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 a high throughput reverse immunology approach for the identification of novel tumor antigen epitopes for T cell based immunotherapy
The identification of novel immunogenic epitopes presented by tumors in the context of common HLA molecules is critical to extending current immune based therapies for cancer. The use of natural TIL to identify and clone the genes that encode for the tumor antigens recognized by these T cells has had significant success in defining therapeutic targets such as the melanocyte differentiation antigens, MART and gp100. However, the difficulty in generating reactive TIL from nearly all other solid tumors has limited this forward immunology approach to antigen discovery. Reverse immunology attempts to predict and identify immunogenic peptides from the sequence of a gene product that is believed to be specific and highly expressed in the tumor. This strategy typically uses in silico computer based HLA binding algorithms to help predict putative peptides which are then used to stimulate lymphocytes to evaluate their veracity. The inherent weakness of this peptide mining approach is the incredibly low probability of identifying a peptide that is naturally processed, presented, and sufficient to induce tumor lysis upon T cell recognition. As a consequence, low throughput attempts to screen limited numbers of peptides are typically unsuccessful. To overcome this obstacle, we hypothesized that the rapid T cell cloning technology, described in Project I, could be adapted to serve as an efficient platform to perform high throughput screening of large numbers of predicted peptides. The evaluation of hundreds of putative epitopes for their ability to stimulate human PBMC would facilitate the identification of the rare true epitopes, and thus lead to more efficient antigen and epitope discovery. The newly identified epitopes could then serve as novel peptides to clone antigen specific CD8+ T cells for adoptive transfer evaluation in humans (as outlined in Project I). Based on the identification of commonly shared mutated proteins in a variety of epithelial cancers, we further hypothesized that discovery of immunogenic mutated tumor specific epitopes might allow for the isolation of T cells for the therapy of common malignancies. Further, given the tumor specific nature of these mutations, their expressed epitopes may serve as immunologically ideal antigens that would have minimal on target toxicity of normal tissues
This page was last updated on 10/29/2013.