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

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

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. 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. 2004 Apr 16;22(13-14):1700-8.

Perales M, Diab A, Cohen A, Huggins D, Guevara-Patino J, Hubbard V, Engelhorn M, Kochman A, Eng J, Mortazavi F, Alpdogan O, Terwey T, Heller G, Wolchok J, Houghton A, van den Brink M. DNA immunization against tissue-restricted antigens enhances tumor immunity after allogeneic hemopoietic stem cell transplantation. J Immunol 2006;177(6):4159-67.

Guevara-Patino J, Engelhorn M, Turk M, Liu C, Duan F, Rizzuto G, Cohen A, Merghoub T, Wolchok J, Houghton A. Optimization of a self antigen for presentation of multiple epitopes in cancer immunity. J Clin Invest. 2006 May;116(5):1382-90

Engelhorn M. Guevara-Patino J, Noffz G., Hooper A., Lou O., Gold J., Kappel B. and Houghton A. Autoimmunity and tumor immunity induced by immune responses to mutations in self. Nature Medicine 2006 May;116(5):1382-90

Goldberg S, Bartido S, Gardner J, Guevara-Patino J, Montgomery S, Perales M, Maughan M, Dempsey J, Donovan G, Olson W, Houghton A, Wolchok J. Comparison of two cancer vaccines targeting tyrosinase: plasmid DNA and recombinant alphavirus replicon particles. Clin. Cancer Res.  2005 Nov 15;11(22):8114-21.

Segal N, Blachere N, Guevara-Patino J, Gallardo H, Shiu H, Viale A, Antonescu C, Wolchok J, Houghton A. Identification of cancer-testis genes expressed by melanoma and soft tissue sarcoma using bioinformatics. Cancer Immun. 2005 Feb 1;5:2.

Palomba M, Roberts W, Dao T, Manukian G, Guevara-Patino J, Wolchok J, Scheinberg D, Houghton A. CD8+ T-cell-dependent immunity following xenogeneic DNA immunization against CD20 in a tumor challenge model of B-cell lymphoma. Clin. Cancer Res. 2005 Jan 1;11(1):370-9.

Houghton C, Engelhorn M, Liu C, Song D, Gregor P, Livingston P, Orlandi F, Wolchok J, McCracken J, Houghton A, Guevara-Patino J. Immunological validation of the EpitOptimizer program for streamlined design of heteroclitic epitopes. Vaccine. 2007 Jul 20;25(29):5330-42.

Denman C, McCracken J, Hariharan V, Klarquist J, Oyarbide-Valencia K, Guevara-Patiño J, Caroline Le Poole I. HSP70i Accelerates Depigmentation in a Mouse Model of Autoimmune Vitiligo. J Invest Dermatol. 2008 Mar 13.

Engelhorn M, Guevara-Patiño J, Merghoub T, Liu C, Ferrone C, Rizzuto G, Cymerman D, Posnett D, Houghton A, Wolchok J. Mechanisms of immunization against cancer using chimeric antigens. Mol Ther. 2008 Apr;16(4):773-81. 2008 Feb 26.