Our Science – Kammula Website
Udai S. Kammula, M.D.
Dr. Kammula's research is focused on studies of tumor immunology and the development of effective immunotherapies for the treatment of patients with cancer. He was awarded a federal technology transfer award in 2011 for his studies in T cell isolation. His clinical interests are in the management of malignancies of the liver, pancreas, and gastrointestinal tract.
Dr. Kammula has active clinical trials for patients with metastatic cutaneous and ocular melanoma.
The overall goal of my laboratory and clinical efforts is to develop effective immune based therapies for patients with advanced cancer. Our strategy involves a comprehensive approach utilizing preclinical in vitro experimentation, in vivo murine models, and innovative human clinical trials. The analysis of clinical results feeds further basic experimentation in an iterative process that is aimed at elucidating important immunologic principles for the successful treatment of human cancers. My laboratory has specifically focused on the isolation of novel human T cell populations for cancer therapy and translational studies to define the molecular and biologic T cell characteristics that are associated with therapeutic response. This work can be summarized in the following bench to bedside projects:
Project I: Iterative translational strategy to define optimal T cells for the adoptive immunotherapy of human cancers
There has been significant progress made in the understanding of T cell recognition of human tumor antigens, however the properties that enable T cells to mediate clinical cancer regression remain unclear. We hypothesized that an iterative translational strategy involving isolation and clinical adoptive transfer of sequential populations of well characterized melanoma specific T cell clones could help systematically define the specific antigenic targets and lymphocyte characteristics associated with T cell persistence, therapeutic efficacy, and toxicity. To overcome the significant obstacle in isolating multiple clonal variants for use in cancer therapy, we recently described a novel T cell isolation platform to rapidly obtain antigen specific T cell clones under GMP standards from the peripheral blood of patients. The methodology utilizes high throughput cytokine gene expression profiling to identify rare antigen specific T cells within heterogeneous cell populations. The technology is the subject of U.S. Patent Application (12/866,919) and was evaluated by the NCI Technology Advisory Group in 2011 and voted as one of NCIs top intramural inventions with respect to significance, innovation, and commercial potential. This work has also resulted in a federal technology transfer award in 2011 (Recipient: Kammula).
The versatility of the rapid cloning technology has allowed us to isolate a variety of CD8+ T cell clones that have specificity for common tumor antigens including gp100, MART, tyrosinase, NY-ESO, MAGE, and mesothelin. Further molecular characterization of these cells revealed that the stoichiometric production of IL-2 and IFN-g mRNA by these CD8+ T cells could further define a highly proliferative central memory (TCM) population. In the initial iteration of our research strategy, we translated these novel in vitro findings to a first-in-human clinical trial in which we adoptively transferred gp100 specific effector clones derived from TCM parental cells to patients with metastatic melanoma (NCI 08-C-0104). Analysis of this trial has revealed that these clones were able to target skin melanocytes in an autoimmune fashion, persist long term, and reacquire TCM attributes after transfer. This represents the first evidence in humans that TCM-derived effector clones can exert potent antigen specific effector function and also undergo self renewal to repopulate the memory pool after adoptive transfer. These findings have direct implications on the selection of T cells for future adoptive immunotherapy. The methodology for isolation of tumor specific central memory cells is the subject of a second U.S. Patent Application (PCT/US2011/47719).
Project II: Development of personalized adoptive immunotherapy targeting driver mutations expressed in uveal melanoma
Uveal melanoma: a rare and lethal cancer with no effective systemic therapies. Uveal melanoma (UM) is the most common intraocular tumor in adults and accounts for ∼5% of all melanomas. Unlike cutaneous melanoma (CM), UM originates from melanocytes of the choroid, ciliary body, and iris (collectively known as the uvea). Its annual incidence is 5.1 per million or approximately 1600 new cases each year in the U.S. Based on these statistics, UM represents a "rare disease" as defined by The Rare Disease Act of 2002 (HR 4013) and the U.S. Orphan Drug Act. Approximately half of patients diagnosed with primary UM will develop metastatic disease, typically involving the liver. The median survival after diagnosis of liver metastases is approximately 4 to 6 months with a 1-year survival of approximately 10% to 15%. Although progress has been made in the treatment of metastatic CM, there are currently no effective systemic therapies for the treatment of metastatic UM.
Rational for immunologic targeting of driver mutations in uveal melanoma. The last 30 years has provided substantial evidence that the human immune system can naturally generate a vigorous immunologic response against tumor antigens expressed by metastatic cutaneous melanoma. Not surprisingly, a number of immune based therapies have shown the ability to mediate durable cancer remission in this, once thought of, fatal disease. Uveal melanoma, however, still represents a mystery in terms of its responsiveness to immune therapies. From an immune targeting perspective, UM share many of the same melanocyte differentiation antigens (gp100, MART, tyrosinase) as CM, but mutational analyses have shown that the profile for UM is very different from that of CM. Whereas CM often have mutations in BRAF or NRAS, more than 80% of UMs will have activating mutations in either GNAQ or GNA11. These mutations convert the Gq and G11 proteins into a constitutively active form, which in turn, activate the MAPK pathway. Thus, mutant GNAQ/11 act as classic driver mutations by inducing constitutive downstream signaling that contribute to UM development and maintenance of the malignant phenotype. We hypothesized that highly prevalent and conserved non-synonymous driver mutations, as in GNAQ/11, may generate ideal neo-epitope immunogens that can be recognized by endogenous T cells. In theory, therapeutic use of mutation specific T cells should have no normal tissue toxicity and mediate potent cancer control, given the essential role of these driver mutations to the malignant phenotype. Furthermore, immunologic targeting of tumors harboring these mutations may prove to be more durable when compared to pharmacologic molecular inhibition of the MAPK pathway, which often has a transient tumor effect due to the recruitment of robust alternative signaling pathways. In support of the novelty of this approach, to date, no known common driver mutations have been successfully targeted by antigen specific immunotherapies in clinical trials.
This page was last updated on 7/16/2014.