TIM-3, LAG-3, or 2B4 gene disruptions increase the anti-tumor response of engineered T cells.

Autor: Cianciotti BC; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Magnani ZI; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Ugolini A; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Camisa B; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Innovative Immunotherapies Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Merelli I; Institute for Biomedical Technologies, National Research Council, Segrate, Italy., Vavassori V; Gene Transfer Technologies and New Gene Therapy Strategies Unit, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., Potenza A; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Imparato A; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Manfredi F; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Abbati D; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Perani L; Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy., Spinelli A; Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy., Shifrut E; The School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.; Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Dotan Center for Advanced Therapies, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Ciceri F; Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Università Vita-Salute San Raffaele, Milan, Italy., Vago L; Università Vita-Salute San Raffaele, Milan, Italy.; Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Di Micco R; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Naldini L; Gene Transfer Technologies and New Gene Therapy Strategies Unit, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Università Vita-Salute San Raffaele, Milan, Italy., Genovese P; Gene Transfer Technologies and New Gene Therapy Strategies Unit, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Department of Pediatric Oncology, Harvard Medical School, Boston, MA, United States., Ruggiero E; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Bonini C; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Università Vita-Salute San Raffaele, Milan, Italy.
Jazyk: angličtina
Zdroj: Frontiers in immunology [Front Immunol] 2024 Feb 29; Vol. 15, pp. 1315283. Date of Electronic Publication: 2024 Feb 29 (Print Publication: 2024).
DOI: 10.3389/fimmu.2024.1315283
Abstrakt: Background: In adoptive T cell therapy, the long term therapeutic benefits in patients treated with engineered tumor specific T cells are limited by the lack of long term persistence of the infused cellular products and by the immunosuppressive mechanisms active in the tumor microenvironment. Exhausted T cells infiltrating the tumor are characterized by loss of effector functions triggered by multiple inhibitory receptors (IRs). In patients, IR blockade reverts T cell exhaustion but has low selectivity, potentially unleashing autoreactive clones and resulting in clinical autoimmune side effects. Furthermore, loss of long term protective immunity in cell therapy has been ascribed to the effector memory phenotype of the infused cells.
Methods: We simultaneously redirected T cell specificity towards the NY-ESO-1 antigen via TCR gene editing (TCR ED ) and permanently disrupted LAG3 , TIM-3 or 2B4 genes (IR KO ) via CRISPR/Cas9 in a protocol to expand early differentiated long-living memory stem T cells. The effector functions of the TCR ED -IR KO and IR competent (TCR ED -IR COMP ) cells were tested in short-term co-culture assays and under a chronic stimulation setting in vitro . Finally, the therapeutic efficacy of the developed cellular products were evaluated in multiple myeloma xenograft models.
Results: We show that upon chronic stimulation, TCR ED -IR KO cells are superior to TCR ED -IR COMP cells in resisting functional exhaustion through different mechanisms and efficiently eliminate cancer cells upon tumor re-challenge in vivo . Our data indicate that TIM-3 and 2B4-disruption preserve T-cell degranulation capacity, while LAG-3 disruption prevents the upregulation of additional inhibitory receptors in T cells.
Conclusion: These results highlight that TIM-3, LAG-3, and 2B4 disruptions increase the therapeutic benefit of tumor specific cellular products and suggest distinct, non-redundant roles for IRs in anti-tumor responses.
Competing Interests: CB, ER, ZM, BC, AP, LV, FC, PG, LN and BCC are inventors on different patents on cancer immunotherapy and genetic engineering. CB has been member of Advisory Board and Consultant for Molmed, Intellia, TxCell, Novartis, GSK, Allogene, Kite/Gilead, Miltenyi, Kiadis, Evir, Janssen and received research support from Molmed s.p.a and Intellia Therapeutics. LV received royalties and research support from GEN-DX and research support from Moderna Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
(Copyright © 2024 Cianciotti, Magnani, Ugolini, Camisa, Merelli, Vavassori, Potenza, Imparato, Manfredi, Abbati, Perani, Spinelli, Shifrut, Ciceri, Vago, Di Micco, Naldini, Genovese, Ruggiero and Bonini.)
Databáze: MEDLINE
Externí odkaz: