Abstract 2301: Intraperitoneal CAR-T infusion results in durable protection against peritoneal metastases and control of systemic tumor growth

Abstract

Abstract Colorectal carcinomatosis due to peritoneal metastases (PM) is a significant cause of morbidity and mortality. Present treatments fail to cure the majority of patients with PM. We are developing a chimeric antigen receptor T cell (CAR-T) regional infusion immunotherapy platform for PM. We treated mice with established CEA+ MC38 PMs with anti-CEA CAR-Ts either via regional intraperitoneal (IP) or systemic tail vein (TV) infusion. When compared to TV infusion, IP delivery resulted in significantly improved responses (37-fold reduction in tumor growth, p<0.01). To measure the durability of protection from IP tumor growth, we re-challenged mice with IP tumor following successful treatment with IP CAR-Ts. Mice who had received initial IP CAR-T treatment were protected from tumor growth following re-challenge for 20 days compared to control animals (1390-fold reduction in tumor growth, p = 0.016). Assessment of IP tumor 10 and 28 days following tumor re-challenge revealed a high proportion of intratumoral CAR-Ts (Day 10- 70.0%, Day 28- 46.6%; p = 0.10) and the proportion of CAR-Ts with an effector memory phenotype (CD44+CD62L-CCR7-, Day 10- 19.3%, Day 28- 60.0%; p<0.01). In separate experiments, we studied the effect of IP CAR-T infusions on tumor growth at distant sites. We established both IP and subcutaneous (SQ) flank tumors in mice prior to CAR-T infusions. Following treatment, IP CAR-T infusion resulted in a significant decrease in SQ tumor growth on day 8 compared to control (5.7-fold, p = 0.03), and a trend toward improvement compared to TV (4.9-fold, p = 0.224). While CAR-Ts were not detected in whole blood, SQ tumor, or draining lymph nodes following IP CAR-T infusion, serum IFNγ levels were significantly elevated on day 4 compared to control mice (p = 0.04), and returned to baseline by day 7. Our findings demonstrate that regional IP CAR-T delivery provides durable protection against IP tumor growth in association with CAR-T effector memory programming, in addition to a systemic anti-tumor effect. Citation Format: Marissa Cunetta, Gary Point, Zhi Liu, Prajna Guha, Josephine Darpolor, Matthew Lima, N J. Espat, Nader Hanna, Cherif Boutros, Richard P. Junghans, Steven Katz. Intraperitoneal CAR-T infusion results in durable protection against peritoneal metastases and control of systemic tumor growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2301.