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Title

Dual-targeted DOTA CAR T cells with image-guided monitoring for solid tumor treatment

Principal Investigators

Dr. Daniel Powell

Dr. Michael Farwell

Description

CAR T cells can mediate deep, durable cancer remissions but their activity is not controllable once infused, they are not easily tracked, their risk for toxicity remains an issue, and they are seldom designed to combat the immunosuppressive tumor microenvironment (TME). To provide a means for quantitative control of CAR T cell activity, our team first created universal immune receptors (UniCARs), a versatile CAR-like platform for the de novo generation and quantitative control of tumor antigen-specific T cells where human T cells are genetically engineered with adaptable docking immune receptors and can be conferred with highly personalized tumor specificity via pre-targeting with “tagged” antigen-specific small molecules, antibodies, scFvs or receptor ligands. Building upon these principles, and with a multidisciplinary team of physicians and researchers with scientific expertise in advanced T cell gene-engineering with molecular imaging and chemistry, we propose clinical development of an orthogonal imaging-enabled, adaptable CAR T cell (ImAC) platform where localization of infused UniCAR T cells can monitored via noninvasive PET imaging and UniCAR activity can be controlled through the administration of “tagged” biologics in order to facilitate safe and effective targeted therapy for cancer. This theranostic ImAC method utilizes a single UniCAR construct with two novel and distinct agents that share the same clinically-validated CAR-binding tag (DOTA); an imaging small molecule, [18F]-DOTA-Y, that permits tracking of the cellular product, and a new targeting biologic, folate-DOTA-Y, that redirects the specificity and activity of UniCAR T cells against folate receptor expressing cells. Folate receptor isoforms are expressed by the majority of ovarian cancers and by most immunosuppressive tumor-associated macrophages (TAMs) in the TME, allowing simultaneous targeting of cancer and TAMs via dosing with a single agent. An additional benefit, beyond the immediate scope of this study, is that targeting biologics can also be applied for diagnostic imaging prior to CAR T cell delivery to assess localization of the agent to the tumor, to predict response to therapy, and to test for potential on-target off-tumor toxicity. In the UG3 phase, the goal of our multidisciplinary team is to refine and optimize the ImAC method to validated optimal dosing schedules, routes and concentrations that confer a strong tumor response, and to confirm small molecule-based imaging of the administered CAR T cells in mouse xenograft models of ovarian cancer. With this data in hand, and with the small molecule targeting biologic being generated by the Immune Cell Network Core (ICN), we will seek to conduct a 3+3 dose-escalation phase I clinical trial of administration of autologous UniCAR T cells with folate-DOTA-Y for recurrent high grade serous ovarian cancer with PET-based imaging of the infused cell product in the UH3 phase of the study. Successful clinical development of this ImAC platform will significantly advance CAR gene therapy by allowing for the therapeutic coupling of adaptable antigen-targeted T cells with PET-guided monitoring for therapeutic activity, drug delivery and safety in vivo, which can be readily re-deployed for the treatment of other malignancies.