Antigenic Differences Between Normal and Malignant Cells as a Basis for Treatment of Intracerebral Neoplasms Using a DNA-Based Vaccine

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. The application of DNA-based genomic vaccines for the treatment of a variety of brain tumors is being explored.

Investigating the Diagnostic and Therapeutic Potential of a T Cell Receptor (TCR)-like single Domain Antibody (sDAb)-Human IgG1 Antibody against Heat Shock Protein (HSP) 16KDa/HLA-A2 for Latent Tuberculosis

“…The immune surveillance of the intracellular proteome of all nucleated cells is carried out by the major histocompatibility complex (MHC) class I system, commonly known as the human leukocyte antigen (HLA) system [19]. Antigen peptide presentation distinguishes between malignant or infected cells and their healthy counterparts, resulting in the creation of abnormal cells that serve as the basis for identification [20]. Therefore, the 16-kDa peptide MHC can give precise diagnostic and therapeutic targets for latent MTB infection.…”

Development of a DNA-Based Vaccine for Treatment of an Intracerebral Tumor

“…Previous studies indicated that transfection of genomic DNA from the malignant cells into a fibroblast cell line resulted in stable integration and expression of the transferred DNA [Cohen, 2001;Lichtor et al, 2005;Lichtor et al, 2006;Lichtor et al, 2008]. Both the genotype and the phenotype of the cells that took up the exogenous DNA were altered as portions of the transferred DNA were expressed.…”

“…Another concern related to therapy with DNA-based vaccines is that genes specifying normal "self" antigens are likely to be expressed by the DNA-transfected cells, creating a danger that autoimmune disease might develop, although this has not been observed thus far. Inbred mice immunized with the DNA-based vaccine or tumor-bearing mice injected with therapeutic DNA-based vaccines failed to exhibit adverse effects [Lichtor et al, 2006]. Of course, protocols that depend upon the use of tumor cell-extracts, peptide eluates of tumor cells, fusion cells, cDNAs or RNAs derived from tumor cells are subject to the same concern.…”

Tumor-DNA Based Vaccines Fail to Induce Autoimmune Disease in Mice

“…Successful immuno-therapies for intracerebrally metastasizing breast cancer have previously been reported with interleukin-2-secreting fibroblasts [6], various interleukin (IL) secreting syngeneic/allogeneic fibroblasts transfected with DNA from breast cancer cells [7][8][9], and syngeneic/allogeneic fibroblasts transfected with cDNA from spontaneously arising breast cancer cells [10]. The efficacy was compared in combined immunotherapy with paclitaxel [11].…”