Abstract 4940: Nonredundant roles for immune checkpoint blockade and agonistic CD40 in mediating T-cell responses in pancreatic ductal adenocarcinoma
Authors: Morrison Alexander H. , Byrne Katelyn T. , Vonderheide Robert H. 
Published: August 2018

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive cancer that is resistant to most treatments, with a five-year survival rate of ~10%. Immune checkpoint blockade (ICB) has had dramatic effects in many tumor histologies, but is ineffective in PDA. CD40 lies upstream of the immune checkpoints in the T-cell activation pathway, presenting a unique opportunity to intercede with T-cell activation independently of ICB. We hypothesized that administering agonistic CD40 antibody would prime effector T-cell populations, synergizing with ICB to provide therapeutic benefit in PDA. We administered agonistic CD40 monoclonal antibody (clone FGK45, anti-CD40) combined with anti-PD1 and anti-CTLA4 monoclonal antibodies (ICB) to mice bearing subcutaneous PDA tumors established using syngeneic tumor cell lines derived from the KrasG12D+/-;Trp53R172H+/-;Pdx-1 Cre (KPC) genetically engineered mouse model of PDA. While tumor regressions were rare in mice treated with ICB or anti-CD40 alone (1/7 mice in each group), 100% of mice treated with ICB + anti-CD40 experienced tumor regressions (7/7 mice). Cell depletion experiments showed early tumor regressions depended primarily on CD4 T cells, although both CD4 and CD8 T cells were required for long-term remission. 50% of mice (4/8) treated with ICB + anti-CD40 remained tumor-free (median survival 112 days) and 3/4 mice resisted tumor rechallenge, indicative of a long-lived memory T-cell response against PDA. Treatment with ICB + anti-CD40, but neither alone, increased the total intratumoral CD3+ T-cell population 3.8-fold (p&lt;0.01), with increases in both the CD4+ and CD8+ T-cell compartments (6.7-fold and 3.3-fold, respectively, p &lt;0.016). CD40 stimulation, but not ICB, modulated the CD4 compartment in the TME, increasing the proportion of CD43+CD11a+ antigen-specific CD4 T helpers (41 - 43% v. 10%, +/-ICB v. control, p &lt;0.03) and reducing FoxP3+ CD4+ T regulatory cells (Tregs) 2.7 to 3.7-fold (+/- ICB, p &lt; 0.0001). This resulted in an increased ratio of CD8 T effector cells to Tregs (7.5 to 10.7 CD8/Treg, anti-CD40 +/-ICB, p&lt;0.01) specifically after treatment with anti-CD40, regardless of ICB addition. ICB alone increased the proportion of proliferating CD8 T cells in the tumor draining lymph node that were ‘"reinvigorated" Eomes+Tbet-Ki67+ (17-19% +/- CD40 v. 8% control, p &lt;0.01), but was unable to increase the same CD8 T-cell population in the tumor. However, the addition of CD40 to ICB reduced the frequency of PD1+ CD8 T effectors in the tumor (25% v. 52% control, p &lt; 0.05), suggesting a tumor-specific benefit of ICB on the exhausted T-cell compartment. These studies reveal the nonredundant roles that agonistic CD40 and ICB play in generating a robust T-cell response against PDA, and highlight the clinical potential of combining CD40 activation with ICB as a novel therapeutic approach in ICB-resistant tumors.

Citation Format: Alexander H. Morrison, Katelyn T. Byrne, Robert H. Vonderheide. Nonredundant roles for immune checkpoint blockade and agonistic CD40 in mediating T-cell responses in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4940.