Immunotherapy, including T-cell checkpoint inhibition, has rapidly changed the outcome of advanced cancers in a subset of patients. To extend benefit of these promising therapies to more patients, we must delineate predictive biomarkers and develop approaches to enhance the efficacy of checkpoint blockade. Our long-term goal is to define the contribution of tumor genetics to clinical benefit from checkpoint blockade immunotherapies and to use this information to develop better therapeutic modalities. Our group has shown that an elevated mutational burden correlates with benefit from therapy in melanoma patients treated with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) therapies. For the proposed project, we have collected melanoma tumors (N=42) from pembrolizumab-treated patients and will perform the correlative genetics analyses for a Phase II trial of nivolumab ipilimumab in advanced ovarian cancer (planned accrual, N=96). Using these samples, in Aim 1 we will examine our working hypothesis that an elevated mutational burden increases the likelihood of response to checkpoint blockade in melanoma and ovarian cancers. We will then integrate T cell receptor (TCR) sequencing data available from the melanoma tumors and peripheral blood to investigate the hypothesis that TCR oligoclonal dominance will add to mutational burden as a predictor of response.
In Aim 2, we will identify and clone neoantigen-specific T cells from melanoma patients treated with pembrolizumab, and then use these clones to investigate our hypothesis that neoantigen-specific T cells can be activated by homologous peptides. Finally, in Aim 3, we will characterize whether therapy-induced DNA damage can sensitize melanoma and ovarian cancer cell lines to checkpoint blockade therapy using in vitro and in vivo models of melanoma and ovarian cancer. These experiments will determine whether therapy-induced mutagenesis can sensitize tumors to checkpoint blockade therapy. The preclinical and correlative studies outlined in this proposal have the potential to (a) elucidate mechanisms of response to immunotherapy in two fatal cancers, and (b) provide data to begin to answer the clinically important question of whether non-immunogenic tumors can be sensitized to checkpoint blockade therapy by inducing mutations. The studies will be led by Dr. Alexandra Snyder, a junior faculty member at Memorial Sloan Kettering Cancer Center under the mentorship of Dr. Timothy Chan, a leading tumor geneticist; Dr. Jedd Wolchok, a renowned tumor immunologist; and Dr. Carol Aghajanian, a world leader in Gynecologic Oncology. To achieve her long-term goal of become an independent investigator, Dr. Snyder has assembled an advisory committee of leading scientists, and has developed a structured curriculum aimed at deepening her knowledge base so she can advance the field.

Public Health Relevance

Immunotherapy, a type of medication that causes a patient's own immune system to attack his/her cancer, has shown that the immune system can control and even cure some advanced cancers. First, we will try to figure out why these therapies work in certain patients but not others. Then, we will use cell and mouse models to try to turn non-responding cancers into responding cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA201544-01
Application #
9013345
Study Section
Subcommittee J - Career Development (NCI-J)
Program Officer
Lim, Susan E
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$180,036
Indirect Cost
$13,336
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Snyder, Alexandra; Nathanson, Tavi; Funt, Samuel A et al. (2017) Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis. PLoS Med 14:e1002309
Nathanson, Tavi; Ahuja, Arun; Rubinsteyn, Alexander et al. (2017) Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade. Cancer Immunol Res 5:84-91