Pancreatic cancer and immune checkpoint inhibitors-still a long way to go.

Abstract

Transl Gastroenterol Hepatol 2020 | http://dx.doi.org/10.21037/tgh.2020.04.03 Despite advances in immunotherapy in multiple solid tumor types, the role of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) remains limited. PDAC has been reported to express a low tumor mutational burden and an immunosuppressive tumor microenvironment, both of which pose challenges to the success of immunotherapy for pancreatic cancer (1,2). Earlier immunotherapy efforts in pancreatic cancer focused on vaccines, but thus far no large scale vaccine trials have demonstrated long-term efficacy. Notable completed pancreatic cancer vaccine studies include the TeloVac, IMPRESS, and ECLIPSE trials. Telomerase is expressed in pancreatic cancer, and GV1001 is a telomerase peptide vaccine that demonstrated an immune response in phase I/II studies (3). TeloVac was an open-label, randomized, phase III trial evaluating the immunogenic telomerase peptide vaccine GV1001 in combination with gemcitabine and capecitabine in 1,062 patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned 1:1:1 to receive chemotherapy alone, chemotherapy and sequential GV1001, or chemotherapy and concurrent GV1001. Median overall survival was 7.9 months with chemotherapy alone, 6.9 months with chemotherapy and sequential GV1001, and 8.4 months with chemotherapy and concurrent GV1001. The trial was terminated early in March 2011 due to decreased survival in the chemotherapy and sequential GV1001 groups (4). IMPRESS was a phase III study of the pancreatic cancer vaccine algenpantucel-L in 722 patients with surgically resected pancreatic cancer. Algenpantucel-L is a vaccine comprised of allogeneic pancreatic cancer cells modified to express surface alpha-1,3-galactosyltransferase leading to hyperacute rejection of the vaccine allograft with a goal of inducing immune-mediated toxicity towards endogenous pancreatic cancer cells. Study patients received algenpantucel-L in combination with adjuvant gemcitabine with or without 5-FU and radiation versus adjuvant gemcitabine with or without 5-FU and radiation alone. Results were published in May 2016. The study did not reach its primary endpoint of improved overall survival; median overall survival was 30.4 months for the control group and 27.3 months for the study group (5). A more recently completed pancreatic cancer vaccine trial was a phase IIb, randomized, multicenter study of GVAX pancreas and CRS-207 compared to singleagent chemotherapy in patients with previously treated metastatic pancreatic cancer (ECLIPSE). GVAX is an irradiated, autologous pancreatic cancer vaccine genetically modified to secrete granulocyte-macrophage colony stimulating factor with a goal of stimulating an immune response against pancreatic cancer cells. CRS-207 is a live, attenuated Listeria-based cancer vaccine expressing human mesothelin which can activate an immune response against mesothelin-overexpressing pancreatic cancer cells. ECLIPSE compared low-dose cyclophosphamide/GVAX/ CRS-207 (arm A) versus CRS-207 alone (arm B), or singleEditorial