalbasi, A., Moding, E. J. 2025; 10 (3): 101718

  Abstract

  Synovial sarcoma (SS) is a rare, aggressive soft tissue malignancy that is divided into biphasic and monophasic histologic subtypes. In addition to surgical resection, radiation therapy (RT) improves local control in patients at higher risk of recurrence. This study aimed to investigate the impact of histologic subtype on radiation response and survival outcomes in patients treated with RT as part of definitive management.We retrospectively identified patients with SS treated with RT and surgical resection from 1997 to 2020 at Stanford Medical Center. We assessed the association between histologic subtypes (biphasic vs monophasic) and response to preoperative RT based on imaging and pathology. Volumetric response was calculated using the pre-RT and post-RT/preoperative postcontrast T1-weighted magnetic resonance imaging images. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Univariable and multivariable analyses were conducted using Cox regression models. Variables for univariable and multivariable analyses included age, histologic subtypes, tumor location, tumor size, margin status, chemotherapy, and performance status.In our study, 50 patients met the inclusion criteria. The median age was 34.8 years at diagnosis, and 36% (n = 18) received concurrent chemotherapy. Biphasic (n = 18, 36%) and monophasic (n = 32, 64%) tumors exhibited significant differences in negative margin status (94% vs 66%, P = .036). Of the 22 patients who underwent preoperative RT, 15 patients had pre-RT and post-RT imaging to assess volumetric changes. Biphasic tumors demonstrated less necrosis at the time of surgical resection but a significantly greater volumetric decrease with preoperative RT (42% vs 5%, P = .004). PFS and OS were superior in biphasic tumors (P = .003 and P = .009, respectively). Multivariable analyses identified histologic subtypes (monophasic vs biphasic) as a significant factor impacting PFS (HR, 5.65; 95% CI, 1.78-17.91; P = .003).Biphasic tumors exhibit an improved volumetric response to preoperative RT and improved outcomes. These findings underscore the importance of considering histology when tailoring treatment for patients with SS.

  View details for DOI 10.1016/j.adro.2025.101718

  View details for PubMedID 40092155

  View details for PubMedCentralID PMC11910705

• Proceedings of the National Cancer Institute Workshop on combining immunotherapy with radiotherapy: challenges and opportunities for clinical translation. The Lancet. Oncology Morris, Z. S., Demaria, S., Monjazeb, A. M., Formenti, S. C., Weichselbaum, R. R., Welsh, J., Enderling, H., Schoenfeld, J. D., Brody, J. D., McGee, H. M., Mondini, M., Kent, M. S., Young, K. H., Galluzzi, L., Karam, S. D., Theelen, W. S., Chang, J. Y., Huynh, M. A., Daib, A., Pitroda, S., Chung, C., Serre, R., Grassberger, C., Deng, J., Sodji, Q. H., Nguyen, A. T., Patel, R. B., Krebs, S., Kalbasi, A., Kerr, C., Vanpouille-Box, C., Vick, L., Aguilera, T. A., Ong, I. M., Herrera, F., Menon, H., Smart, D., Ahmed, J., Gartrell, R. D., Roland, C. L., Fekrmandi, F., Chakraborty, B., Bent, E. H., Berg, T. J., Hutson, A., Khleif, S., Sikora, A. G., Fong, L. 2025; 26 (3): e152-e170

  Abstract

  Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear. The National Cancer Institute-Immuno-Oncology Translational Network-Society for Immunotherapy of Cancer-American Association of Immunology Workshop on Combining Immunotherapy with Radiotherapy was convened to identify and prioritise opportunities and challenges for radiotherapy and immunotherapy combinations. Sessions examined the immune effects of radiation, barriers to anti-tumour immune response, previous clinical trial data, immunological and computational assessment of response, and next-generation radiotherapy-immunotherapy combinations. Panel recommendations included: developing and implementing patient selection and biomarker-guided approaches; applying mechanistic understanding to optimise delivery of radiotherapy and selection of immunotherapies; using rigorous preclinical models including companion animal studies; embracing data sharing and standardisation, advanced modelling, and multidisciplinary cross-institution collaboration; interrogating clinical data, including negative trials; and incorporating novel clinical endpoints and trial designs.

