Abstract 1496: KK-LC-1 targeting T cell receptor for adoptive T cell therapy

Abstract

Abstract Introduction: As T cell receptor (TCR) therapy emerges as a powerful therapy in cancer treatment, the field is still limited by a relatively small number of targets that are expressed widely in tumor cells but not expressed healthy normal tissues. Kita-Kyushu lung cancer antigen 1 (KK-LC-1) is a cancer-testis antigen that is expressed only in the testis of normal adult tissues. KK-LC-1 is widely expressed across a large percentage of solid tumors. Transcriptional profiling reveals expression in triple-negative breast (TNBC, 53% of tumors), non-small cell lung (NSCLC, 40%), gastric (81%), and cervical cancers (40%). T-Cure is developing a TCR targeting KK-LC-1 (820TCR) that is restricted to HLA-A*01, which is expressed in approximately 25-30% of the U.S. population. The 820TCR was identified to be specific for KK-LC-152-60 peptide NTDNNLAVY from a responder cervical carcinoma patient. Methods: KK-LC-1 gene expression was measured by qPCR in donor total RNA. Jurkat cells and PBMCs from 5 healthy donors were transduced with a retroviral construct containing the 820TCR, and transduction efficiency was measured by flow staining of the mouse TCR-B constant region. Cell-free binding assays were performed using A*01 tetramers loaded with KK-LC-152-60 peptide labeled with fluorescent markers assayed by flow. TCR specificity was measured by co-culture of transduced Jurkat and T cells with peptide pulsed APCs and on/off-target tumor cell panels. Off-target reactivity was assayed by co-culture of transduced T cells with a panel of normal primary cells across multiple organ systems. All co-cultures measured cytokine release by ELISA and multi-cytokine Luminex panels. Results: Gene expression analysis of RNA from a panel of normal primary donor tissues shows that KK-LC-1 expression is restricted to testis. Cell lines derived from affected histologies also maintain high KK-LC-1 expression in vitro. 820TCR transduced Jurkat and donor T cells showed over 85% of transduced T cells exhibited A*01-KK-LC-152-60 tetramer binding. 820TCR-transduced donor T cells displayed high specificity in co-culture with a panel of cell lines of mixed A*01 and KK-CL-1 status. Reactivity was observed in all naturally expressing KK-LC-1 lines that are A*01+. Reactivity was observed across a wide range of expression levels, and high expression was not required for tumor reactivity. No reactivity was observed in any non-A*01 HLA type or in A*01+/KK-LC-1- tumors. Reactivity could be induced in these cells by exogenous expression of A*01 in non-A*01/KK-LC1+ cells and KK-LC-1 in A*01/KK-LC-1- cells. Off target analysis revealed no reactivity of 820TCR with any normal primary cells. Conclusion: KK-LC-1 is a promising target for adoptive TCR cell therapy, and the 820TCR targeting KK-LC-1 is a highly potent and specific TCR with no observed off-target effects. A phase I clinical trial with 820TCR is being planned for patients with cervical, NSCLC, TNBC, and gastric cancers. Citation Format: Nicholas S. Davis, Catherine Leites, Helicia Paz, Leslie Ryan, Nathaniel Magilnick, Christian Hinrichs, Gang Zeng, Erika von Euw. KK-LC-1 targeting T cell receptor for adoptive T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1496.