Abstract 2721: Sustained delivery of low-dose anti-CTLA-4 by genetically engineered encapsulated cells to the tumor microenvironment drives tumor response and prolongs survival in a colorectal cancer model
Authors: Grogg Julien , Charrier Emily , Vernet Remi , Urwyler Muriel , Von Rohr Olivier , Saingier Valentin , Courtout Fabien , Lathuiliere Aurelien , Engel Adrien , Mach Nicolas 
Published: April 2023

Introduction: Systemic therapy with CTLA-4 blocking antibody (aCTLA-4) restores endogenous antitumor immunity and induces remarkable long-term clinical benefits in patients with melanoma. Yet immune-related side effects remain a major hurdle to extending its label to many more types of cancer. Intra- and peritumoral administration of aCTLA-4 has recently emerged as a means to optimize its dose/efficacy ratio while preventing its off-target, systemic toxicities. Sustained peritumoral delivery of low-dose aCTLA-4 by genetically engineered encapsulated cells could offer a promising option for cancer treatment addressing the shortcomings of systemic therapy.

Material and Methods: The efficacy of sustained, low-dose aCTLA-4 delivered by genetically engineered encapsulated cells was assessed in human CTLA4 knock-in mice subcutaneously engrafted with MC38 colon adenocarcinoma cells. In a therapeutic model, mice were treated with either encapsulated human myoblast cells secreting aCTLA-4 (MVX-3) in the vicinity of the tumor, or i.p. injections of Ipilimumab (10mg/kg BIW x 4). Encapsulated wild-type cells (WT) and PBS were used as respective controls. A subgroup of mice was terminated at day 7 post-treatment for early pharmacological characterization. Tumor size and survival were measured to evaluate the efficacy. Secretion of aCTLA-4 by MVX-3 and aCTLA-4 titer in plasma was quantified by ELISA. Tumors, spleens, and draining lymph nodes were collected for flow cytometry analyses.

Results: Peritumoral administration of MVX-3 induced durable complete tumor rejection (2/7) and tumor growth control (4/7) when administered at doses 1’000 times lower than i.p ipilimumab, whereas rapid tumor growth without any tumor rejection was observed in mice treated with control vehicles. I.p. ipilimumab induced durable complete tumor rejection (9/12), while treatment-related toxicities upon dosing led to premature mice termination (3/12). MVX-3 was found as equally effective as i.p. ipilimumab in decreasing the proportion of CTLA4+ helper and regulatory T cells in the tumor at Day 7 post-treatment. Survival was also improved by MVX-3 compared to control vehicles.

Conclusions: These findings suggest that sustained delivery of low-dose aCTLA-4 by genetically engineered encapsulated cells to the tumor microenvironment could achieve similar therapeutic benefits as systemic therapy, without the commonly associated toxicities. The safety and biological efficacy profile of MVX-3 encourage further preclinical and clinical explorations.

Citation Format: Julien Grogg, Emily Charrier, Remi Vernet, Muriel Urwyler, Olivier Von Rohr, Valentin Saingier, Fabien Courtout, Aurelien Lathuiliere, Adrien Engel, Nicolas Mach. Sustained delivery of low-dose anti-CTLA-4 by genetically engineered encapsulated cells to the tumor microenvironment drives tumor response and prolongs survival in a colorectal cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2721.