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Abstract
Introduction/Background Mucin 16 (MUC16) is a membrane associated glycoprotein that is over expressed by most ovarian cancers and possesses an extracellular domain that undergoes proteolytic cleavage to become the source of the soluble ovarian cancer-related tumor marker CA125. MUC16 is also generally absent from healthy tissue, therefore, it is a highly attractive target for CAR-based adoptive T cell therapy.
Methodology We conducted a phase I study of autologous CAR T cells engineered to recognize MUC16 and armored to express IL-12. Eligible patients had recurrent high-grade serous ovarian cancer (HGSOC) that was MUC16-positive. We incorporated both intravenous and intraperitoneal delivery of the CAR T cells for all patients. Standard dose escalation proceeded based on dose-limiting toxicity (DLT) assessments and the primary endpoint was safety. Secondary endpoints included response and CAR T cell expansion in the blood and ascites fluid. To elucidate mechanisms of response and toxicity, we performed soluble biomarker and cytokine profiling utilizing multiplexed proteomics assays at baseline and following cell infusion.
Results Eighteen subjects received CAR T cells and the best response was stable disease. Cytokine release syndrome (CRS) was observed at all doses, but there were no DLTs observed in any of the cohorts where CAR T cells were given alone. In the cohort that received lymphodepleting chemotherapy, 2/3 patients experienced severe CRS, and we identified IFNg and IL-6 as major drivers of this toxicity. One patient who derived clinical benefit remains in remission nearly 5 years later having received PD-1 blockade immediately post study. Proteomic analysis of this exceptional case implicated a unique inflammatory signature associated with CD4 and TNFa.
Conclusion This trial provided the first-in-human evidence that delivery CAR T cells directly to the tumor site by intraperitoneal administration was feasible and revealed unique biomarkers associated with response and toxicity.
Disclosures Dr. Klebanoff acknowledges funding fom Affini-T Therapeutics. Dr. O’Cearbhaill acknowledges institutional funding from Juno.
