Abstract 1848: A novel murine tumor model for assessing the efficacy of neoadjuvant dosing regimens for immunotherapies
Authors: Prijic Sara , Wood Jason , Liberzon Arthur , Nistala Harikiran , Winquist Raymond J. , Lopes Jared E. 
Published: June 2023

Immunotherapy extends survival for patients with several cancer types, especially in combination with surgery. Consistently, recent evidence demonstrated improved efficacy with neoadjuvant/adjuvant pembrolizumab in combination with debulking surgery in patients with melanoma (Patel et al, ESMO 2022). However, evaluating these regimens preclinically is challenging due to the rarity of appropriate models. To address this question, we have established a novel murine tumor model involving partial tumor-debulking surgery which enables monitoring of the temporal response to immunotherapy in neoadjuvant, neoadjuvant/adjuvant and adjuvant settings. We utilized the MC38 tumor model which represents a ‘hot’ tumor microenvironment (TME), analogous to the TME in melanoma patients. MC38 tumor-bearing C57Bl/6 mice were subcutaneously administered murine nemvaleukin alfa (mNemva), an engineered IL-2 immunotherapy that selectively activates and expands cytotoxic NK cells and antigen-experienced CD8+ T cells. Partial tumor-debulking surgery was performed under general anesthesia 3 days after the first dose of mNemva along with neoadjuvant and neoadjuvant/adjuvant regimens, or 1 day before the first dose of mNemva in the adjuvant regimen. Whereas a single dose of mNemva was administered to mice in the neoadjuvant setting, four and five doses were given in the adjuvant and neoadjuvant/adjuvant settings, respectively. Two types of control groups were also evaluated: vehicle in combination with partial tumor-debulking surgery, and five doses of mNemva without the debulking procedure.The neoadjuvant/adjuvant treatment regimen was superior to neoadjuvant or adjuvant in all aspects with 28% of animals exhibiting complete responses, tumor growth inhibition (TGI) of 82% and prolonged median survival from 17 to 27 days. While the neoadjuvant regimen yielded 10% complete responders, TGI was only 7% and median survival was not extended. No complete responders were observed with the adjuvant regimen. Importantly, tumors in both control groups grew to the predefined endpoint irrespective of treatment and surgical procedure. Following tumor re-challenge, 75% of prior complete responders were protected, suggesting that mNemva induced immunological memory in most mice. Moreover, long-term immunity was 100% effective if the re-challenge experiment was performed out to 5 months after the last dose of mNemva had been administered.Therefore, the neoadjuvant/adjuvant dosing regimen exhibits a superior response in this preclinical model, when combined with partial tumor-debulking surgery, similar to the recent findings in patients with melanoma that were treated with pembrolizumab. In addition, this strategy enables sampling of tumor tissue for analyses of the immune response and the identification of potential predictive markers of response.

Citation Format: Sara Prijic, Jason Wood, Arthur Liberzon, Harikiran Nistala, Raymond J. Winquist, Jared E. Lopes. A novel murine tumor model for assessing the efficacy of neoadjuvant dosing regimens for immunotherapies [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 1848.