Off-the-shelf CAR-T Therapy via Tumor-Selective Immuno-engagers

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PROJECT SUMMARY Today, there is renewed hope that mortality associated with various cancer types will be dramatically reduced based on the potential success of novel immunotherapeutic agents, such as chimeric antigen receptor (CAR)- expressing T cells. In some cases, the response from immunotherapeutic agents has been more robust and sustained relative to traditional cancer chemotherapeutics. Despite these successes – albeit very uneven across patient populations – adoptive cell therapy will remain confined to a relatively small subgroup of patients until two of its major hurdles are overcome: (1) the reliance on narrow differentiation between cancer and healthy cells due to the lack of bona fide, targetable, tumor- specific markers, and (2) the lack of common targetable tumor biomarkers among all patients. Here, we will exploit the inherent acidic microenvironment and negatively charged membranes of cancer cells by using the pH(Low) Insertion Peptide (pHLIP), a peptide that selectively anchors onto cancer cell surfaces, to selectively graft the surface of cancer cells with a non-native epitope for recognition and destruction by cognate CAR-T cells. At each stage of structural iterations, agents will be selected based on their chemico-physical properties, efficacy in recruiting CAR-T cells, induction of selective toxicity towards cancer cells, and in vivo tumor targeting and efficacy. The proposed work will combine areas of ongoing research in our respective laboratories: specific delivery of synthetic immuno-engager agents to tumors based on their inherent acidity (Thévenin), and discovery and clinical testing of CAR-T immunotherapy (Snook). Given the critical need to improve on current cancer immunotherapeutic modalities, we anticipate that the successful development of our system has the potential to extend treatment options to many cancer patients, as it would allow for (i) off-the-shelf strategies based on a single and common exogenous antigen, (ii) a standardized genetic manipulation of patients' T cells, (iii) streamlined clinical evaluation of therapies for a larger set of human tumor types, and (iv) the production of these therapeutics at a scale that is commercially viable.