WT1 Peptide Cancer Vaccine for Patients with Hematopoietic Malignancies and Solid Cancers

Yoshihiro Oka,Yusuke Oji,Ichiro Kawase,Manabu Kawakami,Toshiaki Shirakata,Fumihiro Fujiki,Sumiyuki Nishida,Akihiro Tsuboi,Hiroko Nakajima,Olga A Elisseeva,Haruo Sugiyama,Naoki Hosen

doi:10.1100/tsw.2007.119

Abstract

Wild-type Wilms' tumor gene WT1 is expressed at a high level in hematopoietic malignancies including acute leukemia, chronic myelogenous leukemia, and myelodysplastic syndromes, as well as in various kinds of solid cancers. Human cytotoxic T lymphocytes (CTLs), which could specifically lyse WT1-expressing tumor cells with HLA class I restriction, were generated in vitro. It was also demonstrated that mice immunized with the WT1 peptide rejected challenges by WT1-expressing cancer cells and survived with no signs of autoaggression to normal organs that physiologically expressed WT1. Furthermore, we and others detected IgM and IgG WT1 antibodies in patients with hematopoietic malignancies, indicating that the WT1 protein was highly immunogenic, and that immunoglobulin class-switch-inducing, WT1-specific, cellular immune responses were elicited in these patients. CD8+ WT1-specific CTLs were also detected in peripheral blood or tumor-draining lymph nodes of cancer patients. These results provided us with the rationale for elicitation of CTL responses targeting the WT1 product for cancer immunotherapy. On the basis of these findings, we performed a phase I clinical trial of a WT1 peptide cancer vaccine for the patients with malignant neoplasms. These results strongly suggested that the WT1 peptide cancer vaccine had efficacy in the clinical setting because clinical responses, including reduction of leukemic blast cells or regression of tumor masses, were observed after the WT1 vaccination in patients with hematopoietic malignancies or solid cancers. The power of a tumor-associated-antigen (TAA)-derived cancer vaccine may be enhanced in combination with stronger adjuvants, helper peptide, molecular-target-based drugs, or some chemotherapy drugs, such as gemcitabine, which has been revealed to suppress regulartory T-cell function. In contrast, reduction of WT1 peptide dose may be needed for the treatment of patients with hematological stem cell diseases, because rapid and strong destruction of malignant cell-sustained hematopoiesis before recovery of normal hematopoiesis may lead to pancytopenia in these patients.

Highlights

Despite recent progress in surgical, chemotherapeutic, and radiotherapeutic approaches, cancer is still one of the diseases that is difficult to treat and cure, especially in patients with advanced stages of the disease
These results showed that Th1-biased WT1-specific immune responses, which were essentially needed for cancer immunotherapy targeting WT1, might be elicited in patients with hematopoietic malignancies
We showed that HLA-A*2402/WT1 tetramer-binding CD8+ T cells were detected in peripheral blood of HLA-A*2402–positive patients with leukemia or solid tumors at higher frequencies than that of healthy donors[58]

Summary

INTRODUCTION

Despite recent progress in surgical, chemotherapeutic, and radiotherapeutic approaches, cancer is still one of the diseases that is difficult to treat and cure, especially in patients with advanced stages of the disease. We demonstrated more recently that Th1-type WT1 antibodies, such as IgG1, IgG2, and IgG3, were significantly increased in patients with leukemia and MDS compared to those in healthy volunteers, whereas Th2-type WT1 antibody, such as IgG4, did not increase in these patients[53] These results showed that Th1-biased WT1-specific immune responses, which were essentially needed for cancer immunotherapy targeting WT1, might be elicited in patients with hematopoietic malignancies. SLX began to decrease after the first vaccination and returned to a normal level[65] In this patient, WT1 vaccination has been repeated with maintained clinical benefit for more than 1 year without significant adverse effects, indicating that the induced WT1-specific CTLs did not give damage to physiologically WT1-expressing normal tissues, including normal hematopoietic stem/progenitor cells and kidney podocytes. WT1-directed cancer immunotherapy targeting NHL and multiple myeloma should be planned (Table 1)

FUTURE DIRECTIONS

Findings

Activation of different kinds of CTLs