Jose Guevara-Patino, M.D., Ph.D.

Research Summary

The main challenge of cancer vaccine development is to overcome the physiological state of tolerance or ignorance of the immune system towards self antigens. It is well accepted that the immune system has been educated to remain tolerant to self molecules. However, the paradoxical existence of a “self”-reactive CD8 T-cell repertoire in the periphery of cancer patients, healthy individuals and mice supports a model of incomplete tolerization, where peripheral mechanisms ensure immunological silencing. Therefore, to achieve long-lasting anti-tumor responses that can eliminate cancer cells, we must investigate the mechanisms that control immune tolerance.

The primary objectives of my laboratory are:

1. Develop new immunological strategies to eliminate cancer cells. In view of the increasing need of new therapies against cancer, we have centered our work on designing DNA vaccines in which we convert immunologically inert self antigens into potent therapeutic vaccines by gene optimization. In this regard, we developed and validated an immune-informatics approach, in which computer-designed amino acid substitutions are introduced into cancer related antigens by altering the DNA sequence encoding that antigen. The purpose of these vaccines is to induce cellular immune responses that can effectively recognize and destroy those cancer cells remaining after the patient has received conventional treatment.

2. Define the mechanisms that articulate immune tolerance to self-antigens. Upon vaccination, expansion and contraction of lymphocytes are regulated by several homeostatic mechanisms; yet, the outcome is remarkably different for “self” and “non-self”-reactive cells: “self-reactive” CD8 T cells are selectively down-regulated and “non-self”-reactive CD8 T cells can become immunological memory.

We developed a unique melanoma model to address this issue: we converted immunologically inert mouse tyrosinase related protein-1 (TRP1) into an effective CD8 T
cell immunogen. This vaccine was created by introducing multiple epitopes with improved binding to MHC-I molecules (optimized epitope) in TRP1. DNA immunization with altered TRP1 vaccine induces strong CD8 T cell responses that protect mice against melanoma tumor challenge and prolongs survival in mice immunized therapeutically. Importantly, immunization with this vaccine simultaneously induces two types of immune responses in the same host: “self”-reactive CD8 T cells that cross-react with both wild-type and optimized epitopes, and “non-self”-reactive CD8 T cells that only recognize the optimized epitope. Therefore, DNA immunization with this selectively modified TRP1 vaccine provides a unique model which we can use to determine the therapeutic impact of “self” and “non-self”-reactive CD8 T cells in the same host.

We aim to investigate and manipulate the mechanisms by which CD8 T cell responses against tumors are generated, leading to the development of therapeutic vaccines that can be used in combination with our current armamentarium against cancer.

Selected Papers

Guevara-Patino J, McBride J, Holder A and Blackman M. (1997). Naturally-acquired human anti-malarial antibodies block recognition of a malaria surface protein by invasion-inhibitory antibodies. J. Exp. Med 186(10):1689-99.

Guevara-Patino J, Ivanov V, Marino M, Elkon K, Lacy E and Nikolic-Zugic J. (2000). TNFa is the critical mediator of cAMP-mediated apoptosis of CD8+4+ double-positive thymocytes. J. Immunol. 164(4):1689-94.

Guevara-Patino J, Ivanov V, Marino M, Elkon K, Lacy E and Nikolich-Zugich J. (2000). Sex steroids induce apoptosis of CD8+4+ double-positive thymocytes via TNFa. Eur. J. Immunol. 30:2586-92.

Messaoudi I, Guevara-Patino J, Dyall R, LeMaoult J, Nikolich-Zugich J. (2002). Direct link between mhc polymorphism, T cell avidity, and diversity in immune defense. Science 29;298(5599):1797-800.

Guevara-Patiño J, Turk M, Wolchok J and Houghton A. (2003). Cellular and humoral immune responses to melanoma differentiation antigens. Adv. Cancer Res. 90:157-77.

Gold J, Ferrone C, Guevara-Patino J, Hawkins W, Dyall R, Engelhorn M, Wolchok J, Lewis J and Houghton A. (2003). A single heteroclitic epitope determines cancer immunity following xenogeneic DNA immunization against a tumor differentiation antigen. J. Immunol. 170(10):5188-94.

Gregor P, Wolchok J, Ferrone C, Buchinshky H, Guevara-Patino J, Perales M, Mortazavi F, Bacich D, Heston W, Latouche J, Sadelain M, Allison J, Scher H and Houghton A. (2004). CTLA-4 blockade in combination with xenogeneic DNA vaccines enhances T-cell responses, tumor immunity and autoimmunity to self antigens in animal and cellular model systems. Vaccine. 22(13-14):1700-8.

Houghton AN, Guevara-Patino J. (2004). Immune recognition of self in immunity against cancer. J. Clin. Invest.114(4):468-71.

Turk M, Guevara-Patino J, Rizutto G, Engelhorn M and Houghton A. (2004). Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J. Exp. Med. 200: 771-782.