Direct identification of T cell epitopes in cancer tissues.

Prediction of tumor-specific T cell epitopes is an important part of cancer immunotherapies. In the past, tumor-specific T cell epitopes were identified by mapping the epitopes on the known cancer-testis antigens and tumor-associated antigens or antigens that react to the T cells induced by the cancer vaccine therapy. More recently, in silico prediction of mutation-associated neoepitopes from the whole-exome sequencing (WES) results has become another approach. However, although this approach often identifies many predicted peptides, only few have been shown to be immunogenic. Mass spectrometry (MS) has also been used to directly identify the T cell epitopes presented on tumor cell by eluting the peptides from human leukocyte antigens (HLA) class I and class II molecules. This approach of identifying neoepitopes was demonstrated to be feasible in high tumor mutation burden (TMB) tumors such as melanoma. However, identifying low-TMB-tumor-specific T cell epitopes has been challenging. Recently, Fujiwara et al. reported their successful result in identifying T cell epitopes in a low TMB tumor, namely pancreatic ductal adenocarcinoma (PDAC). Using the MS approach, they identified T cell epitopes shared by multiple pancreatic cancer patients with different HLA types. Moreover, they demonstrated that the identified epitopes bound non-matched HLA molecules and induced T cell response in peripheral T cells from non-HLA-type matched patients. Their study has opened a new venue for identifying T cell epitopes in a non-immunogenic tumor such as PDAC for the design and development of vaccine and T cell therapy.

A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma.

A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.