Journal Articles

Experimental Immunotherapy

Preclinical and clinical cancer immunotherapy approaches

GMP-Grade Manufacturing of T Cells Engineered to Express a Defined gammadeltaTCR

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gamma9delta2T cells play a critical role in daily cancer immune surveillance by sensing cancer-mediated metabolic changes. However, a major limitation of the therapeutic application of gamma9delta2T cells is their diversity and regulation through innate co-receptors. In order to overcome natural obstacles of gamma9delta2T cells, we have developed the concept of T cells engineered to express a defined gammadeltaT cell receptor (TEGs). This next generation of chimeric antigen receptor engineered T (CAR-T) cells not only allows for targeting of hematological but also of solid tumors and, therefore, overcomes major limitations of many CAR-T and gammadeltaT cell strategies. Here, we report on the development of a robust manufacturing procedure of T cells engineered to express the high affinity Vgamma9Vdelta2T cell receptor (TCR) clone 5 (TEG001). We determined the best concentration of anti-CD3/CD28 activation and expansion beads, optimal virus titer, and cell density for retroviral transduction, and validated a Good Manufacturing Practice (GMP)-grade purification procedure by utilizing the CliniMACS system to deplete non- and poorly-engineered T cells. To the best of our knowledge, we have developed the very first GMP manufacturing procedure in which alphabetaTCR depletion is used as a purification method, thereby delivering untouched clinical grade engineered immune cells. This enrichment method is applicable to any engineered T cell product with a reduced expression of endogenous alphabetaTCRs. We report on release criteria and the stability of TEG001 drug substance and TEG001 drug product. The GMP-grade production procedure is now approved by Dutch authorities and allows TEG001 to be generated in cell numbers sufficient to treat patients within the approved clinical trial NTR6541. NTR6541 will investigate the safety and tolerability of TEG001 in patients with relapsed/refractory acute myeloid leukemia, high-risk myelodysplastic syndrome, and relapsed/refractory multiple myeloma.

Author Info: (1) Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. (2) Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht

Author Info: (1) Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. (2) Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. (3) Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. (4) Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. (5) Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. (6) Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. (7) Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands. (8) CRCINA, INSERM 1232, CNRS, Universite d'Angers, Universite de Nantes, Nantes, France. CHU de Nantes, Hotel Dieu, UTCG, Nantes, France. (9) CRCINA, INSERM 1232, CNRS, Universite d'Angers, Universite de Nantes, Nantes, France. CHU de Nantes, Hotel Dieu, UTCG, Nantes, France. (10) Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands. (11) Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands. (12) Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. (13) Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands.

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Breast Cancer Immunotherapy: An Update

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The immune system plays a major role in cancer surveillance. Harnessing its power to treat many cancers is now a reality that has led to cures in hopeless situations where no other solutions were available from traditional anticancer drugs. These spectacular achievements rekindled the oncology community's interest in extending the benefits to all cancers including breast cancer. The first section of this article reviews the biological foundations of the immune response to different subtypes of breast cancer and the ways cancer may overcome the immune attack leading to cancer disease. The second section is dedicated to the actual immune treatments including breast cancer vaccines, checkpoint inhibitors, monoclonal antibodies, and the "unconventional" immune role of chemotherapy.

Author Info: (1) Divisions of Hematology and Medical Oncology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA. (2) Department of Internal

Author Info: (1) Divisions of Hematology and Medical Oncology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA. (2) Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA. (3) Divisions of Hematology and Medical Oncology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA. (4) Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

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Immunotherapy resistance by inflammation-induced dedifferentiation

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A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T cell transfer therapy (ACT) to the MART-1 antigen, a phenomenon that had only been observed in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART-1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART-1 T-cell receptor expressing T cells or with TNFalpha, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation.

Author Info: (1) David Geffen School of Medicine, University of California Los Angeles. (2) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (3) University

Author Info: (1) David Geffen School of Medicine, University of California Los Angeles. (2) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (3) University of California Los Angeles. (4) Department of Molecular and Medical Pharmacology, University of California Los Angeles. (5) Surgical Oncology, University of California Los Angeles. (6) Hematology and Oncology, University of California Los Angeles. (7) Path & Lab Med-Anatomic Path, University of California Los Angeles. (8) 54-140 CHS, University of California Los Angeles. (9) Oncology, BioGraph 55, Inc. (10) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (11) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles aribas@mednet.ucla.edu.

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Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer

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BACKGROUND: Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. METHODS: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. RESULTS: Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p = 0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR = 0.23; p = 0.04). CONCLUSIONS: These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00005970 . Registered on July 5, 2000.

