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BackgroundCurative responses to immunotherapy require the generation of robust systemic immunity with limited toxicity. Recruitment of T cell populations such as precursor exhausted T cells (Tpex) from lymphoid tissues to tumors is a hallmark of effective treatment. However, the ability to efficiently induce this recruitment is lacking in current immunotherapy approaches. Furthermore, systemic administration of immunotherapies frequently results in dose-limiting toxicities, yielding an inadequate therapeutic window for eliciting durable responses. MethodsIn this investigation, we evaluated the safety and antitumor efficacy of locally administered interleukin 12 (IL-12) using a clinically translatable cytokine delivery platform (NCT05538624) to identify Tpex recruitment capabilities at tolerable cytokine doses. ResultsWe show IL-12 cytokine factories can effectively treat a broad spectrum of cancer types. Single-cell RNA sequencing data suggests that the antitumor efficacy seen in our studies was due to retinal pigmented epithelial cells-mIL12 treatment inducing differentiation of Tpex cells within the tumor microenvironment. When administered in combination with checkpoint therapy, IL-12 cytokine factory treatment generated systemic abscopal immunity, preventing subcutaneous tumor outgrowth in 8/9 mice with colorectal cancer and lung metastasis in mice with melanoma. Furthermore, this platform was well tolerated in a non-human primate without signs of toxicity. ConclusionsOur new immunotherapy approach provides a robust strategy for inducing Tpex recruitment and systemic immunity against a range of solid peritoneal malignancies, many incurable with current immunotherapy strategies. Notably, these features were achieved using IL-12, and by leveraging our technology, we avoided the toxicities that have prevented the translation of IL-12 to the clinic. Our findings provide a strong rationale for the clinical development of IL-12 cytokine factories. 

Background Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer. Methods To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing. Results Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration. Conclusions Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.