  View details for DOI 10.1016/S1470-2045(24)00656-9

  View details for PubMedID 40049206

• Association of Histologic Subtype With Radiation Response and Survival Outcomes in Synovial Sarcoma ADVANCES IN RADIATION ONCOLOGY Matsui, J. K., Jackson, S., Fang, J., Mohler, D. G., Steffner, R. J., Charville, G. W., van de Rijn, M., Million, L., Chin, A. L., Hiniker, S. M., Kalbasi, A., Moding, E. J. 2025; 10 (3)

  View details for DOI 10.1016/j.adro.2025.101718

  View details for Web of Science ID 001436810100001

• IL-9 as a naturally orthogonal cytokine with optimal JAK/STAT signaling for engineered T cell therapy. bioRxiv : the preprint server for biology Jiang, H., Limsuwannarot, S., Kulhanek, K. R., Pal, A., Rysavy, L. W., Su, L., Labiad, O., Testa, S., Ogana, H., Waghray, D., Tao, P., Jude, K. M., Seet, C. S., Crooks, G. M., Moding, E. J., Garcia, K. C., Kalbasi, A. 2025

  Abstract

  Arming T cells with a synthetically orthogonal IL-9 receptor (o9R) permits facile engraftment and potent anti-tumor functions. We considered whether the paucity of natural IL-9R expression could be exploited for T cell immunotherapy given that, in mice, high doses of IL-9 were well-tolerated without discernible immune modulation. Compared to o9R, T cells engineered with IL-9R exhibit superior tissue infiltration, stemness, and anti-tumor activity. These qualities are consistent with a stronger JAK/STAT signal, which in addition to STAT1/3/5, unexpectedly includes STAT4 (canonically associated with IL-12 but not common γ-chain cytokines). IL-9R T cells are exquisitely sensitive to perturbations of proximal signaling, including structure-guided attenuation, amplification, and rebalancing of JAK/STAT signals. Biased IL-9R mutants uncover STAT1 as a rheostat between proliferative stem-like and terminally differentiated effector states. In summary, we identify native IL-9/IL-9R as a natural cytokine-receptor pair with near-orthogonal qualities and an optimal JAK/STAT signaling profile for engineered T cell therapy.

  View details for DOI 10.1101/2025.01.15.633105

  View details for PubMedID 39868284

  View details for PubMedCentralID PMC11760723

• Evolutionary Pressures Shape Undifferentiated Pleomorphic Sarcoma Development and Radiotherapy Response. Cancer research Blomain, E., Soudi, S., Wang, Z., Somani, A., Subramanian, A., Nouth, S. C., Oladipo, E., New, C., Kenney, D. E., Nemat-Gorgani, N., Kindler, T., Avedian, R. S., Steffner, R. J., Mohler, D. G., Hiniker, S. M., Chin, A. L., Kalbasi, A., Binkley, M. S., Fried, M., Gaida, M. M., van de Rijn, M., Moding, E. J. 2025

  Abstract

  Radiotherapy is an integral component in the treatment of many types of cancer, with approximately half of cancer patients receiving radiotherapy. Systemic therapy applies pressure that can select for resistant tumor subpopulations, underscoring the importance of understanding how radiation impacts tumor evolution to improve treatment outcomes. We integrated temporal genomic profiling of 120 spatially distinct tumor regions from 20 patients with undifferentiated pleomorphic sarcomas (UPS), longitudinal circulating tumor DNA (ctDNA) analysis, and evolutionary biology computational pipelines to study UPS evolution during tumorigenesis and in response to radiotherapy. Most unirradiated UPS displayed initial linear evolution followed by subsequent branching evolution with distinct mutational processes during early and late development. Metrics of genetic divergence between regions provided evidence of strong selection pressures during UPS development that further increased during radiotherapy. Subclone abundance changed following radiotherapy with subclone contraction tied to alterations in calcium signaling, and inhibiting calcium transporters radiosensitized sarcoma cells. Finally, ctDNA analysis accurately measured subclone abundance and enabled non-invasive monitoring of subclonal changes. These results demonstrate that radiation exerts selective pressures on UPS and suggest that targeting radioresistant subclonal populations could improve outcomes after radiotherapy.