Author Info: (1) Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA. (2) Department of Pathology, Medicine and Dermatology, Columbia University Medical Center, New York, NY

Author Info: (1) Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA. (2) Department of Pathology, Medicine and Dermatology, Columbia University Medical Center, New York, NY, 10032, USA. (3) Department of Pathology, Medicine and Dermatology, Columbia University Medical Center, New York, NY, 10032, USA. (4) Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA. (5) Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA. (6) Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA. (7) Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA. (8) Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, 85259, USA. (9) Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, 32224, USA. (10) Sylvester Cancer Center, University of Miami, Miami, FL, 33136, USA. (11) Department of Medicine, Stanford University, Stanford, CA, 94305, USA. (12) Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, 32224, USA. (13) Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, 32224, USA. perez.edith@mayo.edu. (14) Department of Pathology, Medicine and Dermatology, Columbia University Medical Center, New York, NY, 10032, USA. rclynes@xencor.com. (15) Department of Immunology, Mayo Clinic, Jacksonville, FL, 32224, USA. knutson.keith@mayo.edu.

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PD-L1 assessment in pediatric rhabdomyosarcoma: a pilot study

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BACKGROUND: Rhabdomyosarcomas (RMSs) are the most frequent soft tissue sarcoma in children and adolescents, defined by skeletal muscle differentiation and the status of FOXO1 fusions. In pediatric malignancies, in particular RMS, scant and controversial observations are reported about PD-L1 expression as a putative biomarker and few immune checkpoint clinical trials are conducted. METHODS: PD-L1 assessment was evaluated by immunohistochemistry (IHC) utilizing two anti-PDL1 antibodies, in a pilot cohort of 25 RMS. Results were confirmed in primary and commercial RMS cell lines by cytofluorimetric analysis and IHC. RESULTS: PD-L1 expression was detectable, by both anti-PD-L1 antibodies, in the immune contexture of immune cells infiltrating and/or surrounding the tumor, in 15/25 (60%) RMS, while absent expression was observed in neoplastic cells. Flow cytometry analysis and PD-L1 IHC of commercial and primary RMS cell lines confirmed a very small percentage of PD-L1 positive-tumor cells, under the detection limits of conventional IHC. Interestingly, increased PD-L1 expression was observed in the immune contexture of 4 RMS cases post chemotherapy compared to their matched pre-treatment samples. CONCLUSION: Here we identify a peculiar pattern of PD-L1 expression in our RMS series with scanty positive-tumor cells detected by flow cytometry, and recurrent expression in the immune cells surrounding or infiltrating the tumor burden.

Author Info: (1) Department of Research, Tumor Genomics Unit, Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via venezian 1, 20133, Milan, Italy. (2) Department of Pediatric

Author Info: (1) Department of Research, Tumor Genomics Unit, Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via venezian 1, 20133, Milan, Italy. (2) Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. (3) Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. (4) Soft tissues and bone, and pediatric pathology unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. (5) Soft tissues and bone, and pediatric pathology unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. (6) Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. (7) Pathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. (8) Department of Research, Tumor Genomics Unit, Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via venezian 1, 20133, Milan, Italy. Clinical Research Lab (CRAB), Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. (9) Department of Research, Tumor Genomics Unit, Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via venezian 1, 20133, Milan, Italy. (10) Unit of Thoracic Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Clinical Research Lab (CRAB), Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. (11) Pathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. (12) Department of Research, Tumor Genomics Unit, Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via venezian 1, 20133, Milan, Italy. (13) Department of Research, Tumor Genomics Unit, Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via venezian 1, 20133, Milan, Italy. (14) Department of Research, Tumor Genomics Unit, Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via venezian 1, 20133, Milan, Italy. patrizia.gasparini@istitutotumori.mi.it.

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TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

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Inhibitors targeting the PDCD1 (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PDCD1 ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer. Using 812 colon and rectal carcinoma cases from the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association of tumor characteristics and survival outcomes with four TIME subtypes (TIME 1, CD274(low)/TIL(absent); TIME 2, CD274(high)/TIL(present); TIME 3, CD274(low)/TIL(present); and TIME 4, CD274(high)/TIL(absent)). In survival analyses, Cox proportional hazards models were adjusted for potential confounders, including microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, LINE-1 methylation level, and KRAS, BRAF, and PIK3CA mutation status. TIME subtypes 1, 2, 3 and 4 had 218 (27%), 117 (14%), 103 (13%), and 374 (46%) colorectal cancer cases, respectively. Compared with TIL-absent subtypes (TIME 1 and 4), TIL-present subtypes (TIME 2 and 3) were associated with high-level MSI, high-degree CIMP, BRAF mutation, and higher amounts of neoantigens (p < 0.001). TIME subtypes were not significantly associated with colorectal cancer-specific or overall survival. In conclusion, TIL-present TIME subtypes of colorectal cancer are associated with high levels of MSI and neoantigen load, supporting better responsiveness to cancer immunotherapy. Further studies examining tumor molecular alterations and additional factors in the tumor microenvironment may inform development of immunoprevention and immunotherapy strategies.

