The present invention relates generally to therapy and diagnosis of cancer, such as prostate cancer. The invention is more specifically related to polypeptides comprising at least a portion of a SPAS-1 protein, and to polynucleotides encoding such polypeptides. Such polypeptides and polynucleotides can be used in vaccines and pharmaceutical compositions for prevention and treatment of prostate cancer, and for the diagnosis and monitoring of such cancers including but not limited to prostate cancer and other tumors that express this gene. The present invention also relates to methods of identifying and cloning T cell-defined tumor antigens.
Cancer is a significant health problem throughout the world. Although advances have been made in detection and therapy of cancer, no vaccine or other universally successful method for prevention or treatment is currently available. Current therapies, which are generally based on a combination of chemotherapy or surgery and radiation, continue to prove inadequate in many patients.
In North America, prostate cancer is the most common type of cancer and the second leading cause of death from cancer among men. Metastatic prostate cancer is initially treated by androgen deprivation, which has temporary beneficial effects in over 80% of patients. However, despite a variety of hormonal treatments, all patients ultimately develop hormone refractory prostate cancer (HRPC) with a median survival of approximately one-year.
There is a considerable literature demonstrating immunological targets for a few other types of cancer, including notably melanoma. However, there are very few immunological targets for prostate cancer that have been demonstrated in either animal models or in man. Among the few that have been examined, largely on the basis of fairly restricted expression in prostate, are prostate specific antigen (PSA), and prostatic acid phosphase (PAP), and prostate stem cell antigen (PCSA). Although there have been an occasional reports of induction of T cell responses, there have been no documented cases showing strong therapeutic effects of immunization to any of these proteins. Nor have there been any instances of antigens from prostate cancer cells isolated by virtue of their ability to stimulate T cells. It is clearly very desirable to identify additional targets to be used in immunological therapy of prostate cancer, as well as other cancers.
A theme that is emerging in immunological studies of both experimental models in mice and in clinical situations is that immune responses to tumor cells are very often reacted against normal unmutated, normal tissue specific antigens. Many experimental strategies for vaccination against tumors have been devised (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO EDUCATIONAL BOOK Spring: 60-62; Logothetis, C., 2000, ASCO EDUCATIONAL BOOK SPRING: 300-302; Khayat, D., 2000, ASCO EDUCATIONAL BOOK Spring: 414-428; Foon, K., 2000, ASCO EDUCATIONAL BOOK Spring: 730-738; see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V. et al. (eds.), 1997, CANCER: PRINCIPLES AND PRACTICE OF ONCOLOGY, Fifth Edition (Lippincott-Raven Publishers, Philadelphia, Pa.). In these strategies, a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al., 1993, Proc. Natl. Acad. Sci U.S.A. 90: 3539-43).
Previous studies have shown that the T cell activation molecule CTLA-4 is an important down regulator of T cells responses (Thompson C. B. and Allison J. P., 1997, Immunity 7:445-50). Further, blockade of CTLA-4 alone or in combination with a variety of types of vaccines can lead to rejection of both immunogenic as well as tumors considered to be non-immunogenic in experimental tumor models such as mammary carcinoma (Hurwitz et al., 1998, supra) and primary prostate cancer (Hurwitz A. et al., 2000, Cancer Research 60: 2444-8). In these instances, non-immunogenic tumors, such as the B16 melanoma, have been rendered susceptible to destruction by the immune system.
One study demonstrated that one could achieve irradication of a murine melanoma B16, an extremely aggressive and non-immunogenic model tumor, by immunizing mice with a vaccine consisting of GM-CSF producing irradiated tumor cells along with CTLA-4 blockade (van Elsas, A et al., 1999, J. Exp. Med. 190:355-66)). Irradication of the tumor was followed development of vitiligo, a progressive depigmentation syndrome often observed in human melanoma patients that undergo spontaneous remission. A peptide was derived from the normal, unmutated trp-2 gene as a major target for the anti-melanoma response. Interestingly, the trp-2 gene has been previously shown to encode a target of T cells regularly detected in human melanoma patients.
In spite of considerable research into therapies for these and other cancers, prostate cancer remains difficult to diagnose and treat effectively. Accordingly, there is a need in the art for improved methods for detecting and treating such cancers. The present invention fulfills these needs and further provides other related advantages.
USPTO Backgrounds
USPTO Backgrounds