  View details for DOI 10.1158/0008-5472.CAN-24-3281

  View details for PubMedID 39808162

• Gold-siRNA supraclusters enhance the anti-tumor immune response of stereotactic ablative radiotherapy at primary and metastatic tumors. Nature biotechnology Jiang, Y., Cao, H., Deng, H., Guan, L., Langthasa, J., Colburg, D. R., Melemenidis, S., Cotton, R. M., Aleman, J., Wang, X. J., Graves, E. E., Kalbasi, A., Pu, K., Rao, J., Le, Q. T. 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

• 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 Baldini, E. H., Guadagnolo, B. A., Salerno, K. E., Chung, P., Bishop, A. J., Kalbasi, A., Miah, A., Bedi, M., Harris, J. P., Petersen, I., Gillham, C., Wiltink, L. M., Alektiar, K. M., Haas, R. L., Kirsch, D. G. 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

• Effect of palliative radiation dose on symptom response in metastatic sarcomas. Clinical and translational radiation oncology Matsui, J. K., Jackson, S., Fang, J., Million, L., Chin, A. L., Hiniker, S. M., Kalbasi, A., Moding, E. J. 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

• Targeted Bias: The Next Swing at IL2 Therapy. Cancer discovery Kulhanek, K. R., Kalbasi, A. 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

• Letting Radiation Therapy "Make Its Bones". International journal of radiation oncology, biology, physics Rao, P., Kalbasi, A. 2024; 118 (5): 1161

  View details for DOI 10.1016/j.ijrobp.2023.10.021

  View details for PubMedID 38492964

• Antitumor Immune Responses in B2M-Deficient Cancers. Cancer immunology research Torrejon, D. Y., Galvez, M., Abril-Rodriguez, G., Campbell, K. M., Medina, E., Vega-Crespo, A., Kalbasi, A., Comin-Anduix, B., Ribas, A. 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

• Patterns of local recurrence and risk of skin recurrence in soft tissue sarcomas after surgical resection. Practical radiation oncology Ewongwo, A., Oladipo, E. D., Hui, C., Avedian, R. S., Steffner, R. J., Mohler, D. G., Kalbasi, A., Chin, A. L., Million, L., Hiniker, S. M., Moding, E. J. 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

• IGF2BP3 as a Prognostic Biomarker in Well-Differentiated/Dedifferentiated Liposarcoma. Cancers Klingbeil, K. D., Tang, J. P., Graham, D. S., Lofftus, S. Y., Jaiswal, A. K., Lin, T. L., Frias, C., Chen, L. Y., Nakasaki, M., Dry, S. M., Crompton, J. G., Eilber, F. C., Rao, D. S., Kalbasi, A., Kadera, B. E. 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

• Adopting shorter radiation regimens: rules of engagement for sarcoma. The Lancet. Oncology Kalbasi, A. 2023; 24 (2): e70

  View details for DOI 10.1016/S1470-2045(23)00008-6

  View details for PubMedID 36725150

• Lifelong Imaging Surveillance is Indicated for Patients with Primary Retroperitoneal Liposarcoma. Annals of surgical oncology Eckardt, M. A., Graham, D. S., Klingbeil, K. D., Lofftus, S. Y., McCaw, T. R., Bailey, M. J., Goldring, C. J., Kendal, J. K., Kadera, B. E., Nelson, S. D., Dry, S. M., Kalbasi, A. K., Singh, A. S., Chmielowski, B., Eilber, F. R., Eilber, F. C., Crompton, J. G. 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

• 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 Stern, L. A., Gholamin, S., Moraga, I., Yang, X., Saravanakumar, S., Cohen, J. R., Starr, R., Aguilar, B., Salvary, V., Hibbard, J. C., Kalbasi, A., Shepphird, J. K., O'Hearn, J., Garcia, K. C., Brown, C. E. 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