Author Info: (1) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (2) Program in MPE Molecular Pathological Epidemiology, Department of Pathology

Author Info: (1) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (2) Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (3) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (4) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (5) Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (6) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (8) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (9) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development, Ministry of Health, Metabolic Disease Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, P.R. China. (11) Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (12) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Hubei, P.R. China. (13) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. College of Pharmacy, Zhejiang Chinese Medical University, Zhejiang, P.R. China. (14) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Department of Medical Oncology, Chinese PLA General Hospital, Beijing, P.R. China. (15) Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan. (16) Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. (17) Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. (18) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. (19) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (20) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (21) Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (22) Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (24) Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (25) Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. (26) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (27) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (28) Yale Cancer Center, New Haven, CT, USA. Department of Medicine, Yale School of Medicine, New Haven, CT, USA. Smilow Cancer Hospital, New Haven, CT, USA. (29) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (30) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (31) Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

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Increase in PD-L1 expression after pre-operative radiotherapy for soft tissue sarcoma

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Soft tissue sarcomas (STS) have minimal expression of PD-L1, a biomarker for PD-1 therapy efficacy. Radiotherapy (RT) has been shown to increase PD-L1 expression pre-clinically. We examined the expression of PD-L1, pre- and post-RT, in 46 Stage II-III STS patients treated with pre-operative RT (50-50.4 Gy in 25-28 fractions) followed by resection. Five additional patients who did not receive RT were utilized as controls. PD-L1 expression on biopsy and resection samples was evaluated by immunochemistry using the anti PD-L1 monoclonal antibody (E1L3 N clone; Cell Signaling). Greater than 1% membranous staining was considered positive PD-L1 expression. Changes in PD-L1 expression were analyzed via the Fisher exact test. Kaplan-Meier statistics were used to correlate PD-L1 expression to distant metastases (DM) rate. The majority of STS were T2b (87.0%), high-grade (80.4%), undifferentiated pleomorphic histology (71.7%), and originated from the extremities (84.6%). Zero patients demonstrated PD-L1 tumor expression pre-RT. Post-RT, 5 patients (10.9%) demonstrated PD-L1 tumor expression (p = 0.056). Tumor associated macrophages (TAM) expression of PD-L1 increased after RT: 15.2% to 45.7% (p = 0.003). Samples from controls demonstrated no baseline (0%) or change in tumor PD-L1 expression. Freedom from DM was lower for patients with PD-L1 TAM expression post-RT (3 years: 49.7% vs. 87.8%, log-rank p = 0.006); TAM PD-L1 positivity remained an independent predictor for DM on multivariate analyses (Hazard ratio - 0.16, 95% confidence interval: 0.034-0.721, p = 0.042). PD-L1 expression on human STS tumor and TAM appears to elevate after pre-operative RT. Expression of PD-L1 on TAM after RT was associated with a higher rate of DM.

Author Info: (1) Department of Therapeutic Radiology, Smilow Cancer Center, Yale University School of Medicine, New Haven, CT, USA. (2) Deparment of Pathology, Emory University School of

Author Info: (1) Department of Therapeutic Radiology, Smilow Cancer Center, Yale University School of Medicine, New Haven, CT, USA. (2) Deparment of Pathology, Emory University School of Medicine, Atlanta, GA, USA. (3) Department of Therapeutic Radiology, Smilow Cancer Center, Yale University School of Medicine, New Haven, CT, USA. (4) Deparment of Pathology, Emory University School of Medicine, Atlanta, GA, USA. (5) Deparment of Pathology, Emory University School of Medicine, Atlanta, GA, USA. (6) Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (7) Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (8) Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (9) Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (10) Division of Orthopaedic Oncology, Department of Orthopedic Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (11) Division of Orthopaedic Oncology, Department of Orthopedic Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (12) Division of Orthopaedic Oncology, Department of Orthopedic Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (13) Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (14) Deparment of Pathology, Emory University School of Medicine, Atlanta, GA, USA. (15) Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.

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Anti-CTLA-4 based therapy elicits humoral immunity to galectin-3 in patients with metastatic melanoma

