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Hepatic Artery Transfusion of NKG2D CAR-T Cells to Treat Patients with Previously Treated Liver Metastatic Colorectal Cancer: a Prospective, Multicenter Clinical Trial

ABSTRACT: Interventions: Group 1:CAR-T infusion;Group 2:CAR-T infusion;Group 3:CAR-T infusion Primary outcome(s): Adverse events;Anti-tumor response Study Design: Single arm

DISEASE(S): Colorectal Liver Metastases

PROVIDER: 2707769 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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NKG2D CAR-T Cells to Treat Patients With Previously Treated Liver Metastatic Colorectal Cancer

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Project description:Despite a high response rate in chimeric antigen receptor (CAR) T therapy for acute lymphocytic leukemia (ALL), approximately 50% of patients relapse within the first year, representing an urgent question to address in the next stage of cellular immunotherapy. To investigate the molecular determinants of ultra-long CAR T persistence, we obtained single-cell multi-omics sequencing data from 695,819 pre-infusion CAR T cells at the basal level or upon CAR-specific stimulation from 82 pediatric ALL patients enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type-2 functionality in CAR T infusion products was significantly associated with patients maintaining a median B-cell aplasia duration of 8.4 years. Analysis of ligand-receptor interactions unveiled that type-2 cells regulate a distinct dysfunctional population, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing functional fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of post-infusion sera revealed a higher level of circulating type-2 cytokines in 5-year or 8-year relapse-free responders. In a leukemic mouse model, type-2 high CAR T products demonstrated superior expansion and antitumor activity particularly upon leukemia rechallenge. Restoring antitumor efficacy in type-2 low CAR T cells was attainable by enhancing their type-2 functionality, either through incorporating IL-4 into the manufacturing process or priming manufactured CAR T products with IL-4 prior to infusion. Our findings provide key insights into the mediators of CAR T longevity and suggest potential therapeutic strategies to sustain long-term remission by boosting type-2 functionality in CAR T cells.

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