Determinants of resistance to engineered T-cell therapies targeting CD19 in lymphoma

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Determinants of resistance to engineered T-cell therapies targeting CD19 in lymphoma The outcomes for patients with large B-cell lymphoma (LBCL) that are relapsed or refractory to frontline therapy remain quite poor. While anti-CD19 chimeric antigen receptor (CAR19) T-cells have emerged as a promising treatment option for this group of patients, over half of these patients still go on to exhibit disease progression. The mechanisms through which resistance to CAR19 T-cell therapy develops, and factors predictive of poor outcomes, have not yet been well characterized. In this proposal we seek to elucidate these mechanisms with the ultimate goal of informing the design of improved immunotherapies that will result in better outcomes for patients with LBCL. Novel methods to profile tumor-derived cell-free DNA from the blood plasma of patients, also referred to as circulating tumor DNA (ctDNA), have unlocked significant opportunities to monitor treatment response and study tumor biology both prior to and after therapy. We recently applied one such method called Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq), a targeted sequencing approach for ctDNA detection and profiling, to a cohort of patients with LBCL undergoing therapy with the CAR19 platform axicabtagene ciloleucel (axi-cel). We found that ctDNA levels prior to and following CAR19 T-cell infusion were predictive of response, and also identified several genes involved in B-cell lineage commitment that are recurrently altered in patients who ultimately progressed. In this proposal we will build on this prior data by expanding our cohort and validating our findings in an independent cohort of patients undergoing therapy with an alternate CAR19 platform (Aim 1). We will then assess the downstream effects these alterations have on tumor phenotype and the tumor microenvironment. By integrating gene expression data and cutting-edge immunophenotyping and computational tools we will resolve the components of the intratumoral immune milieu to gain a better understanding of how different immune cell populations contribute to response and resistance. (Aim 2). Finally, we will employ a novel organoid tissue culture system to directly assess how alterations in these genes effect the interaction between CAR19 T-cells and tumor cells in the context of an intact immune microenvironment. Ultimately we hope that these studies will have implications not only in development of improved CAR19 platforms for lymphoma, but also in the improvement of immunotherapies for other cancer types as well. This proposal will be carried out at the Stanford University School of Medicine, under the mentorship of Ash Alizadeh, MD/PhD. Through completion of this proposal, I will gain the relevant experience in bioinformatics and tumor immunology to successfully launch a career as an independent investigator focused on developing and translating new immunotherapies for patients with lymphoma.