IgG response to MHC class I epitope peptides is a quantitative predictive biomarker in the early course of treatment of colorectal cancer using therapeutic peptides

Abstract

Cancer vaccines have been developed as a new therapeutic approach, however, their clinical benefit remains limited. We previously performed a phase II study for advanced colorectal cancer (CRC) using five human leukocyte antigen (HLA-A*24:02)-restricted peptides derived from kinase of the outer chloroplast membrane 1, translocase of outer mitochondrial membrane 34 (TOMM34), ring finger protein 43 (RNF43), vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2. In the present study the relationship between overall survival (OS) and several biomarkers, including cytotoxic T lymphocyte (CTL) and immunoglobulin G (IgG) responses to these five peptides, was investigated. In 89 advanced CRC patients treated with a combination therapy consisting of these five peptides and oxaliplatin-based chemotherapy, plasma was collected before and after 3 months of vaccine administration. IgGs reactive to each of the five peptides were assessed using the multiplex bead suspension Luminex system. Antigen-specific T-cell responses were estimated by enzyme-linked immunoSpot assay. Plasma levels of TOMM34 IgG (P<0.001), RNF43 IgG (P<0.001) and VEGFR2 IgG (P<0.001) were significantly increased after vaccination and stronger VEGFR2 IgG responses correlated significantly with OS in HLA-matched patients (P=0.034). CTL responses to VEGFR1 and VEGFR2 were also significantly increased in the HLA-matched group (P=0.049 and P<0.001, respectively). However, increased CTL response did not correlate with OS. Multivariate analysis indicated that IgG responses to VEGFR2 were the most significant predictor for OS in the HLA-A*24:02-matched group (P=0.04). Our findings indicated that VEGFR2 IgG responses may be an important immunological biomarker in the early course of treatment for CRC patients treated with therapeutic epitope peptides.

CD4/CD8 ratio is a prognostic factor in IgG nonresponders among peptide vaccine‐treated ovarian cancer patients

“…In contrast to the detection of CTL responses, the measurement of IgG has several benefits, ie, it is easier and more robust than the time‐consuming CTL assay. Several research groups are thus using the IgG response as a prognostic biomarker for vaccine therapy …”

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…370 Kanekiyo and colleagues (Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan) combined a vaccine based on 5 HLA-A*24:02-restricted peptides with oxaliplatin in patients with colorectal cancer, finding humoral responses to multiple peptides that were associated with cytotoxic T-cell responses and/or improved overall survival (OS). 371 Geyer and collaborators (Memorial Sloan Kettering Cancer Center, New York, NY, USA) employed CD19-targeting chimeric antigen receptor (CAR) T cells in patients afflicted by residual CLL upon chemotherapy with pentostatin (is a purine analog that inhibits nucleic acid synthesis), cyclophosphamide and rituximab (a CD20targeting monoclonal antibody). 205 This approach achieved 38% ORR, with two patients exhibiting complete responses exceeding 28 months in the absence of severe cytokine release syndromes.…”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…[34,43,93] Immunotherapy has become a mainstay in cancer treatment, mainly via the blockage of T cell-associated proteins (PD-1/PD-L1 or CTLA-4). [134,140,141,144,145] The compatibility of RAPTA-C with approved immune-oncology treatments needs to be established and compared to other ruthenium-based compounds prior to further development in clinical trials. [134,140,141,144,145] The compatibility of RAPTA-C with approved immune-oncology treatments needs to be established and compared to other ruthenium-based compounds prior to further development in clinical trials.…”

“…After vaccination, IgG levels targeting VEGFR2 were significantly increased, which correlated with overall survival in HLA‐matched patients. CTL responses to VEGFR1 and VEGFR2 were also significantly increased in the HLA‐matched group …”

“…[147][148][149][150][151][152] Platinum-based drugs lead to an enhancement of the immune response directly at the tumor site, and therefore, it is very possible that certain ruthenium compounds will harbor similar properties. [134,141] For example, NAMI-A affects chemokine (monocyte chemoattractant protein-1 [MCP-1] and VEGF)-mediated migration of cancer cells, [45] inhibits the circulation of immunocyte-derived pro-metastatic signals that influence the homeostasis of immune cells, [141] and modulates lymphocyte recruitment. It appears that the clinically evaluated complexes NAMI-A and KP1019 modulate cancer-immune cross-talk without altering the expression of surface markers of cancer cells.…”