Abstract 4491: Association of intratumoral immunologic profile with overall survival in metastatic pancreatic cancer patients treated with combination immunotherapy with or without PD-1 blockade
Authors: Wu Annie A. , Tsujikawa Takahiro , Choe Gina , Beechwood Teresa , Coussens Lisa M. , Durham Jennifer N. , Jaffee Elizabeth M. , Le Dung T. 
Published: August 2019

Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5-year survival rate of 8%. Single-agent immunotherapies fail to show clinical activity due to a complex tumor microenvironment (TME) and lack of effector T cells. We previously showed in a neoadjuvant clinical trial that an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) recruited T cells into tumor and upregulated the PD-1/PD-L1 pathway1. Here we describe the first clinical testing of GVAX prime given with attenuated listeria monocytogenes expressing mesothelin (CRS-207) boost alone or in combination with nivolumab to block PD-1 signaling in metastatic PDAC patients, and evaluated changes in the TME.

Experimental Design: 22 metastatic PDAC biopsy pairs were obtained at baseline and after 2 GVAX prime and 1 CRS-207 boost from 96 vaccinated patients. Nivolumab was administered with each vaccine in patients randomized to vaccine + nivolumab arm. Biopsies containing &gt;30% tumor cellularity were chosen for multiplex immunohistochemistry (IHC) to examine changes in immune cell subtypes and their signaling pathways in tumors. We did a comparative analysis looking at lymphoid and myeloid complexity, immune function, and PD-L1 status of patients with overall survival (OS) &lt;150 days [short OS, n=6], 150-300 days [middle OS, n=11], and &gt;300 days [long OS, n=5] or by treatment arm.

Results: Favorable OS correlated with low CD68+ myeloid cell and high lymphoid cell numbers, which was detected after prime-boost. Evaluation of the functional status of CD8+ T cells after prime-boost of patients with long OS revealed a 10.2% increase in EOMES+PD1- effector memory and 1.4% decrease in EOMES+PD1+ exhausted T cells. At baseline, fewer CSF1R+ tumor associated macrophages (TAMs), CD68+CD163+ and CD163- myeloid cells in tumors was associated with long OS. We analyzed nivolumab’s effect on the TME and found that tumors from nivolumab-treated patients displayed a decrease in CD68+ myeloid cells after prime-boost compared to baseline. Interestingly, CD163+ TAMs in tumors of nivolumab-treated patients expressed higher PD-L1 levels.

Conclusion: This study suggests that induction of lymphoid-inflamed expression profiles with less exhausted and more effector memory CD8+ T cells during treatment is associated with long OS independent of nivolumab treatment. Fewer TAMs in pre-treatment biopsies and a low myeloid: lymphoid cell ratio in post-immunotherapy tumor samples may be predictive of improved survival. Our findings also suggest that nivolumab induces PD-L1 expression on myeloid cells. Continual identification of key tissue-based biomarkers that correlate with OS may be useful for predicting therapeutic response.

1) Lutz E. (2014) Cancer Immunol Res. Jul;2(7):616-31.

Citation Format: Annie A. Wu, Takahiro Tsujikawa, Gina Choe, Teresa Beechwood, Lisa M. Coussens, Jennifer N. Durham, Elizabeth M. Jaffee, Dung T. Le. Association of intratumoral immunologic profile with overall survival in metastatic pancreatic cancer patients treated with combination immunotherapy with or without PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4491.