Madhav Dhodapkar, M.D.

Olivera Finn, Ph.D.

University of Pittsburgh

Funded in June 2004: $690,000 for 4 years

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Identifying Immune System Responses to Premalignant Lung Cancer and Multiple Myeloma

Collaborating investigators will test the hypothesis that patients with one of two types of premalignant cancers have immune systems that recognize the premalignancies, and that it is the strength of their immune responses that determines which patients will develop malignant cancers and which will not.  If the investigators can identify the factors that determine the strength of the immune response to premalignancies, the research may lead to the development of therapeutic vaccines that strengthen the immune attack and prevent premalignancies from developing into malignant cancers.

Cancers start as a series of premalignant changes in tissues that are produced by harmful precancerous “antigens.”  Over time, the precancerous tissue develops into a clinically evident malignant tumor.  The premalignant changes usually go undetected by patients and their doctors because there are no symptoms.   Contrary to scientific speculation that premalignant disease escapes detection by patients’ immune systems; however, the investigators have found that certain precancerous changes are indeed detected by patients’ immune systems.  The investigators hypothesize that the strength of the subsequent immune attack determines whether patients with premalignant disease eventually develop malignant cancer.

Significance:  These collaborative studies may reveal the conditions under which innate and adaptive immune cells, respectively, detect and attack harmful antigens that produce changes in lung tissue and blood plasma cells.  The research also may show how and why these responses in some people are too weak to prevent these premalignancies from progressing to malignant disease.  By understanding how insufficient immune responses allow premalignancies to become malignant, scientists may be able to develop vaccines to enhance weak immune responses.  This new approach to cancer therapy would be based on strengthening the immune response rather than using drugs to destroy cells once they have become malignant.

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Immune Markers of Premalignant Disease Consortium

Most studies to date on human immune responses against cancer have been conducted in patients with advanced disease. Several groups have recently obtained evidence that the immune system can recognize early changes on the road to malignant transformation. The hypothesis we would like to test is that premalignancy is recognized and possibly contained by a host response, including an adaptive, antigen-specific immune response by T and B lymphocytes.

We are proposing a collaborative program between scientists on two groups of patients: a) patients with monoclonal gammopathy of undetermined significance (MGUS) as premalignant precursor of hematological tumors; and b) long term smokers with premalignant lung lesions, precursors to lung adenocarcinomas. The two groups will work together to validate the relevant antigens and assays that can be used to detect and measure immune responses to premalignant lesions. The two groups will share expertise, assays and patient samples. The Pittsburgh group has pioneered the study of cyclin B1 and MUC-1 as antigenic targets in cancer and premalignant lesions, both of which may also be valuable targets in MGUS. They will validate these antigens as targets for immune responses against premalignant disease. The Rockefeller/Yale group will in addition pursue cancer-testis antigens, which are expressed in both myeloma and epithelial cancers, and validate those as immune targets. Dr. Finn's group has expertise in assays for antibody responses to antigens in premalignancy, while Dr. Dhodapkar's group has expertise in T cell and dendritic cells in detecting immunity to premalignancy. This complementation will yield improved understanding of the host response to antigens on preneoplastic cells, and should suggest approaches to strengthen and harness the immune system for prevention of cancer.

Madhav Dhodapkar, M.D.

Dr. Madhav V. Dhodapkar is the newly appointed Arthur H. and Isabel Bunker Professor of Hematology at the Yale University School of Medicine. Until recently, he was the Irene Diamond Associate Professor and Head of Laboratory of Tumor Immunology and Immunotherapy at the Rockefeller University in New York. He also holds an adjunct clinical faculty appointment at the neighboring Memorial Sloan Kettering Cancer Center.

Dr. Dhodapkar obtained his medical degree from the All India Institute of Medical Sciences in New Delhi, India. He completed his medical training in hematology and medical oncology at the Mayo Clinic. In 1995, Dr. Dhodapkar was appointed as an assistant professor at the myeloma institute at the University of Arkansas. In 1998, Dr. Dhodapkar moved to the Rockefeller University as an assistant professor in the Laboratory of Cellular Physiology. In 2001, he was promoted to Head of laboratory at Rockefeller, and in 2004, to an Associate Professor. Dr. Dhodapkar has received numerous awards for his research, including those from the Mayo Clinic, American Society of Clinical Oncology, Irma T Hirshl Trust, Damon Runyon Cancer Research Foundation, and the New York Community Trust.

Dr. Dhodapkar's research and clinical activities focus on plasma cell dyscrasias, including multiple myeloma. His laboratory is focused on studying the role of host tumor interactions in the development of myeloma, with a particular focus on the immune system. He is also studying several approaches to boost the immune system against cancer, including the use of dendritic cell based vaccines. He has also served as the principal investigator on several major national clinical studies in plasma cell dyscrasias, and currently serves as the vice chair of the myeloma committee of the South West Oncology Group. He has authored over 60 publications in his area of research.

Olivera Finn, Ph.D.

Dr. Finn has been working in the area of tumor immunology for over 20 years. She obtained her Ph.D. in 1980 from Stanford University School of Medicine, where she also completed her postdoctoral training. She was on the faculty of Duke University before coming to Pittsburgh in 1991. She currently directs the University of Pittsburgh Cancer Institute Immunology Program.

Dr. Finn has a long and distinguished track record as a superb research mentor of both predoctoral students and postdoctoral fellows. Her laboratory was one of the first to study human T cell responses against tumors, and one of the first to identify a human tumor antigen, MUC1, capable of stimulating cytotoxic T cells. Her work led to the identification of a unique peptide epitope on that molecule culminating in 1993 in the approval of the synthetic version of this epitope as an investigational new drug by the FDA, which is now in Phase II clinical trials as a vaccine for pancreatic cancer.

Dr. Finn has recently undertaken a similar research strategy in lung cancer, and her laboratory has identified a cyclin B1 antigen in lung tumor cells. Her new data demonstrate that the cyclin B1 protein is over-expressed in preneoplastic lesions of the human airway, as well as in most lung tumors. In addition to her interest in cyclin B1 as a target for immunotherapy, Dr. Finn is now directing her research toward use of cyclin B1 as a biomarker for early detection of lung cancer.