On November 11, 2022 Immunocore Holdings plc (Nasdaq: IMCR), a commercial-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, autoimmune and infectious diseases, reported that new translational data on KIMMTRAK (tebentafusp-tebn) in patients with metastatic uveal melanoma at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 37th Annual Meeting (Press release, Immunocore, NOV 11, 2022, View Source [SID1234623837]).
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"We previously showed that some patients with radiographic progression can still have long survival on KIMMTRAK. In this analysis, we demonstrate that patients with longer survival retain expression of the antigen processing machinery required to ensure recognition by KIMMTRAK," said Koustubh Ranade, Ph.D., Head of Translational Medicine at Immunocore. "Downregulation of the antigen processing machinery is a known mechanism of resistance for all T cell therapies, including checkpoint inhibitors. We also demonstrate that gp100 protein remains unchanged even in patients who had disease progression."
Biopsies were obtained in up to 18 metastatic uveal melanoma patients shortly after radiographic progression. These tumors were analyzed by immunohistochemistry (n=18) or by RNAseq (n=14) for full-length gp100, and for components of the antigen processing machinery (APM) including HLA-A, the HLA that presents the gp100 peptide recognized by KIMMTRAK. The expression of gp100 protein was unchanged relative to baseline and was not associated with overall survival (OS). However, patients with longer OS, despite radiographic progression had higher expression of the APM, including HLA, and higher levels of T cells, compared to those with shorter OS. HLA downregulation has previously been reported as a mechanism of resistance to immune checkpoint inhibitors, including anti-PD(L)1 (Zaretzky et. Al. N. Engl J Med 2016; 375:819-829).