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The combination of CTLA-4 blockade ipilimumab (Ipi) with VEGF-A blocking antibody bevacizumab (Bev) has demonstrated favorable clinical outcomes in patients with advanced melanoma. Galectin-3 (Gal-3) plays a prominent role in tumor growth, metastasis, angiogenesis, and immune evasion. Here we report that Ipi plus Bev (Ipi-Bev) therapy increased Gal-3 antibody titers by 50% or more in approximately one third of treated patients. Antibody responses to Gal-3 were associated with higher complete and partial responses and better overall survival. Ipi alone also elicited antibody responses to Gal-3 at a frequency comparable to the Ipi-Bev combination. However, an association of elicited antibody responses to Gal-3 with clinical outcomes was not observed in Ipi alone treated patients. In contrast to being neutralized in Ipi-Bev treated patients, circulating VEGF-A increased by 100% or more in a subset of patients after Ipi treatment, with most having progressive disease. Among the Ipi treated patients with therapy-induced Gal-3 antibody increases, circulating VEGF-A was increased in 3 of 6 nonresponders but in none of 4 responders as a result of treatment. Gal-3 antibody responses occurred significantly less frequently (3.2%) in a cohort of patients receiving PD-1 blockade where high pre-treatment serum Gal-3 was associated with reduced OS and response rates. Our findings suggest that anti-CTLA-4 elicited humoral immune responses to Gal-3 in melanoma patients which may contribute to the antitumor effect in the presence of an anti-VEGF-A combination. Furthermore, pre-treatment circulating Gal-3 may potentially have prognostic and predictive value for immune checkpoint therapy.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. (2) Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. (2) Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, MA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. (8) Department of Pathology Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, MA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.

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CD133-directed CAR T cells for advanced metastasis malignancies: A phase I trial

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Expressed by cancer stem cells of various epithelial cell origins, CD133 is an attractive therapeutic target for cancers. Autologous chimeric antigen receptor-modified T-cell directed CD133 (CART-133) was first tested in this trial. The anti-tumor specificity and the postulated toxicities of CART-133 were first assessed. Then, we conducted a phase I clinical study in which patients with advanced and CD133-positive tumors received CART-133 cell-infusion. We enrolled 23 patients (14 with hepatocellular carcinoma [HCC], 7 with pancreatic carcinomas, and 2 with colorectal carcinomas). The 8 initially enrolled patients with HCC were treated by a CART-133 cell dose escalation scheme (0.05-2 x 10(6)/kg). The higher CAR-copy numbers and its reverse relationship with the count of CD133+ cells in peripheral blood led to the determination of an acceptable cell dose is 0.5-2 x 10(6)/kg and reinfusion cycle in 23 patients. The primary toxicity is a decrease in hemoglobin/platelet (

Author Info: (1) Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China. (2) Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China. (3) Department of

Author Info: (1) Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China. (2) Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China. (3) Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China. (4) Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China. (5) Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China. (6) Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China. (7) Department of 3Geriatric Hematology, Chinese PLA General Hospital, Beijing, China. (8) Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China. (9) Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China. (10) Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China. (11) Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China. (12) Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China. (13) Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China. (14) Department of Molecular & Immunology, Chinese PLA General Hospital, Beijing, China. Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China.

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Safety and efficacy of concurrent immune checkpoint inhibitors and hypofractionated body radiotherapy

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Integration of hypofractionated body radiotherapy (H-RT) into immune checkpoint inhibitor (ICI) therapy may be a promising strategy to improve the outcomes of ICIs, although sufficient data is lacking regarding the safety and efficacy of this regimen. We, hereby, reviewed the safety and efficacy of this combination in 59 patients treated with H-RT during or within 8 weeks of ICI infusion and compared results with historical reports of ICI treatment alone. Most patients had RCC or melanoma. Median follow-up was 11 months. Most patients received either Nivolumab alone or with Ipilimumab; 83% received stereotactic RT and 17% received conformal H-RT. Any grade adverse events (AEs) were reported in 46 patients, and grade 3-4 in 12 patients without any treatment-related grade 5 toxicity. The most common grade 3 AEs were fatigue and pneumonitis. Grade 3-4 toxicities were higher with ICI combination and with simultaneous ICIs. Overall, most any-grade or grade >/=3 AE rates did not differ significantly from historically reported rates with single-agent or multi-agent ICIs. Toxicity did not correlate with H-RT site, dose, fraction number, tumor type, or ICI and H-RT sequencing. Median progression-free survival was 6.5 months. Objective response rate (ORR) was 26%; 10% had complete response (CR). Median duration of response was 9.4 +/- 4.6 months. H-RT of lung lesions was more likely to achieve CR than other sites. H-RT of bone lesions had a lower ORR than non-bone H-RT. In conclusion, combining body H-RT with ICIs is safe and promising. Prospective validation is warranted.

Author Info: (1) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (2) University of Texas Southwestern Medical Center, Department of Radiology, Dallas

Author Info: (1) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (2) University of Texas Southwestern Medical Center, Department of Radiology, Dallas, Texas, USA. (3) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (4) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (5) University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (6) University of Texas Southwestern Medical Center, Department of Internal Medicine, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (7) University of Texas Southwestern Medical Center, Department of Internal Medicine, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (8) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. (9) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (10) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (11) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (12) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (13) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (14) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (15) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. (16) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (17) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (18) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (19) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (20) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA.

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