Most patients with cancers arising from solid organs, such as the colon, pancreas, and breast, do not benefit from current immunotherapies. A major barrier to progress has been the identification of markers, known as antigens, on the surfaces of cancer cells that can be targeted by T cells. Patients who respond to immunotherapy develop T cells that recognize fragments of mutated proteins unique to cancer cells. These are known as neo-antigens, and in most cases they are “private,” or restricted to individual patients. Thus, immunotherapies targeting “private” neo-antigens must be customized, which is an expensive and time-consuming process that is impractical for treating large numbers of people.
To overcome this critical limitation, Dr. Klebanoff’s laboratory has recently developed a screen to identify neo-antigens shared between patients that they have termed “public” neo-antigens. Unlike private neo-antigens, public neo-antigens are derived from common mutations in driver genes that directly promote the processes of cancer growth and metastasis. Using this screen, he has discovered that commonly mutated driver genes in human solid cancers can generate public neo-antigens.
In this proposal, Dr. Klebanoff seeks to study the natural T cell response to public neo-antigens in cancer patients. As part of these studies, he will retrieve the genetic sequences encoding T cell receptors (TCRs) specific for these shared neo-antigens. This information will enable tracking of T cells specific for public neo-antigens within the blood and tumors of individual patients over time and in response to different cancer treatments. Additionally, Dr. Klebanoff will perform detailed functional characterization of patient-derived TCRs and compare their function to TCRs specific for the same antigens but retrieved from healthy donors. The success of this research will provide for the near-term possibility of treating common solid cancers with precision T cell-based immunotherapies. This includes adoptive transfer of TCR engineered T cells or active vaccination against public neoepitopes.
Projects and Grants
Clonal Dynamics and Functional Characterization of Patient-Derived T Cell Receptors Specific for Shared “Public” Neoantigens
Memorial Sloan Kettering Cancer Center | All Cancers | 2020
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