Abstract CT153: Phase I trial of intratumoral administration of autologous CCL21 gene-modified dendritic cells in combination with pembrolizumab for advanced NSCLC: Feasibility of repeated IT injections
Authors: Liu Bin , Lisberg Aaron , Salehi-Rad Ramin , Oh Michael , Lee Jay M. , Tran Linh M. , Krysan Kostyantyn , Lim Raymond J. , Dumitras Camelia , Jing Zhe , Abtin Fereidoun , Suh Robert D. , Genshaft Scott J. , Oh Scott S. , Fishbein Gregory A. , Kaul Anita , Kahlon Kanwarpal S. , Ashouri Shahryar A. , Goldman Jonathan W. , Elashoff David A. , Garon Edward , Dubinett Steven M. 
Published: April 2024

Abstract
Background: Effective immunotherapy options are lacking for patients with advanced non-small cell lung cancer (NSCLC) who progress on a programmed cell death-(ligand)1 [PD-(L)1] inhibitor and for those who are epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement positive after progression on tyrosine kinase inhibitor (TKI) therapy. One potential approach to improve immune checkpoint efficacy in these patient populations is to promote cytolytic T cell infiltration into tumors. This can be accomplished via in situ vaccination with chemokine gene-engineered functional antigen presenting cells (APCs) which can take advantage of the full repertoire of tumor antigens and convert the tumor into a lymph node-like environment to promote both local and systemic antitumor responses. The chemokine CCL21 promotes co-localization of naive T cells and antigen-experienced dendritic cells (DCs) to facilitate T cell activation. Our preclinical studies and phase I trial of intratumoral (IT) administration of DC genetically modified to overexpress CCL21 (CCL21-DC) revealed augmentation of tumor antigen presentation in situ, resulting in systemic antitumor immunity. However, increased PD-L1 expression was observed in some patient tumors, suggesting that tumor-mediated impairment of T cell function may be forestalling a more robust CCL21-DC mediated antitumor response. Similarly, improved PD-(L)1 inhibitor efficacy may be possible with enhanced T cell infiltration and augmented APC function following IT CCL21-DC. Therefore, we are conducting a phase I trial, combining IT CCL21-DC with pembrolizumab in patients with advanced NSCLC.
Methods: Phase I, dose-escalating, multi-cohort trial followed by dose expansion. Maximum of 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection and are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy. Three IT injections of autologous CCL21-DC (days 0, 21, 42) will be concurrently administered with pembrolizumab, followed by pembrolizumab once every three weeks for up to 1 year. Primary objective of dose escalation is safety and determination of maximum tolerated dose (MTD) of IT CCL21-DC when combined with pembrolizumab. Primary objective of dose expansion is objective response rate at MTD. Secondary objectives include adverse event profiling and determination of drug target activity by immune monitoring studies. This trial, NCT03546361, is currently open for enrollment, and this updated abstract will highlight the feasibility of repeated IT injections in treated patients.
Citation Format: Bin Liu, Aaron Lisberg, Ramin Salehi-Rad, Michael Oh, Jay M. Lee, Linh M. Tran, Kostyantyn Krysan, Raymond J. Lim, Camelia Dumitras, Zhe Jing, Fereidoun Abtin, Robert D. Suh, Scott J. Genshaft, Scott S. Oh, Gregory A. Fishbein, Anita Kaul, Kanwarpal S. Kahlon, Shahryar A. Ashouri, Jonathan W. Goldman, David A. Elashoff, Edward Garon, Steven M. Dubinett. Phase I trial of intratumoral administration of autologous CCL21 gene-modified dendritic cells in combination with pembrolizumab for advanced NSCLC: Feasibility of repeated IT injections [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT153.