) Anti-CD19 chimeric antigen receptor (CAR) T cells work well in treating patients with acute lymphoblastic leukemia (ALL), but much less so in other more indolent B cell malignancies, such as chronic lymphocytic leukemia (CLL). Improved CAR T cells are necessary to enhance antitumor efficacy in the treatment of these cancers. Our lab has recently demonstrated that constitutive expression of the co-stimulatory molecule CD40 ligand (CD40L, CD154) improves cytotoxicity and antitumor efficacy of CAR T cells in vitro and in an immune- compromised xenograft mouse model. My hypotheses are that CD40L-modified CAR T cells promote an improved antitumor response through several mechanisms: (i) by enhancing the activation of CAR T cells resulting in improved cytotoxicity and functional CAR T cell persistence; (ii) by increasing the immunogenicity of tumor cells leading to their recognition by host immune effector cells; and/or (iii) via activation of host immune cells to mediate a sustained endogenous antitumor response. The long-term objectives of this proposed study aim to investigate the biology of CD40L-modified CAR T cells to provide mechanistic insights into how CD40L-modified CAR T cells achieve an enhanced antitumor efficacy when compared to T cells expressing the CAR alone. The first specific aim will be to transfer the CD40L-modified CAR T cell platform into a fully immune-competent syngeneic lymphoma mouse model and to determine its antitumor efficacy. Based on preliminary data, we anticipate that the results of these proposed experiments will validate the use of CD40L-modified CAR in this setting. The second specific aim will determine the effect CD40L-modified T cells have on the immunogenic phenotype of tumor cells and their clearance. The third specific aim will be to investigate the ability of CD40L-modified CAR T cells to change the cellular composition of the tumor microenvironment and to induce an antitumor response by endogenous T cells. The implications of this work will extend beyond its application in indolent B cell malignancies, but also provide insight into how genetic engineering of T cells can alter the tumor microenvironment and provide a rationale for utilizing this CD40L- based CAR T cell approach in solid tumors.

Public Health Relevance

The significance of new strategies aimed at optimizing chimeric antigen receptor (CAR) T cell therapy is emphasized by the lack of clinical success in certain hematological diseases and solid tumors. This project follows the strategy of ?armoring? CAR T cells with a biologically active molecule, CD40L, which has immune- stimulatory properties and can, thereby, help in eliciting a more effective immune response against the tumor. Utilizing a clinically relevant immune-competent syngeneic mouse model, we will assess the effect of ?armored? CAR T cells on the tumor microenvironment and how they interact with tumor and other immune cells. This could provide a rationale for using this approach in the setting of solid tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA213668-02
Application #
9412752
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schmidt, Michael K
Project Start
2017-01-09
Project End
2021-01-08
Budget Start
2018-01-09
Budget End
2019-01-08
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065