المؤلفون: Daud, Adil I, Loo, Kimberly, Pauli, Mariela L, Sanchez-Rodriguez, Robert, Sandoval, Priscila Munoz, Taravati, Keyon, Tsai, Katy, Nosrati, Adi, Nardo, Lorenzo, Alvarado, Michael D, Algazi, Alain P, Pampaloni, Miguel H, Lobach, Iryna V, Hwang, Jimmy, Pierce, Robert H, Gratz, Iris K, Krummel, Matthew F, Rosenblum, Michael D

المصدر: The Journal of clinical investigation, vol 126, iss 9

مصطلحات موضوعية: Male, Skin Neoplasms, Biopsy, Programmed Cell Death 1 Receptor, Immunology, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Medical and Health Sciences, Antibodies, Cell Line, Cohort Studies, T-Lymphocyte Subsets, Clinical Research, Monoclonal, Tumor Microenvironment, Humans, 2.1 Biological and endogenous factors, CTLA-4 Antigen, Lymphocytes, Tumor-Infiltrating, Neoplasm Metastasis, Aetiology, Melanoma, Humanized, Cancer, Tumor, Inflammatory and immune system, Flow Cytometry, Phenotype, 5.1 Pharmaceuticals, Immune System, Leukocyte Common Antigens, Female, Development of treatments and therapeutic interventions

الوصف: BackgroundImmune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options.MethodsWe performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype.ResultsIncreasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs.ConclusionsOur data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition.FundingThis work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=od_______325::a818e06828529fa7fbe39393b14e44fbTest
https://escholarship.org/uc/item/2x98d6zwTest

المؤلفون: Bhatia, Shailender, Longino, Natalie V, Miller, Natalie J, Kulikauskas, Rima, Iyer, Jayasri G, Ibrani, Dafina, Blom, Astrid, Byrd, David R, Parvathaneni, Upendra, Twitty, Christopher G, Campbell, Jean S, Le, Mai H, Gargosky, Sharron, Pierce, Robert H, Heller, Richard, Daud, Adil I, Nghiem, Paul

المصدر: BASE-Bielefeld Academic Search Engine
Clinical cancer research : an official journal of the American Association for Cancer Research, vol 26, iss 3

مصطلحات موضوعية: Male, Skin Neoplasms, Carcinoma, Oncology and Carcinogenesis, Gene Transfer Techniques, Pilot Projects, CD8-Positive T-Lymphocytes, Middle Aged, Interleukin-12, Cohort Studies, Treatment Outcome, Electroporation, Merkel Cell, 80 and over, Humans, Female, Immunotherapy, Patient Safety, Oncology & Carcinogenesis, Neoplasm Metastasis, Plasmids, Aged

الوصف: PurposeIL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer.Patients and methodsFifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected.ResultsAll patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively.ConclusionsI.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=dedup_wf_001::0936d5b23ca1b9d50e882a25030d5276Test
https://escholarship.org/uc/item/7k4023s9Test