Tumour prevention and rejection with recombinant vaccinia

212

It has been speculated that immunological mechanisms play an important role in the control ofcarcinomas associated with human papillomavirus (HPV), such as cervical cancers. We have now demonstrated that immunization of C3H/HeN mice by syngeneic nontumorigenic fibroblast-like cells that contain the transfected HPV-16 E7 gene conferred protection against transplanted cells from a HPV-16 E7-positive syngeneic tumor. This protection was HPV-16 E7-specific and was mediated by CD8' lymphocytes, which presumably were cytotoxic T lymphocytes. These results indicate that tumor cells containing HPV-16 E7, either as a result of transfection, as in our studies, or naturally, as occurs in many human carcinomas, can induce a tumor-specific rejection response and serve as targets for such a response. The system described here provides an animal model to further study immune responses to HPV-associated malignancies and to test the efficacy of anti-HPV vaccines toward the therapy and prevention of such tumors.The goal of cancer research has been to identify tumor markers that can be used as targets for the selective destruction of neoplastic cells, and it has been hoped since the time ofPaul Ehrlich that such markers may be detected in the form of tumor antigens.The demonstration of tumor-specific transplantation antigen (TSTA) among rodent tumors induced by certain DNA viruses (1, 2) provided much encouragement that this goal may be fulfilled: tumors induced by, e.g., the simian virus 40 (SV40) possess a highly specific TSTA and the expression of this TSTA is closely associated with the neoplastic phenotype (3). However, attempts to find analogous antigens in human neoplasms have failed to yield conclusive information.Human papillomavirus (HPV) genes and their products have been identified in most cervical carcinomas as well as in other anogenital carcinomas (4,5). Of the more than 60 types of identified HPVs (6), HPV- If some HPV oncoproteins could serve as TSTA, efficient immunotherapy may be developed (13). We have, for this reason, introduced the HPV-16 E7 gene into a nontumorigenic, major histocompatibility complex-class I-positive, murine fibroblast line so as to present any putative HPV-16 E7-encoded TSTA as an immunogen to mice, which are then challenged with cells from an HPV-16 E7-positive syngeneic melanoma line. We report here that immunized mice were protected against a challenge with the HPV-16 E7-positive melanoma cells, that this protection was immunologically specific, and that it was mediated by CD8+ lymphocytes. We conclude that the HPV-16 E7 gene encodes a TSTA that may provide a highly specific target for immunotherapy and immunoprevention. MATERIALS AND METHODSMice. Female C3H/HeN mice, 6-10 weeks old, were obtained from Charles River Breeding Laboratories.Cell Lines. The K1735 melanoma line subclone M2 (referred to as "par" cells) (14) and NCTC 2555 fibroblast-cell line (American Type Culture Collection) were of C3H/HeN mouse origin. All cells were maintained at 37°C in Dulbecco's modified Eagle'...

Section: Expression Of the Hpv-16 E7 Genes In Transfected Murinementioning

confidence: 99%

Human papillomavirus type 16 nucleoprotein E7 is a tumor rejection antigen.

Chen

Thomas

et al. 1991

212

“…The ability of poxviruses to induce strong CTL responses has led to consideration of their use as cancer vaccines. Recombinant vaccinia viruses that express viral antigens (101,112) or cellular tumor-associated antigens (113)(114)(115)(116) have provided prophylactic and therapeutic effects against experimental tumors. Cytokines (IL-2 and IL-12) and/or costimulatory molecules (B7-1 and B7-2) may enhance the immune effects in model systems (117,118).…”

mentioning

confidence: 99%

Genetically engineered poxviruses for recombinant gene expression, vaccination, and safety.

Moss

1996

477

256

Vaccinia virus, no longer required for immunization against smallpox, now serves as a unique vector for expressing genes within the cytoplasm of mammalian cells. As a research tool, recombinant vaccinia viruses are used to synthesize and analyze the structure-function relationships of proteins, determine the targets of humoral and cell-mediated immunity, and investigate the types of immune response needed for protection against specific infectious diseases and cancer. The vaccine potential of recombinant vaccinia virus has been realized in the form of an effective oral wild-life rabies vaccine, although no product for humans has been licensed. A genetically altered vaccinia virus that is unable to replicate in mammalian cells and produces diminished cytopathic effects retains the capacity for high-level gene expression and immunogenicity while promising exceptional safety for laboratory workers and potential vaccine recipients.

“…This situation favors the induction of cellular immunity (11), which plays a key role in tumor rejection (12). Promising results have been obtained in mice with recombinant vaccinia viruses expressing tumor virus antigens (13,14).…”

mentioning

confidence: 82%

Recombinant vaccinia virus vaccine against the human melanoma antigen p97 for use in immunotherapy.

Estin

Stevenson

Plowman

et al. 1988

We have constructed a recombinant vaccinia virus, v-p97NY, which expresses the human melanomaassociated glycoprotein p97. Immunization with v-p97NY could induce humoral and cell-mediated immunity to p97, including delayed-type hypersensitivity, in mice and in two of two monkeys (Macaca fascicularis). The fact that an immune response was induced also in monkeys is important because normal cells from monkeys, but not from mice, express a low level of cross-reactive p97. Mice immunized with v-p97NY rejected transplants of syngeneic mouse melanoma expressing p97. A rejection response could be detected also when immunization was started 2 days after tumor transplantation, irrespective of whether the transplanted cells grew subcutaneously or as lung metastases. Evidence was obtained that melanoma cells lacking p97 may be killed as "bystanders" at the site of an immune response to melanoma cells expressing p97.