Abstract C013: Response to combination immunotherapy in a mouse model of PDAC is a function of baseline T cell content
Authors: Cheng Noah C. , Markosyan Nune , Vonderheide Robert H. 
Published: November 2022

Abstract
Findings from the recently reported phase 2 PRINCE trial for patients with metastatic pancreatic cancer suggest potential clinical benefit with certain combinations of chemotherapy and immunotherapy. Overall survival following gemcitabine/nab-paclitaxel and either PD-1 blocking antibody or CD40 agonistic antibody (aCD40) correlated with the prevalence of distinct T cell subsets in circulation at baseline and with the extent of certain tumor infiltrating T cells (Padron et al., Nature Medicine, 2022). Here, we modeled the therapeutic effect of aCD40/PD-1/CTLA-4 therapy in the absence of chemotherapy in mice bearing tumors derived from the autochthonous pancreatic ductal adenocarcinoma (PDAC) KPC model and studied the dependency of tumor regression on the degree of tumor infiltrating T cells. We used a panel of KPC tumor cell clones that exhibit reproducible and transplantable levels of T cell infiltration ranging between high, intermediate, and low amounts. Mice were subcutaneously injected with clonal PDAC lines and treated 14-21 days later with either aCD40 alone or aCD40/PD-1/CTLA-4 (all i.p., n=5-8 mice per cohort of T cell high, intermediate and low clones). Systemic immune dynamics were surveyed by bleeding mice on day 0, 7, and 14 of treatment and analyzing for immune cell activation and exhaustion markers. In mice bearing T cell high and intermediate tumors, aCD40/PD-1/CTLA-4 induced higher rates of complete tumor regressions (71% for T cell high; 25% for T cell intermediate) and prolonged survival (P &lt; 0.001 for T cell high; P = 0.013 for T cell intermediate) compared to untreated controls. Treatment with aCD40 alone was effective in mice with T cell intermediate tumors, leading to regressions in 29% of mice. In mice bearing T cell low tumors, however, tumor regressions after aCD40/PD-1/CTLA-4 were less frequent (12.5%), although survival was improved significantly following the treatment (P &lt;0.001). aCD40 alone improved overall survival of T cell low bearing mice (P = 0.026) without inducing tumor regressions. Regardless of T cell high, intermediate, or low tumors, aCD40/PD-1/CTLA-4 increased the proportions of circulating activated and exhausted CD4+ and CD8+ T cells. aCD40/PD-1/CTLA-4 also increased T cell infiltration into T cell low tumors, but this enhanced infiltration did not correlate with complete regressions. Thus, using tumor clones derived from the same autochthonous genetic model, we show that response to combination immunotherapy is a function of baseline T cell content, with ‘hot’ tumors responding the best and ‘cold’ tumors responding the worst. Additional tumor cell-intrinsic factors such as those revealed in other mouse experiments and in the human samples from the PRINCE study likely restrict a robust anti-tumor immune response even when T cells have been recruited.
Citation Format: Noah C. Cheng, Nune Markosyan, Robert H. Vonderheide. Response to combination immunotherapy in a mouse model of PDAC is a function of baseline T cell content [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C013.