Abstract 611: PD-1-based combination immunotherapy reinvigorates CD8+ T cells in metastatic pancreatic cancer patients with improved survival
Authors: Wu Annie A. , Tsujikawa Takahiro , Choe Gina , Beechwood Teresa , Coussens Lisa M. , Durham Jennifer N. , Jaffee Elizabeth M. , Le Dung T. 
Published: August 2018

Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is lethal with a 5-year survival rate of 2%. Single-agent immunotherapies fail to show clinical activity due to a complex tumor microenvironment (TME) and lack of effector T cells. We previously showed that an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as neoadjuvant recruited T cells into the tumor and upregulated the PD-1/PD-L1 pathway. Here we described the first testing of GVAX prime given with attenuated listeria monocytogenes expressing mesothelin (CRS-207) boost given with or without nivolumab to block PD-1 signaling and evaluated changes in the TME.

Experimental Design: Metastatic pancreatic tumor biopsies were obtained at baseline and after 2 GVAX prime and 1 CRS-207 boost from vaccinated patients. Nivolumab was administered with each vaccine in patients randomized to the nivolumab arm. Biopsies containing high density of tumor cells (&gt;30%) were chosen for multiplex immunohistochemistry (IHC) to examine changes in the immune cell subtypes and their signals in tumors. We did a comparative analysis looking at lymphoid, myeloid complexity, and immune functional status in the tumor microenvironment of patients who have overall survival &lt;6 months [short OS] and &gt;6 months [long OS].

Results: Post-immunotherapy changes in immune cell profiles correlated with overall survival. After prime-boost, expansion of CD8+ T cells was observed in the long OS group. Evaluation of the functional status of CD8+ T cells after prime-boost of short OS group showed an EOMES+PD1+ exhausted phenotype. In the myeloid compartment, low CSF1R+ tumor associated macrophages and CD68+ CD163+ and CD163- myeloid frequency in post-immunotherapy tumors were associated with less exhaustion of CD8+ T cells and long OS. The clinical trial is ongoing and blinded to study arm; thus, we have not yet analyzed whether nivolumab influences results. These data will be available at the time of abstract presentation.

Conclusion: This study provides evidence that longitudinal changes in immune cell complexity profiles can be correlated with overall survival. Increases in CD8+ early effectors and decreases in monocytes in baseline versus post-immunotherapy tumors are associated with improved survival. The exhausted CD8+ T cell profile in short OS patients may predict early responders versus nonresponders to vaccine containing immunotherapy.

Citation Format: Annie A. Wu, Takahiro Tsujikawa, Gina Choe, Teresa Beechwood, Lisa M. Coussens, Jennifer N. Durham, Elizabeth M. Jaffee, Dung T. Le. PD-1-based combination immunotherapy reinvigorates CD8+ T cells in metastatic pancreatic cancer patients with improved survival [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 611.