• Infrequent chromosomal loss and recurrent gains lead to imbalanced expression of HLA genes in melanoma Campbell, K. M., Saco, J., Medina, E., Amouzgar, M., Pfeiffer, S. M., Gonzalez, C. R., Steiner, G., Champhekar, A., Saus, C., Zaretsky, J., Rodriguez, G., Vega-Crespo, A., Carretero, I., Tariveranmoshabad, M., Kalbasi, A., Spencer, C., Skidmore, Z. L., Griffith, M., Griffith, O. L., Wells, D. K., Ribas, A. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509509177

• Human chimeric orthogonal IL9 receptor signaling promotes stemness and polyfunctionality for adoptive T cell therapy of cancer Tariveranmoshabad, M., Su, L. L., Sun, A. L., Picton, L. K., Ribas, A., Garcia, K., Kalbasi, A. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509507393

• Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature Kalbasi, A., Siurala, M., Su, L. L., Tariveranmoshabad, M., Picton, L. K., Ravikumar, P., Li, P., Lin, J., Escuin-Ordinas, H., Da, T., Kremer, S. V., Sun, A. L., Castelli, S., Agarwal, S., Scholler, J., Song, D., Rommel, P. C., Radaelli, E., Young, R. M., Leonard, W. J., Ribas, A., June, C. H., Garcia, K. C. 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

• Orthogonal IL-9 receptor signaling reprograms T cells to obviate conditioning chemotherapy before adoptive cell therapy. Kalbasi, A., Tariveranmoshabad, M., Escuin-Ordenas, H., Kremer, S., Su, L. L., Picton, L., Parisi, A., Garcia, C., Ribas, A. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000680263500048

• PAK4 inhibition improves PD-1 blockade immunotherapy. Nature cancer Abril-Rodriguez, G., Torrejon, D. Y., Liu, W., Zaretsky, J. M., Nowicki, T. S., Tsoi, J., Puig-Saus, C., Baselga-Carretero, I., Medina, E., Quist, M. J., Garcia, A. J., Senapedis, W., Baloglu, E., Kalbasi, A., Cheung-Lau, G., Berent-Maoz, B., Comin-Anduix, B., Hu-Lieskovan, S., Wang, C. Y., Grasso, C. S., Ribas, A. 2020; 1 (1): 46-58

  Abstract

  Lack of tumor infiltration by immune cells is the main mechanism of primary resistance to programmed cell death protein 1 (PD-1) blockade therapies for cancer. It has been postulated that cancer cell-intrinsic mechanisms may actively exclude T cells from tumors, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. Here, we show that p21-activated kinase 4 (PAK4) is enriched in non-responding tumor biopsies with low T cell and dendritic cell infiltration. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD-1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of anti-PD-1 with the PAK4 inhibitor KPT-9274 improved anti-tumor response compared with anti-PD-1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and a lack of response to PD-1 blockade, which could be reversed with PAK4 inhibition.

  View details for DOI 10.1038/s43018-019-0003-0

  View details for PubMedID 34368780

  View details for PubMedCentralID PMC8340852

• Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma. Science translational medicine Kalbasi, A., Tariveranmoshabad, M., Hakimi, K., Kremer, S., Campbell, K. M., Funes, J. M., Vega-Crespo, A., Parisi, G., Champekar, A., Nguyen, C., Torrejon, D., Shin, D., Zaretsky, J. M., Damoiseaux, R. D., Speiser, D. E., Lopez-Casas, P. P., Quintero, M., Ribas, A. 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

• Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma. Cancer cell Grasso, C. S., Tsoi, J., Onyshchenko, M., Abril-Rodriguez, G., Ross-Macdonald, P., Wind-Rotolo, M., Champhekar, A., Medina, E., Torrejon, D. Y., Shin, D. S., Tran, P., Kim, Y. J., Puig-Saus, C., Campbell, K., Vega-Crespo, A., Quist, M., Martignier, C., Luke, J. J., Wolchok, J. D., Johnson, D. B., Chmielowski, B., Hodi, F. S., Bhatia, S., Sharfman, W., Urba, W. J., Slingluff, C. L., Diab, A., Haanen, J. B., Algarra, S. M., Pardoll, D. M., Anagnostou, V., Topalian, S. L., Velculescu, V. E., Speiser, D. E., Kalbasi, A., Ribas, A. 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

• Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade. Cancer discovery Torrejon, D. Y., Abril-Rodriguez, G., Champhekar, A. S., Tsoi, J., Campbell, K. M., Kalbasi, A., Parisi, G., Zaretsky, J. M., Garcia-Diaz, A., Puig-Saus, C., Cheung-Lau, G., Wohlwender, T., Krystofinski, P., Vega-Crespo, A., Lee, C. M., Mascaro, P., Grasso, C. S., Berent-Maoz, B., Comin-Anduix, B., Hu-Lieskovan, S., Ribas, A. 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

• 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 Kalbasi, A., Kamrava, M., Chu, F. I., Telesca, D., Van Dams, R., Yang, Y., Ruan, D., Nelson, S. D., Dry, S. M., Hernandez, J., Chmielowski, B., Singh, A. S., Bukata, S. V., Bernthal, N. M., Steinberg, M. L., Weidhaas, J. B., Eilber, F. C. 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

• Adopting shorter radiation regimens: rules of engagement for sarcoma LANCET ONCOLOGY Kalbasi, A. 2020; 24 (2): E70

  View details for Web of Science ID 000931567800001

• Tumour-intrinsic resistance to immune checkpoint blockade. Nature reviews. Immunology Kalbasi, A., Ribas, A. 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

• Interleukin 32 expression in human melanoma. Journal of translational medicine Paz, H., Tsoi, J., Kalbasi, A., Grasso, C. S., McBride, W. H., Schaue, D., Butterfield, L. H., Maurer, D. M., Ribas, A., Graeber, T. G., Economou, J. S. 2019; 17 (1): 113

  Abstract

  Various proinflammatory cytokines can be detected within the melanoma tumor microenvironment. Interleukin 32 (IL32) is produced by T cells, NK cells and monocytes/macrophages, but also by a subset of melanoma cells. We sought to better understand the biology of IL32 in human melanoma.We analyzed RNA sequencing data from 53 in-house established human melanoma cell lines and 479 melanoma tumors from The Cancer Genome Atlas dataset. We evaluated global gene expression patterns associated with IL32 expression. We also evaluated the impact of proinflammatory molecules TNFα and IFNγ on IL32 expression and dedifferentiation in melanoma cell lines in vitro. In order to study the transcriptional regulation of IL32 in these cell lines, we cloned up to 10.5 kb of the 5' upstream region of the human IL32 gene into a luciferase reporter vector.A significant proportion of established human melanoma cell lines express IL32, with its expression being highly correlated with a dedifferentiation genetic signature (high AXL/low MITF). Non IL32-expressing differentiated melanoma cell lines exposed to TNFα or IFNγ can be induced to express the three predominant isoforms (α, β, γ) of IL32. Cis-acting elements within this 5' upstream region of the human IL32 gene appear to govern both induced and constitutive gene expression. In the tumor microenvironment, IL32 expression is highly correlated with genes related to T cell infiltration, and also positively correlates with high AXL/low MITF dedifferentiated gene signature.Expression of IL32 in human melanoma can be induced by TNFα or IFNγ and correlates with a treatment-resistant dedifferentiated genetic signature. Constitutive and induced expression are regulated, in part, by cis-acting sequences within the 5' upstream region.

  View details for DOI 10.1186/s12967-019-1862-y

  View details for PubMedID 30953519

  View details for PubMedCentralID PMC6449995

• A Pilot Trial of the Combination of Transgenic NY-ESO-1-reactive Adoptive Cellular Therapy with Dendritic Cell Vaccination with or without Ipilimumab. Clinical cancer research : an official journal of the American Association for Cancer Research Nowicki, T. S., Berent-Maoz, B., Cheung-Lau, G., Huang, R. R., Wang, X., Tsoi, J., Kaplan-Lefko, P., Cabrera, P., Tran, J., Pang, J., Macabali, M., Garcilazo, I. P., Carretero, I. B., Kalbasi, A., Cochran, A. J., Grasso, C. S., Hu-Lieskovan, S., Chmielowski, B., Comin-Anduix, B., Singh, A., Ribas, A. 2019; 25 (7): 2096-2108

