Enhanced CD138 peptide-specific cytotoxic T lymphocyte activities against breast, colon and pancreatic cancers in combination with pembrolizumab (anti-PD1).

Abstract

e14302 Background: We investigated the ability of CD138 antigen-specific CD8+ cytotoxic T lymphocytes (CD138-CTL), generated using a novel HLA-A2-specific CD138260-268 (GLVGLIFAV) peptide, in combination with various immune checkpoint inhibitors, to target breast, colon, and pancreatic cancer. Methods: This study was designed to evaluate anti-tumor activities of CD138-CTL, alone or in combination with Pembrolizumab (anti-PD1), against solid tumors. Results: Upregulation of CD138 protein expression was detected on breast, colon, and pancreatic cancer cells. CD138-CTL induced ex vivo by repeated stimulations with HLA-A2-specific CD138260-268 (GLVGLIFAV) peptide were enriched for CD45RO+ memory CTL and demonstrated antigen-specific and HLA-A2-restricted anti-tumor activities. Treatment of CD138-CTL with anti-PD1, anti-TIM3, or anti-LAG3 or tumor cells with anti-PDL1, anti-Gal9 or anti-LAG3 resulted in an increased proliferation of CD138-specific CD8+ CTL, which express costimulatory and activation markers (CD28, CD40L, 41BB, CD69, CD38). However, expression of immune checkpoints (PD1, LAG3, CTLA4) was also induced on these CD138-CTL upon stimulation. Importantly, anti-tumor activities of CD138 peptide-CTL was significantly enhanced in combination with Pembrolizumab, especially within the antigen-specific memory CD8+ T cell subsets (central memory > effector memory), directed against HLA-A2+ breast cancer, colon cancer and pancreatic cancer. Conclusions: These data provide the framework for an immunotherapeutic strategy encompassing a CD138260-268 (GLVGLIFAV) peptide-based cancer vaccine in combination with Pembrolizumab to enhance antigen-specific central memory cells with more potent and long-lasting CD8+ CTL immune responses in patients with solid tumors. Based on these result, clinical trials evaluating CD138260-268 (GLVGLIFAV) in multi-peptide cancer vaccine are on-going in patients with triple negative breast cancer in combination with anti-PD1 (Pembrolizumab) in metastatic setting (NCT 03362060) or anti-PD-L1 (Durvalumab) in stage II/III, adjuvant setting (NCT 02826434).