Principal Investigator: Christopher Wheeler, PhD

Administration of vaccines to many forms of human cancer is ongoing at multiple clinical research centers. Although these vaccines can elicit anti-tumor cellular immune responses in most cancer patients, there is no clear indication that any measurable aspect of cellular immunity accounts for clinical benefits observed in a small minority of vaccinated cancer patients. This has hampered efforts to rationally improve the clinical efficacy of cancer vaccines. In addition, it is unclear whether even optimized vaccines, by themselves, will ever be able to elicit the complete destruction of a majority of large established human tumors, in part because immune processes can effectively select for the outgrowth of more aggressive, immune-resistant tumors. Whether and how immunotherapy synergizes with more conventional cancer therapies, or otherwise impacts tumor malignant behavior has not been explored.

A specific immune parameter, circulating levels of CD8+ recent thymic emigrant T cells (CD8+ RTEs), has been identified that accounts for the strong prognostic influence of age in GBM clinical progression. Estimates of the number of CD8+ RTEs responding after vaccination also uniquely accounted for clinical benefits (slower progression and longer survival) observed in vaccinated GBM patients. Comparing how these and other immune cells recognize and respond to tumors should facilitate substantial improvements in the design of vaccines for GBM and possibly other cancer patients. We have been able to manipulate tumor antigen recognition and/or responsiveness by CD8+ RTEs and other CD8+ T cells by specific enzymatic treatment.

Circulating level of CD8+ RTEs was also the best correlate of chemotherapeutic responsiveness in vaccinated GBM patients, and vaccinated GBM patients receiving subsequent chemotherapy progressed significantly slower and survived longer than patients without chemotherapy after vaccination. This raises the possibility that tumors immuno-selected through the activity of CD8+ RTEs may be more sensitive to conventional chemotherapy. Moreover, CD8+ RTEs correlated with glioma non-invasiveness in patients, and T cell activity abrogated in vivo invasiveness of the mouse GL26 glioma.

Analysis of the genes involved in clinical chemotherapeutic responsiveness after vaccination and invasiveness should identify discrete targets to enhance therapeutic efficacy for glioma and possibly other cancer patients, in addition to providing therapeutically relevant clues as to how CD8+ RTE-mediated immunity impacts tumor growth. To this end, a core clinical study is proposed, whereby immune, chromosomal and gene expression changes will be monitored in enrolled patients. To complement this study, mouse studies testing immune-dependent chemotherapeutic and invasive differences in gliomas will be conducted. Specifically, genes implicated in glioma invasiveness, drug resistance and/or metabolism that are significantly altered after vaccination will be modulated in GL26 glioma cells, and the affects of such modulation on in vivo chemosensitivity, tumor invasiveness, and host survival assessed in immune-deficient mice. EGFR, which is down-regulated by T cell activity in human and mouse glioma tissue and is known to promote glioma chemoresistance, invasiveness and malignancy, has been chosen as the first gene to be so analyzed.

Zhang, X.-x., Black, K.L., Ong, J.M., Bogler, O., Zhai, Y., and Wheeler, C.J. (2005) T cell activity in glioma chemoresponsiveness and genetics. Gene Ther Mol Biol 9:401-416.

Liu, G., Akasaki, Y., Khong, H.T., Wheeler, C.J., Das, A., Black, K.L., and Yu, J.S. (2005) Cytotoxic T cell targeting of TRP-2 sensitizes human malignant glioma to chemotherapy. Oncogene 24:5226-34.

Wheeler, C.J., and Black, K. (2005) Dendritic Cell Vaccines and Obstacles to Beneficial Immunity in Glioma Patients. Current Opinion Mol Ther 7:35-47.

Wheeler, C.J., Das, A., Liu, G., Yu, J.S., and Black, K. (2004) Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clin Cancer Res 10:5316-5326. (selected as featured article)

Yu, J.S., Liu, G., Ying, H., Yong, W.H., Black, K.L., and Wheeler, C.J. (2004) Vaccination with tumor lysate-pulsed dendritic cells elicits specific cytotoxic T cells in patients with malignant glioma. Cancer Res 64:4973-4979.

Liu, G., Ying, H., Zeng, G., Wheeler, C.J., Black, K.L., and Yu, J.S. (2004) HER-2, gp100 and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res 64:4980-4986.

Prins, R.M., Incardona, F., Lau, R., Lee, P.K., Black, K.L., Claus, S., Zhang, W., and Wheeler, C.J. (2004) Characterization of defective CD4-8- T cells in murine tumors generated independent of antigen specificity. J Immunol 172, 1602-1611.

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