Clinical Implications of CD4+CD25+Foxp3+Regulatory T Cell Frequencies After CHP-MAGE-A4 Cancer Vaccination.

BACKGROUND/AIM: The aim of this study was to explore whether the treatment effect or immune response to a cancer vaccine can be predicted by the percentage of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in peripheral blood mononuclear cells (PBMCs) after vaccination. PATIENTS AND METHODS: Sixteen patients (9 men, 7 women; median age 61.5 years) enrolled in the CHP-MAGE-A4 cancer vaccine clinical trial who had a fixed dose (300 µg of CHP-MAGE-A4 cancer vaccine and 0.5 Klinische Einheit (KE) of OK432 and received at least four vaccinations were investigated. Safety, immune response, and clinical effects were assessed before and after the cancer vaccination. RESULTS: Treg ratios that remained low both before and after vaccination were associated with a good prognosis, and a low Treg/CD4 lymphocyte ratio 7-weeks after the initial vaccination was correlated with a better prognosis. CONCLUSION: The Treg ratio following vaccination appears to have some utility for predicting patient prognosis.

Serum immunoglobulin E response as a marker for unfavorable prognosis following cholesteryl pullulan-MAGE A4 vaccination.

Since 2009, a cancer vaccine clinical trial was conducted with melanoma antigen gene-A4 as an immunogenic agent. The levels of IgG1, IgG2 and IgG3, which are known to be Type 1 T helper cell-associated antibodies, and the levels of IgG4 and IgE, which are known to be Type 2 T helper cell-associated antibodies, were measured and used as biomarkers for predicting therapeutic effect. The results of the present study indicated a strong positive correlation between IgG2 and IgG4, with a correlation coefficient of R=0.808 (P<0.0001). The survival time of patients in which IgE responses were induced was significantly shorter compared with the survival time of patients with no IgE induction. The results of the present study suggest that caution is required when antigen-specific IgE responses are induced during cancer vaccination therapy.

Clinical relevance of antigen spreading pattern induced by CHP-MAGE-A4 cancer vaccination.

AIM: To investigate the antigen spreading pattern in the CHP-MAGE-A4-vaccinated patients and analyze the clinical relevance of antigen spreading pattern as a surrogate marker of patient survival. MATERIALS & METHODS: 12 patients who had been injected with 300 µg of CHP-MAGE-A4 and 0.5 Klinische Einheit of OK-432 in more than five vaccinations were analyzed. RESULTS: Increases in the anti-MAGE-A4-specific antibody response were observed in eight patients (66.7%), compared with six patients (50%) for anti-NY-ESO-1 and five patients (41.7%) for anti-MAGE-A3 after five vaccinations. We identified frequent antigen spreading following MAGE-A4 vaccinations without associations with the clinical response or patient prognosis. CONCLUSION: Antigen spreading pattern might reflect tumor shrinkage as a response to treatment and treatment history (clinical trial registration number: UMIN000001999).

The key role of calreticulin in immunomodulation induced by chemotherapeutic agents.

BACKGROUND: It has recently been shown that certain chemotherapeutic agents can improve host immune responses. The present study aimed to demonstrate the mechanism by which chemotherapeutic agents modify the tumor microenvironment and induce tumor-specific immune responses. METHODS: Three mouse cancer cell lines [CT26 mouse colon cancer cells, B16 melanoma cells and Lewis lung carcinoma (LLC)], 5 human carcinoma cell lines (human esophageal squamous cell carcinoma cell lines TE8 and HEC46 and the human pancreatic carcinoma cell lines PK-9, AsPC-1 and SUIT-2) and 5 chemotherapeutic agents [mitoxantrone (MIT), mitomycin C(MMC), 5-fluorouracil (5FU), camptothecin (CPT-11) and cisplatin (CDDP)] that are frequently used in a clinical setting for cancer treatment were utilized to investigate the surface expression level of calreticulin and HLA class I after exposure to chemotherapeutic agents. RESULTS: Increased calreticulin (CRT) expression on the surface of mouse cell lines and, moreover, increased surface expression levels of both CRT and HLA class I in all human cell lines were observed in cells treated by the chemotherapeutic agents as compared with non-treated cells. The surface expression level of CRT was significantly correlated with the HLA class I expression level in all human cell lines. CONCLUSIONS: In conclusion, chemotherapeutic drugs can improve the immunogenicity of cancer cells in a cell-specific manner through the mechanism of translocation of CRT.