Abstract
Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive cancer that is resistant to most treatments, and more than 90% of patients with metastatic PDA die within five years of diagnosis. Recent clinical studies show that combining gemcitabine (Gem) with nanoparticle albumin-bound paclitaxel, Abraxane (Abrx), prolongs progression-free and overall survival as compared to Gem alone, but the objective response rate of the combination was only 23%, and nearly every patient eventually progressed. Given that CD40 activation can reverse tumor-induced immune suppression and promote anti-tumor T cell responses, we administered agonistic CD40 monoclonal antibody (FGK45) with combined Gem/Abrx chemotherapy 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. We found only rare tumor regressions in mice treated with chemotherapy alone (Gem, Abrx, or Gem/Abrx) or FGK45 alone, whereas more than 50% of mice treated with Gem/Abrx/FGK45 experienced tumor regressions (p<0.0001). Mechanistic studies revealed that this effect was T cell dependent, and in some mice treated with Gem/Abrx/FGK45, tumors were completely rejected within 3 weeks and the mice remained tumor free for over 100 days, suggesting long-lived T cell memory directed against PDA. Although the overall CD3+ T cell population in the tumor after therapy did not vary across treatment cohorts, the proportion of FoxP3+CD4+ T regulatory cells (Tregs) was reduced 6.9-fold after treatment with Gem/Abrx/FGK45 (p<0.05, Gem/Abrx/FGK45 treatment versus chemotherapy or FGK45 alone), with a concurrent 1.75-fold increase in activated CD44hiCD4+ T helper cells (p<0.01). As a result, the ratio of CD4 Thelper or CD8 T effector cells to Tregs was increased intratumorally. The reduction of Tregs was observed early after therapy, and in the absence of Treg to Thelper conversion, suggesting a change in the priming of the CD4 compartment. Indeed, within 24 hours after Gem/Abrx/FGK45 treatment, antigen-presenting cells (APCs) in the tumor and draining lymph node had increased expression of both CD86 and MHCII (37% versus 10% in control group, p<0.0001 by ANOVA), as well as increased production of TNF-alpha (39% versus 24% in control group, p<0.0001 by ANOVA). These changes in the activation status of APCs in the Gem/Abrx/FGK45 treated-tumor microenvironment may help promote Thelper differentiation. Furthermore, responses to Gem/Abrx/FGK45 are independent of the TLR4 and MyD88 pathways, which have previously been reported as critical mediators of the anti-tumor immune response generated with chemotherapy. Spontaneous PDA tumors arising in KPC mice were also susceptible to Gem/Abrx/FGK45 therapy, exhibiting slowed growth rates and even tumor regression after treatment (37.5% stable disease or tumor regression, versus 0% in Gem/Abrx combined group), in a CD8 dependent manner. These studies not only highlight the clinical potential of adding CD40 activation to standard-of-care chemotherapy as a novel strategy for PDA, but also underscore an emerging hypothesis that T cell immune surveillance can be effective against this otherwise highly immunosuppressive tumor if triggered by robust vaccination.
This abstract is also presented as Poster A40.
Citation Format: Katelyn T. Byrne, Robert H. Vonderheide. Agonistic CD40 antibody combined with chemotherapy drives TLR4/MyD88 independent regression of pancreatic tumors in a T cell dependent manner. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr PR07.
