Treatment of Brain Tumors Using DNA-Based Vaccines

Terry Lichtor

doi:10.2174/1876401001003010023

Abstract

Antigenic differences between normal and malignant cells of the cancer patient form the rationale for clinical immunotherapeutic strategies. Because the antigenic phenotype of neoplastic cells varies widely among different cells within the same malignant cell-population, immunization with a vaccine that stimulates immunity to the broad array of tumor antigens expressed by the cancer cells is likely to be more efficacious than immunization with a vaccine for a single antigen. A vaccine prepared by transfer of DNA from the tumor into a highly immunogenic cell line can encompass the array of tumor antigens that characterize the patient’s neoplasm. Poorly immunogenic tumor antigens, characteristic of malignant cells, can become strongly antigenic if they are expressed by highly immunogenic cells. A DNA-based vaccine was prepared by transfer of genomic DNA from a breast cancer that arose spontaneously in a C3H/He mouse into a highly immunogenic mouse fibroblast cell line, where genes specifying tumor-antigens were expressed. The fibroblasts were modified in advance of DNA-transfer to secrete an immune augmenting cytokine and to express allogeneic MHC class I-determinants. In an animal model of breast cancer metastatic to the brain, introduction of the vaccine directly into the tumor bed stimulated a systemic cellular anti-tumor immune response measured by two independent in vitro assays and prolonged the lives of the tumor-bearing mice. Furthermore, using antibodies against the various T-cell subsets, it was determined that the systemic cellular anti-tumor immunity was mediated by CD8+, CD4+ and NK/LAK cells. In addition an enrichment strategy has also been developed to increase the proportion of immunotherapeutic cells in the vaccine which has resulted in the development of enhanced anti-tumor immunity. Finally regulatory T cells (CD4+CD25+Fox p3+-positive) were found to be relatively deficient in the spleen cells from the tumor-bearing mice injected intracerebrally with the enriched vaccine. The application of DNA-based genomic vaccines for the treatment of a variety of brain tumors is being explored.

Highlights

Treatment Limitations of Patients with Malignant Brain Tumors technical advances have resulted in marked improvements in the ability to diagnose and surgically treat primary brain tumors, the incidence and mortality rates of these tumors are increasing [1]
LM fibroblasts are derived from C3H/He mice and express H-2k determinants
No prolongation of survival was noted when allogeneic cytokine secreting fibroblasts mixed with tumor cells or tumor antigens were administered subcutaneously in mice with an intracerebral tumor even though a strong anti-tumor immune response was detected in the spleen cells of the treated animals

Summary

Introduction

Treatment Limitations of Patients with Malignant Brain Tumors technical advances have resulted in marked improvements in the ability to diagnose and surgically treat primary brain tumors, the incidence and mortality rates of these tumors are increasing [1]. The DNA-based vaccines are successful because a full complement of genes is transferred to the recipient cells which results in a robust signal for the development of anti-tumor immune responses.

Results

Conclusion