Cancer Immunotherapy Project

Introduction

The Cancer Immunotherapy Project aims to investigate　evidenced-based cancer immunotherapy, repeating basic and translational research. This project is focused on developing not only more effective immunotherapeutic modalities but also immunological methods for suppression of cancer recurrence and prevention.

Glypican-3 (GPC3)

We previously reported that glypican-3 (GPC3) is uniquely overexpressed in human hepatocellular carcinoma and melanoma cells and that it is an ideal tumor antigen for immunotherapy in mouse models. We recently identified HLA-A24 (A*2402)-and H-2Kd-restricted GPC3298–306 (EYILSLEEL) and HLA-A2 ( A*0201)-restricted GPC3144–152 (FVGEFFTDV), both of which can induce GPC3-reactive cytotoxic T cells (CTLs).
A preclinical study in a mouse model
BALB/c mice were intradermally vaccinated at the base of the tail with a mixture of Kd-restricted GPC3298–306 peptide and incomplete Freund ’s adjuvant (IFA), CpG, α GalCer, or aluminum but only the peptide was emulsified in IFA-induced peptide-specific CD8+T cells. Furthermore, proteomic analyses showed that IFA protected the peptide against degradation in human serum. Peptide-reactive CTLs were induced by the peptide vaccine in a dose-dependent manner. In addition, by comparing the proportion of CTLs elicited by 1–4 vaccinations at 7-day intervals, it was noted that induction of GPC3298–306 specific CTLs required at least 2 vaccinations with a dose of >10 μ g each. Repeated vaccination with a lower dose of GPC3298–306 did not induce peptide-specific CTLs. Similarly, induction of an Ag-specific immune response by HLA-A2-restricted GPC3144–152 was dependent on the dose administered.
The results of this study suggested that IFA is an indispensable adjuvant for peptide-based immunotherapy and that the immunological effect of the peptide vaccine depends on the dose of the peptide injected. We devised a schedule for a phase I clinical study on the basis of these results.

Heat shock protein 105 (HSP105)

Heat shock protein (HSP) 105 is overexpressed in various cancers but is expressed at low levels in many normal tissues, except the testis. Vaccination with HSP105-pulsed bone marrow-derived dendritic cells (BM-DC) induced antitumor immunity without causing an autoimmune reaction in a mouse model. Because Apc (Min/+) mice develop multiple adenomas throughout the intestinal tract by 4 months of age, the mice provide a clinically relevant model of human intestinal tumor. We investigated the efficacy of the HSP105-pulsed BM-DC vaccine on tumor regression in the Apc (Min/+) mouse model. Western blotting and immunohistochemical analyses revealed that the tumors of the Apc (Min/+) mice endogenously overexpressed HSP105. Immunization of the Apc (Min/+) mice with an HSP105-pulsed BM-DC vaccine at 6, 8, and 10 weeks of age significantly reduced the number of small-intestinal polyps accompanied by infiltration of both CD4(+) and CD8(+) T cells in the tumors. Cell depletion experiments proved that both CD4(+) and CD8(+) T cells play a critical role in the activation of antitumor immunity that is induced by these vaccinations. These findings indicate that the HSP105-pulsed BM-DC vaccine can provide potent immunotherapy for tumors that appear spontaneously as a result of the inactivation of a tumor suppressor gene, such as in the Apc (Min/+) mouse model (95).

● T. Nakatsura ●

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