MGUS and multiple myeloma — a common, incurable, cancerous tumor characterized by clonal proliferation of plasma cells in the bone marrow — provide a unique model with which to study in vivo the clonal evolution of a human preneoplastic state into overt malignancy. Twenty-five to 30 percent of those diagnosed with MGUS will later develop myeloma or related cancers, but there are no known reliable predictors of this progression nor any known methods to prevent the transition. A goal of the Dhodapkar lab is to study the nature of the immune response against the tumor cells in MGUS and myeloma by carrying out immunologic investigations directly in patients, focusing on the MGUS-multiple myeloma transition. One key aspect of this model is that purification of tumor cells and cells in the tumor’s microenvironment is relatively easy to do. Additionally, in contrast to some of the other preneoplastic states (such as a colon polyp), cells in monoclonal gammo-pathy cannot be surgically removed, allowing for the direct study of a tumor’s evolution in vivo.

Dr. Dhodapkar’s laboratory is currently conducting clinical studies to determine how to boost immune resistance to multiple myeloma tumors. One strategy they’re investigating is the use of antigen-bearing dendritic cells. Dendritic cells are specialized to initiate and regulate immunity, and early studies from the lab show that it’s possible to rapidly boost T cell immunity in cancer patients as well as in healthy volunteers. Because the immune system could potentially be silenced in an antigen-specific manner by inducing regulatory T cells in vivo, members of the lab are looking into how these regulatory T cells are induced with the hope of creating a novel approach to treating autoimmune diseases.

Another focus of the Dhodapkar lab is the use of chemical adjuvants or immunomodulatory drugs such as thalidomide — a drug that has led to clinical tumor remissions in several myeloma patients. Because the mechanism of action of thalidomide is still unknown, the group is working to elucidate that mechanism in plasma cell tumors.

Dr. Dhodapkar is also actively pursuing the use of monoclonal antibodies to target tumor cells. Monoclonal antibodies have been remarkably effective in treating patients with B cell tumors. The group has shown that such antibodies may be used to recruit adaptive immune responses against tumors. But precisely how monoclonal antibodies exert their antitumor effect is not yet fully understood. Dr. Dhodapkar and his lab are now trying to further characterize and define the mechanism by which this immune response enhancement is mediated.

Finally, by studying patients directly, Dr. Dhodapkar aims to provide fundamental insights into the interaction of tumor cells with their microenvironment, as well as the immune responses against them. An improved understanding of this interaction may contribute to novel approaches for the prevention and treatment of human cancer. By addressing the disease from this angle, he recently discovered that an innate immunity to cancer stem cells may help protect people with MGUS against the full-blown disease and that these cells could be an important target for cancer vaccines.

CAREER

Dr. Dhodapkar received his medical degree in 1987 from the All India Institute of Medical Sciences in New Delhi, India. He completed his residency in internal medicine at the St. Louis University Hospital in 1990, pursued a four-year fellowship in hematology and medical oncology at the Mayo Clinic in Rochester, Minnesota and then spent three years as assistant professor of medicine at the Myeloma Institute at the University of Arkansas Medical Sciences in Little Rock. Dr. Dhodapkar came to Rockefeller in 1998 as assistant professor and was appointed associate professor in 2004. He is also an adjunct faculty member at the Memorial Sloan-Kettering Cancer Center.

In 2002, Dr. Dhodapkar was named a New York Community Trust Scholar in Blood Diseases Research. That same year he received the Irma T. Hirschl Career Scientist Award and the Damon Runyon/Eli Lilly Translational Research Award. In 2000, he received a National Institutes of Health Mentored Physician Scientist Award and in 1999 he received the Cancer Research Institute Investigator Award. In 1995, Dr. Dhodapkar received the Florence A. Carter Fellowship in Leukemia Research, and he was a 1994 recipient of the William F.J. Summerskill Award from the Mayo Foundation.