National Cancer Research Institute South of England
Prostate Cancer Collaborative
Research

Genetic Vaccines against Cancer

Funding by a Pilot and Development Award January 2002

Authors
Professor Freda Stevenson, Dr Delin Zhu
University of Southampton

Cancer cells differ from normal cells and those differences are coded in the DNA. When the code is read it can lead to synthesis of tumour-associated proteins. Potentially, these can be perceived as foreign by the immune system of the host. However, once a patient has cancer, the immune system has failed. Our strategy is to repackage the tumour antigens in a vaccine format which can alert immune recognition and induce an effective anti-tumour immunity.

The first tumour we are investigating is B-cell lymphoma where there are many potential tumour antigens. Among the specialised proteins, the idiotypic determinants carried by the immunoglobulin provide a well-defined target for induction of immunity. However, new information from genome analysis is defining a myriad of additional target gene sequences. The same technology is applicable to prostate cancer where several target antigens have already been defined.

Our tumour vaccines are based on new technology developed for vaccines against infectious diseases. Instead of using killed or attenuated organisms, naked DNA which encodes particular antigenic proteins is being used. On injection into muscle or skin, the code is transcribed into RNA, which is translated into protein. The foreign protein then induces antibody and T-cell responses which attack the organism.

Our strategy for DNA vaccine construction relies on obtaining the sequence from the tumour cell which encodes a candidate antigen. Using polymerase chain reaction (PCR), we amplify the chosen gene and place it into a bacterial plasmid vector which consists of a circle of carrier DNA. Interestingly, the carrier DNA itself is immunostimulatory and sets the scene for the immune response.

Induction of immunity against cancer is more difficult than inducing protection against infectious organisms. Patients already have cancer, and may be tolerant to the antigens; they may have a damaged immune system due to the disease, or due to chemotherapy; and the tumour antigens may be weak. To promote recognition and activation of immunity we have fused a gene encoding a pathogen-derived protein to our tumour antigen sequence. The promotional sequence is derived from Tetanus Toxin, and is itself highly immunogenic. When fused to idiotypic antigens, it dramatically increases the anti-tumour response. We are currently conducting a PhaseI/II clinical trial of our idiotypic DNA fusion vaccines involving a small number of patients with follicular lymphomas, and clinical trials for patients suffering from multiple myeloma and chronic lymphocytic leukemia have been planned.

Prostate cancer expresses a number of tumour-associated antigens, such as prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), prostatic acid phosphatase (PAP) and prostein, and we are exploring the same gene-based fusion vaccine strategy as a potential treatment for prostate cancer in our laboratory.

Selected Recent Publications

Zhu, D., J. Rice, N. Savelyeva, and F. K. Stevenson. 2001. DNA fusion vaccines against B-cell tumors. Trends Mol Med 7:566.

Savelyeva, N., R. Munday, M. B. Spellerberg, G. P. Lomonossoff, and F. K. Stevenson. 2001. Plant viral genes in DNA idiotypic vaccines activate linked CD4+ T-cell mediated immunity against B-cell malignancies. Nat Biotechnol 19:760.

Rice, J., T. Elliott, S. Buchan, and F. K. Stevenson. 2001. DNA fusion vaccine designed to induce cytotoxic T cell responses against defined peptide motifs: implications for cancer vaccines. J Immunol 167:1558.

Stevenson, F. K., C. J. Link, Jr., A. Traynor, H. Yu, and M. Corr. 1999. DNA vaccination against multiple myeloma. Semin Hematol 36:38.

Stevenson FK. (1999) DNA vaccines against cancer: from genes to therapy. Ann Oncol 10:1413.

Rice J, King CA, Spellerberg MB, Fairweather N, Stevenson FK. (1999) Manipulation of pathogen-derived genes to influence antigen presentation via DNA vaccines. Vaccine 17:3030.

Hamblin, T. J., Z. Davis, A. Gardiner, D. G. Oscier, and F. K. Stevenson. 1999. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848.

King CA, Spellerberg MB, Zhu D., Rice J, Sahota SS, Thompsett AR, Hamblin TJ, Radl J, Stevenson FK. (1998) DNA vaccines with single chain Fv fused to Fragment C of Tetanus toxin induce protective immunity against lymphoma and myeloma. Nature Medicine 4 (11) 1281.
Spellerberg MB, Zhu D, Thompsett A, King CA, Hamblin TJ, Stevenson FK. (1997) DNA vaccines against lymphoma: Promotion of anti-idiotypic responses induced by single chain Fv genes by fusion to tetanus toxin fragment C. J. Immunol. 159:1885.

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Aetiology and Genetics

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