Drugging the Medullary Thyroid Cancer Surfaceome with T Cell Engagers Targeting CEA, GFRA4 and DLL3 as Monotherapy and In Combination with Tyrosine Kinase Inhibitors

Medullary thyroid cancer (MTC) is a rare form of thyroid cancer, and the definitive treatment is surgical resection. For patients who are not cured by surgery or for patients who present with distant metastatic disease, no curative therapy exists. T cell engagers (TCEs) are an emerging class of biologics that simultaneously bind to tumor cell surface antigens and the CD3 domain of T cells, thereby redirecting endogenous T cells to lyse tumor cells. TCEs can mediate durable tumor regression, including complete responses, and are now approved to treat multiple cancer types outside of MTC. RNASeq analysis of 30 MTC tumors, cross-referencing with public databases and an extensive literature review were used to identify CEA, DLL3 and GFRA4 as promising tumor antigens to target with TCEs. Expression of these antigens was then validated on MTC cell lines. Herein, I describe the discovery, application and development of MTC-targeted TCEs (MTCEs) recognizing the MTC tumor antigens CEA, DLL3 and GFRA4. In vitro, MTCEs mediate potent target-dependent and T cell-dependent cytotoxicity against MTC cell lines at concentrations of just 10 ng/mL. MTCEs also induce target-dependent IFNg secretion from T cells, with no measurable IFNg secretion observed in the presence of antigen-negative cell lines. Further, MTCEs are functionally compatible with the FDA-approved tyrosine kinase inhibitors selpercatinib and cabozantinib, and combination therapy numerically enhances cytotoxicity. These preclinical data provide strong rationale for continued development of MTCEs, which may one day revolutionize the treatment of metastatic MTC.