Abstract CT226: A Phase I trial of in situ vaccination with autologous CCL21-modified dendritic cells (CCL21-DC) combined with pembrolizumab for advanced NSCLC
Authors: Liu Bin , Garon Edward B. , Lisberg Aaron E. , Salehi-Rad Ramin , Lee Jay M. , Tran Linh M. , Krysan Kostyantyn , Li Rui , Lim Raymond J. , Paul Manash , Lin Ying , Jing Zhe , Abtin Fereidoun , Suh Robert D. , Oh Scott , Aberle Denise R. , Winter Lauren E. , Wallace William Dean , Elashoff David , Sharma Sherven , Dubinett Steven M. 
Published: August 2019

Background: The majority of NSCLC patients do not respond to single agent PD-1/PD-L1 inhibitors, in part due to the lack of cytolytic T cell infiltration at the tumor site. To improve the efficacy of checkpoint blockade, in situ vaccination with functional antigen presenting cells (APCs) is designed to take advantage of the full repertoire of tumor antigens. This converts the tumor into a lymph node-like environment to promote T cell activation both locally and systemically. The chemokine CCL21 promotes co-localization of naive T cells and DCs to facilitate T cell activation. Our preclinical studies and recently completed phase I trial demonstrated that intratumoral (IT) administration of DC genetically modified to overexpress CCL21 (CCL21-DC) augments tumor antigen presentation in situ, resulting in more effective T cell responses and systemic antitumor immunity. We also observed increased PD-L1 expression in the tumor microenvironment (TME) in a subset of patients, suggesting that tumor-mediated impairment of T cell function may be forestalling a more robust antitumor response. Similarly, the lack of PD-1/PD-L1 inhibitor efficacy could be combated by enhanced T cell infiltration and augmented APC function following IT CCL21-DC delivery. Therefore, in a phase I trial initiated in November 2018, we are combining IT CCL21-DC with intravenous (IV) pembrolizumab to amplify host antitumor immunity in NSCLC with low or absent baseline PD-L1 expression, who often do not respond to PD-1 inhibition alone.

Methods: This is a single institution, non-randomized, dose-escalating, multi-cohort trial followed by an expansion cohort at the dose established during dose escalation. Patients will be included with pathologically confirmed and radiographically measurable stage IV NSCLC expressing PD-L1 in less than 50% of cells without EGFR or ALK mutations, who have tumor accessible by either CT-guided intervention or bronchoscopy, and who are naïve to systemic treatment for NSCLC. Up to 12 patients will be evaluated in a dose escalation cohort. An additional 12 patients will be enrolled in an expansion cohort. Patients will receive three IT injections of autologous CCL21-DC (days 0, 21, 42) together with IV pembrolizumab. The IV pembrolizumab will continue every 3 weeks for up to 1 year. All patients will be monitored for clinical efficacy as well as local and systemic immune responses to define potential determinants of the response. The primary objective in the dose escalation will be to determine the safety and maximum tolerated dose (MTD) of IT CCL21-DC (5x106, 1x107, 3x107) when combined with IV pembrolizumab. The primary objective in the dose expansion will be to evaluate the objective response rate (ORR) in patients treated with MTD of CCL21-DC combined with IV pembrolizumab. This trial is registered at ClinicalTrial.gov (NCT03546361), and is currently open for enrollment.

Citation Format: Bin Liu, Edward B. Garon, Aaron E. Lisberg, Ramin Salehi-Rad, Jay M. Lee, Linh M. Tran, Kostyantyn Krysan, Rui Li, Raymond J. Lim, Manash Paul, Ying Lin, Zhe Jing, Fereidoun Abtin, Robert D. Suh, Scott Oh, Denise R. Aberle, Lauren E. Winter, William Dean Wallace, David Elashoff, Sherven Sharma, Steven M. Dubinett. A Phase I trial of in situ vaccination with autologous CCL21-modified dendritic cells (CCL21-DC) combined with pembrolizumab for advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT226.