Augmentation of Immunological Response to Cancer Cells
Breast cancer cells have long been supposed to have low antigenecity and to be resistant to immune therapy. So far, reports of nonspecific immune therapies such as BCG have shown that those therapies are not effective for breast cancer13). But since the 1990s, many breast cancer-associated antigens have been reported, and various clinical studies of specific immune therapy for breast cancer, such as vaccination therapy targeted to ErbB2/HER2, are ongoing14, 15). Immune therapy by gene transfer includes: 1) transfer of cytokine genes that enhance immune response, 2) transfer of co-stimulatory molecule genes, and 3) transfer of antigen molecule genes.
A) Transfer of cytokine genes
i) Interleukin-2 (IL-2): Injection of IL-2 gene-adenoviral vector into tumor tissues16), or subcutaneous injection of inactivated tumor cells that were transduced ex vivo by IL-2 gene lipofection (Lyerly) may cause a systemic immune reaction in tumor cells. In a phase I/II study, Stewart et al.17) treated 23 cases with breast cancer or malignant melanoma by injection of 10 7-1010pfu adenovirus-IL-2 into subcutaneous tumors. There was no side effect other than local inflammation of injection sites, and reduction in diameter of subcutaneous tumors was reported in 24% of patients, but there was no PR.
ii) Interleukin-12 (IL-12): Retroviral transfer of IL-12 gene into skin fibroblasts of patients ex vivo, then injection of the fibroblasts into tumor tissues may activate a tumor-specific immune response.
In a phase I study, nine cases with advanced neoplasm including breast cancer were treated by Kang et al. Reduction of tumor at injection sites was shown in four cases, and reduction of tumor at remote sites was shown in one melanoma case.
There was no side effect other than slight pain at the injection sites18).
iii) Granulocyte-macrophage colony stimulating factor (GM-CSF): Retroviral transfer of GM- CSF gene into tumor cells and injection of those cells into subcutaneous tissue may activate systemic immune reaction to tumor cells (Suzuki). The same gene therapy for renal cell cancer has been done in Japan.
iv) Tumor necrosis factor (TNF): Retroviral transfer of TNF gene and Neo gene into tumor cells ex vivo and subcutaneous injection of tumor cells may activate systemic immune response to tumor cells19).
B) Transfer of co-stimulatory molecule gene: Transfer of T cell co-stimulatory molecule CD80 (B7.1) gene into tumor cells by lipofection and injection of those tumor cells into subcutaneous tissue (Urba), or direct injection of CD80-adenoviral vector into tumor tissue (Schuchter) may activate T cell growth and immune response.
C) Transfer of antigen gene: Clinical studies of MUC1(CA15-3) gene transfer by vaccinia virus into tumor cells and injection of tumor cells into subcutaneous tissue (Kufe), simultaneous transfer of MUC1 and CD80 gene (Eder), or HER2 gene transfer (Patel), have been ongoing. Scholl et al. repeatedly administered vaccinia virus containing MUC1 and IL-2 genes (TG1031) intramuscularly to patients with metastatic breast cancer. In 31 patients, two patients (6%) had PR and 15 patients had SD20).