Phase II Study of Personalized Peptide Vaccination for Previously Treated Advanced Colorectal Cancer

Abstract

The prognosis of advanced colorectal cancer (aCRC) remains poor, and development of new therapeutic approaches, including immunotherapy, is needed urgently. Herein we report on our phase II study of personalized peptide vaccination (PPV) in 60 previously treated patients with aCRC, who had failed at least one regimen of standard chemotherapy and/or targeted therapy. For PPV, a maximum of four HLA-matched peptides were individually selected from a pool of 31 different peptide candidates based on preexisting host immunity, and administered subcutaneously without severe adverse events. Boosting of IgG and cytotoxic T lymphocyte (CTL) responses specific to the administered peptides was observed in 49% and 63%, respectively, of the patients, who completed the first cycles of six vaccinations. Median overall survival (OS) time was 498 days, with 1-and 2-year survival rates of 53% and 22%, respectively. Multivariate Cox regression analysis of prevaccination factors showed that plasma IL6, IP-10, and BAFF levels were significantly prognostic for OS [hazard ratio (HR), 1.508, P ¼ 0.043; HR, 1.579, P ¼ 0.024; HR, 0.509, P ¼ 0.002, respectively]. In addition, increased peptide-specific CTL responses after vaccination were significantly predictive of favorable OS (HR, 0.231; P ¼ 0.021), suggesting a causal relationship between biologic and clinical efficacy of PPV. On the basis of the safety profile and potential clinical efficacy, we believe that clinical trials of PPV would be warranted for previously treated patients with aCRC.

Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression

“…This supports a possibility that IL6/sIL6R converts the transferred or in vivo activated CD4 þ T cells into dysfunctional T cells in patients with cancer when T-cellmediated immunotherapy such as adoptive T-cell transfer including chimeric antigen receptor-expressing T cells (CAR-T cells) therapy, vaccination with tumor-associated antigenic peptides, or immune checkpoint blockade, were given. Indeed, recent trials demonstrated that the level of IL6 correlated with overall survival rate of patients treated with immunotherapies (39)(40)(41). It is particularly intriguing that following CAR T-cell infusion, the humanized anti-IL6R Ab tocilizumab is widely used to lessen cytokine release syndrome (CRS)-related toxicities (2,42).…”

Modern strategies and capabilities for activation of the immune response against tumor cells

“…44 To date, peptide-DC therapies are limited to the stimulation of CD8+ cytotoxic responses. 23,[45][46][47][48][49] The problem of inducing CD4+ T cell responses that is also required to treat tumors remains unresolved. 50,51 Therefore, when using lysate/protein/peptide-loaded DCs, the expression duration is limited not only by the affinity of a peptide to a MHC molecule but also by the half-life of a peptide-MHC complex and the turnover of MHC molecules.…”

Personalized immunotherapy in colorectal cancer

“…Multiple (two to four) antigens are selected and administered to increase the likelihood of the vaccinated antigens matching those expressed by the tumor cells [68,69]. A series of early phase (phase I and/or phase II) clinical trials of PPV that were conducted for patients with various types of advanced cancers, including CRC, have shown the feasibility of this new approach [69][70][71][72][73][74][75][76][77][78][79][80]. For example, we have recently demonstrated that the patients treated with PPV showed a significantly longer overall survival (OS) than those with standard care and treatment in randomized phase II studies for bladder cancer and prostate cancer [72,73].…”

“…More recently, a phase II study of PPV was conducted to examine the feasibility of PPV in previously treated CRC patients, who had failed at least one regimen of standard chemotherapies and/or targeted therapies [79]. During PPV, most of the patients (82%) were treated in combination with chemotherapies and/or targeted therapies.…”