Genetic Vaccines against Cancer
Funding by a Pilot and Development Award January 2002
Professor Freda Stevenson, Dr
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
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
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.