  Abstract

  Transgenic adoptive cell therapy (ACT) targeting the tumor antigen NY-ESO-1 can be effective for the treatment of sarcoma and melanoma. Preclinical models have shown that this therapy can be improved with the addition of dendritic cell (DC) vaccination and immune checkpoint blockade. We studied the safety, feasibility, and antitumor efficacy of transgenic ACT with DC vaccination, with and without CTLA-4 blockade with ipilimumab.Freshly prepared autologous NY-ESO-1-specific T-cell receptor (TCR) transgenic lymphocytes were adoptively transferred together with NY-ESO-1 peptide-pulsed DC vaccination in HLA-A2.1-positive subjects alone (ESO, NCT02070406) or with ipilimumab (INY, NCT01697527) in patients with advanced sarcoma or melanoma.Six patients were enrolled in the ESO cohort, and four were enrolled in the INY cohort. Four out of six patients treated per ESO (66%), and two out of four patients treated per INY (50%) displayed evidence of tumor regression. Peripheral blood reconstitution with NY-ESO-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Tracking of transgenic T cells to the tumor sites was demonstrated in on-treatment biopsies via TCR sequencing. Multiparametric mass cytometry of transgenic cells demonstrated shifting of transgenic cells from memory phenotypes to more terminally differentiated effector phenotypes over time.ACT of fresh NY-ESO-1 transgenic T cells prepared via a short ex vivo protocol and given with DC vaccination, with or without ipilimumab, is feasible and results in transient antitumor activity, with no apparent clinical benefit of the addition of ipilimumab. Improvements are needed to maintain tumor responses.

  View details for DOI 10.1158/1078-0432.CCR-18-3496

  View details for PubMedID 30573690

  View details for PubMedCentralID PMC6445780

• SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study CANCER DISCOVERY Ribas, A., Medina, T., Kummar, S., Amin, A., Kalbasi, A., Drabick, J. J., Barve, M., Daniels, G. A., Wong, D. J., Schmidt, E., Candia, A. F., Coffmanm, R. L., Leung, A. C. F., Janssen, R. S. 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

• Antigen Presentation Keeps Trending in Immunotherapy Resistance. Clinical cancer research : an official journal of the American Association for Cancer Research Kalbasi, A., Ribas, A. 2018; 24 (14): 3239-3241

  Abstract

  Through a gain-of-function kinome screen, MEX3B was identified as a mediator of resistance to T-cell immunotherapy not previously identified using CRISPR-based screens. MEX3B is a posttranscriptional regulator of HLA-A, validating the critical role of tumor-intrinsic antigen presentation in T-cell immunotherapy and indicating a new putative molecular target. Clin Cancer Res; 24(14); 3239-41. ©2018 AACRSee related article by Huang et al., p. 3366.

  View details for DOI 10.1158/1078-0432.CCR-18-0698

  View details for PubMedID 29674509

  View details for PubMedCentralID PMC6050090

• Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations. Cancer discovery Shin, D. S., Zaretsky, J. M., Escuin-Ordinas, H., Garcia-Diaz, A., Hu-Lieskovan, S., Kalbasi, A., Grasso, C. S., Hugo, W., Sandoval, S., Torrejon, D. Y., Palaskas, N., Rodriguez, G. A., Parisi, G., Azhdam, A., Chmielowski, B., Cherry, G., Seja, E., Berent-Maoz, B., Shintaku, I. P., Le, D. T., Pardoll, D. M., Diaz, L. A., Tumeh, P. C., Graeber, T. G., Lo, R. S., Comin-Anduix, B., Ribas, A. 2017; 7 (2): 188-201

  Abstract

  Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair-deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in The Cancer Genome Atlas confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.A key functional result from somatic JAK1/2 mutations in a cancer cell is the inability to respond to interferon gamma by expressing PD-L1 and many other interferon-stimulated genes. These mutations result in a genetic mechanism for the absence of reactive PD-L1 expression, and patients harboring such tumors would be unlikely to respond to PD-1 blockade therapy. Cancer Discov; 7(2); 188-201. ©2016 AACR.See related commentary by Marabelle et al., p. 128This article is highlighted in the In This Issue feature, p. 115.

