Cytotoxic T lymphocyte response to peptide vaccination predicts survival in stage III colorectal cancer

Abstract

We previously reported a phase I clinical trial of a peptide vaccine ring finger protein 43 (RNF43) and 34‐kDa translocase of the outer mitochondrial membrane (TOMM34) combined with uracil‐tegafur (UFT)/LV for patients with metastatic colorectal cancer (CRC), and demonstrated the safety and immunological responsiveness of this combination therapy. In this study, we evaluated vaccination‐induced immune responses to clarify the survival benefit of the combination therapy as adjuvant treatment. We enrolled 44 patients initially in an HLA‐masked fashion. After the disclosure of HLA, 28 patients were in the HLA‐A*2402‐matched and 16 were in the unmatched group. In the HLA‐matched group, 14 patients had positive CTL responses specific for the RNF43 and/or TOMM34 peptides after 2 cycles of treatment and 9 had negative responses; in the HLA‐unmatched group, 10 CTL responses were positive and 2 negative. In the HLA‐matched group, 3‐year relapse‐free survival (RFS) was significantly better in the positive CTL subgroup than in the negative‐response subgroup. Patients with negative vaccination‐induced CTL responses showed a significant trend towards shorter RFS than those with positive responses. Moreover, in the HLA‐unmatched group, the positive CTL response subgroup showed an equally good 3‐year RFS as in the HLA‐matched group. In conclusion, vaccination‐induced CTL response to peptide vaccination could predict survival in the adjuvant setting for stage III CRC.

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

“…Interestingly, only one patient failed to mount specific CD8 T cell responses against RNF43 and/or TOMM34 and 83% of patients had stable disease following the vaccination (165). After having demonstrated the safety and immunological responsiveness of this combination therapy, the same group showed that 3-years DFS was significantly better in the group of patients with CD8 T cell responses than in the group without (154,166). In order to improve clinical responses, Okuno et al added to this original combination therapy 5 other TAA-derived peptides to the vaccine.…”

“…Lastly, peptide vaccines are based on the identification and synthesis of antigenic epitopes derived from TAAs able to induce specific antitumor responses (146). Numerous studies have identified TAAs expressed by CRC cells as potential targets for vaccine immunotherapy, including but not limited to CEA (147,148), WT1 (149), MUC1 (150), survivin-2B (151,152), RNF43 (153,154), TOMM34 (154), 5T4 (155,156), GUCY2C (157), SART3 (158), and hTERT (159). CEA is the most extensively explored target in CRC vaccine trials and numerous phase I studies have involved CEA mRNA or CEA peptides loaded onto DCs.…”

Tomm34 is commonly expressed in epithelial ovarian cancer and associates with tumour type and high FIGO stage

“…In these cancers, Tomm34 promotes colorectal cancer cell growth [21] and is a biomarker of poor outcome in early invasive breast cancer [22] and bladder cancer [26]. As a tumour-associated protein, Tomm34 peptide vaccination is under investigation as a therapeutic option for colorectal cancer, with significant Tomm34 cytotoxic T-lymphocyte (CTL) response observed [27][28][29].…”

Retrospective analysis of the efficacy of cytokine‐induced killer cell immunotherapy combined with first‐line chemotherapy in patients with metastatic colorectal cancer

“…In some situations, cell‐based immunotherapy offers a valuable and more effective alternative to conventional cytotoxic therapy . A series of studies have demonstrated the efficacy of adoptive cell immunotherapy, including tumor‐infiltrating lymphocytes, antigen‐specific T lymphocytes, cytokine‐induced killer (CIK) cells and chimeric antigen receptor (CAR) T cells . Among them, CIK cells have characteristics of rapid proliferation, strong antitumor activity, broad spectrum of antitumor activity and minimal toxicity and have been demonstrated as effective in many tumors, including CRC .…”

“…4,7 A series of studies have demonstrated the efficacy of adoptive cell immunotherapy, including tumorinfiltrating lymphocytes, antigen-specific T lymphocytes, cytokine-induced killer (CIK) cells and chimeric antigen receptor (CAR) T cells. [8][9][10][11] Among them, CIK cells have characteristics of rapid proliferation, strong antitumor activity, broad spectrum of antitumor activity and minimal toxicity and have been demonstrated as effective in many tumors, 12 including CRC. 11,[13][14][15] Moreover, our previous studies demonstrated the feasibility and low toxicity of CIK cell treatment for several kinds of cancer, including hepatocellular carcinoma, 16 breast cancer, 17,18 epithelial ovarian cancer, 19 non-small-cell lung cancer 20 and nasopharyngeal carcinoma.…”