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IPSC-derived Trimodal T cells engineered with CAR, TCR, and hnCD16 modalities can overcome antigen escape in heterogenous tumors

ABSTRACT: Although chimeric antigen receptor (CAR) T cells have demonstrated remarkable therapeutic activity in hematopoietic malignancies, antigen escape and tumor heterogeneity have in part impeded the durable efficacy of CAR T cells and their extension into successful solid tumor treatment. To address these challenges, induced pluripotent stem cell (iPSC) - derived T (iT) cells were specifically engineered to uniformly express both CAR and T cell receptors (TCR), enabling targeting of both surface and intracellular antigens, respectively, along with a high-affinity, non-cleavable variant of CD16a (hnCD16) to support antibody-dependent cell cytotoxicity (ADCC) when combined with therapeutic antibodies. Co-expression of each of these unique anti-tumor targeting strategies on engineered iT cells enabled independent and antigen-specific tumor cell killing across a diverse set of liquid and solid tumors. In heterogenous tumor models, coactivation of two or more of these effector modalities was required for measurable anti-tumor efficacy, with all three displaying maximal efficacy. These data highlight the therapeutic potential of an off-the-shelf engineered iPSC-derived Trimodal T cell expressing CAR, TCR, and hnCD16 to combat difficult to treat heterogeneous tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245871 | GEO | 2023/10/24

REPOSITORIES: GEO

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Project description:Adoptive T cell therapies have been transformative in the treatment of a subset of hematological malignancies. However, many patients either fail to respond or relapse, and these therapies still have had much more limited success in solid tumors. A critical challenge for increasing patient response rates and achieving durable efficacy of adoptive T cell therapies is overcoming suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints. Targeted gene editing has the potential to enhance T cell therapeutic function and improve clinical responses. Here we perform multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to nominate genes that could be targeted to prevent T cell dysfunction. These CRISPR screens converged on RASA2 as a target to confer resistance to suppressive conditions found in tumor microenvironments. We identify RASA2 as a signaling checkpoint in human T cells that is downregulated upon acute TCR stimulation but increases gradually with chronic antigen exposure. Antigen titration showed that genetic ablation of RASA2 enhances mitogen activated protein kinase (MAPK) signaling and CAR-T cell cytolytic activity in response to low antigen levels. Repeated tumor antigen stimulation in vitro revealed that RASA2-deficient TCR-T and CAR-T cells have increased activation, cytokine production, and metabolic activity compared to control cells, and show a striking advantage in persistent cancer cell killing. RASA2 KO CAR-T cells showed a competitive fitness advantage over CAR-T control cells in the bone marrow of an in vivo leukemia model. Deletion of RASA2 in multiple preclinical models of TCR- and CAR-T cell therapies prolonged survival in animals xenografted with either liquid or solid tumors. Altogether, our findings from multiple genome-wide screens and preclinical studies highlight RASA2 as a promising new target to enhance both persistence and effector function in TCR-T and CAR-T cell therapies for cancer treatment.

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IPSC-derived Trimodal T cells engineered with CAR, TCR, and hnCD16 modalities can overcome antigen escape in heterogenous tumors

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