  View details for DOI 10.1158/2159-8290.CD-16-1223

  View details for PubMedID 27903500

  View details for PubMedCentralID PMC5296316

• Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research Kalbasi, A., Komar, C., Tooker, G. M., Liu, M., Lee, J. W., Gladney, W. L., Ben-Josef, E., Beatty, G. L. 2017; 23 (1): 137-148

  Abstract

  Local tumor growth is a major cause of morbidity and mortality in nearly 30% of patients with pancreatic ductal adenocarcinoma (PDAC). Radiotherapy is commonly used for local disease control in PDAC, but its efficacy is limited. We studied the impact of selectively intervening on radiotherapy-induced inflammation as an approach to overcome resistance to radiotherapy in PDAC.PDAC cell lines derived from primary pancreatic tumors arising spontaneously in KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx-1 Cre mice were implanted into syngeneic mice and tumors were focally irradiated using the Small Animal Radiation Research Platform (SARRP). We determined the impact of depleting T cells and Ly6C+ monocytes as well as inhibiting the chemokine CCL2 on radiotherapy efficacy. Tumors were analyzed by flow cytometry and IHC to detect changes in leukocyte infiltration, tumor viability, and vascularity. Assays were performed on tumor tissues to detect cytokines and gene expression.Ablative radiotherapy alone had minimal impact on PDAC growth but led to a significant increase in CCL2 production by tumor cells and recruitment of Ly6C+CCR2+ monocytes. A neutralizing anti-CCL2 antibody selectively inhibited radiotherapy-dependent recruitment of monocytes/macrophages and delayed tumor growth but only in combination with radiotherapy (P < 0.001). This antitumor effect was associated with decreased tumor proliferation and vascularity. Genetic deletion of CCL2 in PDAC cells also improved radiotherapy efficacy.PDAC responds to radiotherapy by producing CCL2, which recruits Ly6C+CCR2+ monocytes to support tumor proliferation and neovascularization after radiotherapy. Disrupting the CCL2-CCR2 axis in combination with radiotherapy holds promise for improving radiotherapy efficacy in PDAC. Clin Cancer Res; 23(1); 137-48. ©2016 AACR.

  View details for DOI 10.1158/1078-0432.CCR-16-0870

  View details for PubMedID 27354473

  View details for PubMedCentralID PMC5195913

• (99)mTc-phytate as a diagnostic probe for assessing inflammatory reaction in malignant tumors NUCLEAR MEDICINE COMMUNICATIONS Fernandes, R. S., Mota, L. G., Kalbasi, A., Moghbel, M., Werner, T. J., Alavi, A., Rubello, D., Cardoso, V. N., de Barros, A. L. 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

• Dose-Escalated Irradiation and Overall Survival in Men With Nonmetastatic Prostate Cancer. JAMA oncology Kalbasi, A., Li, J., Berman, A., Swisher-McClure, S., Smaldone, M., Uzzo, R. G., Small, D. S., Mitra, N., Bekelman, J. E. 2015; 1 (7): 897-906

  Abstract

  In 5 published randomized clinical trials, dose-escalated external-beam radiation therapy (EBRT) for prostate cancer resulted in improved biochemical and local control. However, scarce evidence addresses whether dose escalation improves overall survival.To examine the association between dose-escalated EBRT and overall survival among men with nonmetastatic prostate cancer.We conducted a retrospective, nonrandomized comparative effectiveness study of dose-escalated vs standard-dose EBRT for prostate cancer diagnosed from 2004 to 2006 using the National Cancer Database (NCDB), which includes data from patients treated at Commission on Cancer-accredited community, academic, and comprehensive cancer facilities. Three cohorts were evaluated: men with low-risk (n = 12,229), intermediate-risk (n = 16,714), or high-risk (n = 13,538) prostate cancer.We categorized patients in each risk cohort into 2 treatment groups: standard-dose (from 68.4 Gy to <75.6 Gy) or dose-escalated (≥75.6 Gy to 90 Gy) EBRT (1 Gy = 100 rad).We compared overall survival between treatment groups in each analytic cohort using Cox proportional hazard models with an inverse probability weighted propensity score (IPW-PS) approach. In secondary analyses, we evaluated dose response for survival.Dose-escalated EBRT was associated with improved survival in the intermediate-risk (IPW-PS adjusted hazard ratio [HR], 0.84; 95% CI, 0.80-0.88; P < .001) and high-risk groups (HR, 0.82; 95% CI, 0.78-0.85; P < .001) but not the low-risk group (HR, 0.98; 95% CI, 0.92-1.05; P = .54). For every incremental increase of about 2 Gy in dose, there was a 7.8% (95% CI, 5.4%-10.2%; P < .001) and 6.3% (95% CI, 3.3%-9.1%; P < .001) reduction in the hazard of death for intermediate- and high-risk patients, respectively.Dose-escalated EBRT is associated with improved overall survival in men with intermediate- and high-risk prostate cancer but not low-risk prostate cancer. These results add to the evidence questioning aggressive local treatment strategies in men with low-risk prostate cancer but supporting such treatment in men with greater disease severity.

