NCI-trained scientist brings adoptive T-cell immunotherapy to Providence Cancer Center

Walter J UrbaWalter J. Urba, M.D., Ph.D., oncologist and director, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center

Dr. Eric Tran joined Providence Cancer Center to establish the Antitumor T-cell Response Laboratory and to develop more effective T-cell based immunotherapies that will treat patients with metastatic epithelial cancers. His primary focus is on a type of immunotherapy called adoptive T-cell therapy, which involves the isolation of T cells from a patient, followed by amplification of those T cells in the lab to large numbers and reinfusion of those cells back to the patient. The concept behind this approach is that the delivery of a large army of tumor-reactive T cells will mediate tumor destruction.

Clinical trials to treat patients likely will be begin in  18 to 24 months, using Dr. Tran’s novel immunotherapy approach.

AntitumorTcellResponseLaboratoryDr. Tran earned his Ph.D. in biochemistry from the University of Victoria in British Columbia and completed his postdoctoral training and research fellowship in the laboratory of Steven A. Rosenberg, M.D., Ph.D., at the Surgery Branch in the National Cancer Institute.

His graduate studies and fellowships spanned basic T-cell immunology research and translational and clinical research that focused on improving T-cell based immunotherapies for patients with metastatic cancer. According to Dr. Tran, “These experiences gave me a deep appreciation for the importance of basic research as well as an understanding of the challenges and complexities of designing novel immunotherapies for the treatment of patients with cancer.”

Immunotherapies that harness the T-cell response – such as interleukin-2 (IL-2), adoptive T-cell transfer, and inhibitors to the PD-1 and CTLA-4 immune checkpoint pathways – can mediate complete durable tumor regression in a subset of patients with metastatic cancer. Evidence suggests that T cells targeting mutated antigens, which are neoantigens arising as a consequence of random somatic mutations expressed by the cancer, mediated the tumor regressions observed in some of these patients. The first direct demonstration that T cells targeting mutated neoantigens were capable of mediating regression of metastatic epithelial cancers came from two case reports led by Drs. Tran and Rosenberg.

AntitumorTcellGraphicIn these studies, published in the New England Journal of Medicine and Science, Tran et al., reported that one patient with metastatic colorectal cancer and one patient with metastatic bile duct cancer experienced objective regression of their metastatic lesions after the adoptive transfer of over 100 billion T cells targeting a unique neoantigen expressed by the patients’ own tumors. However, this therapeutic strategy has been effective only in a minority of patients, and the majority of patients with metastatic epithelial cancers still do not experience durable clinical benefit with any currently available therapies. Dr. Tran hopes to develop more effective T-cell based immunotherapies for patients with cancer using a combination of approaches.

One of his current projects involves investigating the immunobiology of tumor-reactive T cells infiltrating human epithelial cancers. Tumors progress despite being infiltrated by tumor-reactive T cells. Thus, identifying the mechanisms used by tumors to impair and evade the antitumor T-cell response may allow for developing more effective T-cell based immunotherapies that can counteract these tumor immune evasion mechanisms. The major focus of this project will be on identifying the tumor antigens recognized by tumor-infiltrating T cells, the biological pathways disrupted by antitumor tumor-infiltrating T cells, and the genomic characteristics of the tumor cells.

Another one of his projects will focus on broadening the antitumor T-cell response against human epithelial cancers. Many tumors have high genomic heterogeneity, which ultimately may lead to low or absent antigen expression by some cancer cells within the tumors, thereby potentially limiting the efficacy of therapies that target only a small number of antigens. Harnessing a T-cell response that targets a larger number of tumor antigens may counteract the extensive genomic heterogeneity found in many tumors and may lead to more effective immunotherapies against cancer. The major focus of this project will be on investigating strategies to broaden the T-cell response against multiple tumor-specific antigens.

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