On Thursday, September 4th, 2008 Annelies Jorritsma will defend her thesis titled “Immunotherapy of melanoma: towards clinical application” in order to obtain the doctorate degree from the Leiden University. Her promoter is professor Ton Schumacher. The thesis research was performed in the group of John Haanen.
There are different immunotherapeutic strategies that can be used for the treatment of cancer. Tumor-specific T cell responses can be induced via either active or passive immunization. Jorritsma discusses both approaches. Passive immunization via TCR gene transfer is preferred when targeting tumor self antigens. In addition, Jorritsma and colleagues identified several factors that can improve the anti-tumor activity of TCR modified cells.
A new method has been developed for active immunization using a tattoo device to deliver DNA into the skin. Tattoo vaccination results in faster and more robust antigen specific T cell responses compared to conventional intramuscular DNA vaccination. Combining this DNA tattoo vaccination with sub-lethal irradiation of recipients and adoptive transfer, results in a marked, although transient, skewing of the T cell repertoire towards tumor recognition. In vivo, this combined treatment results in a more pronounced anti-tumor effect compared to DNA vaccination alone.
Active immunization is dependent on the endogenous T cell repertoire. Therefore it may not be the preferred strategy when targeting tumor self antigens. A passive immunization strategy that uses the adoptive transfer of a tumor-specific T cell clone to generate effective anti-tumor responses was developed. The life span of these transferred human T cells is extended by the introduction the telomerase reverse transcriptase (hTERT) gene. hTERT-transduced cells can be cultured far beyond the number of population doublings observed for wild type cells, while maintaining their anti-tumor functionality in vivo.
An attractive alternative to the use of naturally occurring tumor-reactive T cells is passive immunization via the transfer of T cell receptor (TCR) genes. Jorritsma used a mouse model to elucidate the requirements for efficient targeting of self antigens by TCR gene transfer. Various factors were shown to have a marked effect on the anti-tumor efficacy of TCR modified cells. This indicates that these factors should be taken into consideration when designing clinical TCR gene therapy trials.
Jorritsma further shows that gene-modification of melanoma-reactive TCRs can markedly enhance TCR expression and in vivo functionality. She also describes a procedure for the selection of a human TCR that is well expressed and highly affine. This method is therefore likely to enable more efficient targeting of human melanoma.
Proposition 9 which accompanies the thesis states: Wetenschap is als jazz: meeslepend, soms zenuwslopend, maar nooit saai.
The thesis defence is open to the public and will take place in the Academiegebouw, Rapenburg 73, Leiden, at 13.45 hours.