  View details for DOI 10.1001/jamaoncol.2015.2316

  View details for PubMedID 26181727

• Radiation and immunotherapy: a synergistic combination. The Journal of clinical investigation Kalbasi, A., June, C. H., Haas, N., Vapiwala, N. 2013; 123 (7): 2756-63

  Abstract

  Immunotherapy can be an effective treatment for metastatic cancer, but a significant subpopulation will not respond, likely due to the lack of antigenic mutations or the immune-evasive properties of cancer. Likewise, radiation therapy (RT) is an established cancer treatment, but local failures still occur. Clinical observations suggest that RT may expand the therapeutic reach of immunotherapy. We examine the immunobiologic and clinical rationale for combining RT and immunotherapy, two modalities yet to be used in combination in routine practice. Preclinical data indicate that RT can potentiate the systemic efficacy of immunotherapy, while activation of the innate and adaptive immune system can enhance the local efficacy of RT.

  View details for DOI 10.1172/JCI69219

  View details for PubMedID 23863633

  View details for PubMedCentralID PMC4101987

• Prevention of interleukin-2 withdrawal-induced apoptosis in lymphocytes retrovirally cotransduced with genes encoding an antitumor T-cell receptor and an antiapoptotic protein. Journal of immunotherapy (Hagerstown, Md. : 1997) Kalbasi, A., Shrimali, R. K., Chinnasamy, D., Rosenberg, S. A. 2010; 33 (7): 672-83

  Abstract

  Adoptive cell transfer using autologous tumor infiltrating lymphocytes or lymphocytes transduced with antitumor T-cell receptor (TCR) is an effective therapy for patients with metastatic melanoma. A limiting factor in the effectiveness of this treatment is the apoptosis of the transferred cells when Interleukin-2 (IL-2) administration is withdrawn. In an attempt to improve persistence of the transferred lymphocytes, we cotransduced human peripheral blood lymphocytes with retroviruses encoding Bcl-2 or Bcl-xL, antiapoptotic genes of the BCL2 family, and the MART-1 melanoma tumor antigen-specific TCR, DMF5. Lymphocytes were cotransduced with 38% to 64% cotransduction efficiency, and exhibited a marked delay in apoptosis after IL-2 withdrawal. Cotransduction with Bcl-2 or Bcl-xL did not affect cytokine secretion or lytic ability of the DMF5-transduced lymphocytes. After 5 days of IL-2 withdrawal, cotransduced lymphocytes produced similar levels of IFN-γ per cell as DMF5-alone transduced lymphocytes in response to tumor cells. Cotransduction did not alter the phenotype of lymphocytes with respect to a panel of T-cell differentiation markers. In a mouse model of melanoma, adoptively transferred T cells transduced with Bcl-2 persisted better in vivo at the site of tumor, 13 and 21 days after adoptive transfer (P=0.0064 and 0.041, respectively), with evidence of enrichment of the Bcl-2-transduced population over time (P<0.0001). Thus, by coexpressing Bcl-2 or Bcl-xL with a tumor-specific TCR, we have engineered a lymphocyte that resists apoptosis owing to IL-2 withdrawal without altering its tumor-specific function or phenotype, and thus may show improved antitumor effectiveness in vivo after cell transfer.

  View details for DOI 10.1097/CJI.0b013e3181e475cd

  View details for PubMedID 20664359

  View details for PubMedCentralID PMC6390957