Our Science – Yang Website

James C. Yang, M.D.

Surgery Branch Senior Investigator Building 10, Room 2B37 NCI-Bethesda Bethesda, MD 20892 Phone:   301-496-1574 Fax:   301-496-0011 E-Mail:   james_yang@nih.gov

Biography

Dr. Yang graduated from the Massachusetts Institute of Technology with a B.S. in biology. He then completed his M.D. and surgical internship and residency at the University of California, San Diego. In 1984, he came to the Surgery Branch, NCI, as a medical staff fellow. He subsequently became a senior staff fellow, then a senior investigator in 1987. He has been involved in studies of the immune response to tumor-associated antigens and has been a principal investigator of clinical trials in renal cell carcinoma and soft tissue sarcoma.

Research

Tumor Antigens in Murine Models and Human Renal Cancer

The laboratory's major interest is in elucidating mechanisms of immune tumor rejection using murine models and studying human renal cancer. In the last decade, it has been established that the immune system can cause the complete and durable rejection of certain metastatic cancers in some individuals. Our understanding of this process has been greatly enhanced by the discovery of several dozen tumor-associated antigens expressed by human melanoma, which can be recognized by tumor-reactive T cells. At this point, the two major new challenges are to develop ways to manipulate and enhance the reactivity to known antigens to increase the frequency of tumor rejection, and to identify similar antigens from tumors other than melanoma. Towards the first goal, we have been working to identify the dominant native antigens in realistic murine tumor models so that therapeutic strategies can be developed using accurate preclinical systems. We described tyrosinase-related protein-2 (TRP-2) as an antigen for the B16 melanoma and identified the specific epitope processed and recognized by T cells. Another tumor-expressed antigen, p15E, an endogenous murine retroviral envelope protein, was identified as an immune target on the murine MC-38 colon cancer as well as on other syngeneic tumors. The T cell response to these antigens and the parameters which quantitate the response in immune and nonimmune mice were also clarified. We have recently identified two other antigens expressed by the MC-38 tumor and are in the process of characterizing them. Future work will test strategies for enhancing the immune response and therapeutic potential of these immune responses by modifying the antigens and adding vaccine and cytokine adjuncts.

In pursuing the second major goal, we have concentrated on human renal cell cancer (RCC). This malignancy is one that is responsive to immunotherapy, showing some durable complete responses to interleukin 2 (IL-2). We are conducting a randomized trial of 400 patients to determine the effect of IL-2 dose on response rate and overall survival of patients with metastatic RCC. In parallel, we have been developing methods for cloning T cells from patients with RCC that recognize their cancer. This has been successfully accomplished and these cells have been used to identify two antigens from a renal cancer which serve as immune targets. Both of these antigens are unmutated and one is expressed on multiple renal cancers as well as on some samples of prostate and bladder cancer. Current work directed at developing ways to immunize with these antigens may be of utility against a variety of cancers.

Another new clinical initiative in RCC, begun in collaboration with other investigators, has been a clinical trial of an antiangiogenic agent. We are conducting a blinded, randomized, placebo-controlled trial of an antibody which neutralizes vascular endothelial growth factor (VEGF). VEGF is a hormone involved in the growth of cells lining new blood vessels. It is overproduced by nearly all RCCs and this overproduction seems related to the mutation in the von Hippel-Lindau tumor suppressor gene that is found in nearly all clear-cell RCCs. Therefore it is thought that VEGF is important in the growth of the abundance of tumor vessels seen in RCC and represents a favorable target for antiangiogenic therapy. This trial is examining response rate, time-to-progression, and survival in patients with metastatic RCC. In addition, surrogate endpoints for antiangiogenic trials are being sought using experimental imaging techniques in coordination with clinical evaluation.

This page was last updated on 9/25/2008.