MHC Class II Based Tumor Vaccine

Xu, Minzhen

Abstract

Presentation of endogenous tumor antigens by MHC class Il molecules in tumor cells lacking the inhibitory li protein generates an effective anti- tumor response. Tumor cells can be either MHC class Il positive or negative. We have demonstrated potent anti-tumor immunity in mice by selective inhibition of the li protein in MHC class Il positive tumor cells. Others have demonstrated similar results in MHC class Il negative tumor cells by simply expressing exogenous MHC class Il genes (without li gene expression). To produce a universal anti-tumor immunotherapy strategy, we are now developing a gene therapy approach to induce appropriate MHC class II gene expression using the MHC class Il transactivator gene (CIITA) concomitant with inhibition of li gene expression. The CIITA gene has the advantage of inducing the endogenous MHC class Il genes, which is important as these genes are highly polymorphic. However, Ii gene expression is also induced by CIITA, requiring the use of our previously established methodology for li inhibition. We are focussing initially on colon cancer because treatment for recurrent disease is limited and initial clinical trials using broadly immunostimulatory mechanisms have shown promise. During the Phase I portion of this study, we will establish the optimal dosing conditions for MHC class Il induction and li inhibition using recombinant CIITA containing adenovirus and li antisense to achieve in vivo tumor immunity using a murine colon cancer cell line (MC-38). Success will trigger phase Il studies, wherein we will develop appropriate constructs using human gene sequences, demonstrate activity in primary human tumor samples, establish the broad range applicability of our approach and complete all necessary studies requisite to an IND filing.

Proposed Commercial Applications

There is a significant unmet need for cancer therapy. The immunotherapy approach we are developing will be applicable to nearly all types of cancer. As our technology is based on a specific anti-tumor strategy (i.e., as opposed to classical cytotoxic chemotherapeutic agents) it can be readily dovetailed with current treatment modalities.