T cell immunotherapy is emerging as a promising cancer treatment option and has proven effective in a range of malignancy. However, a concern has been that prolong circulation and/or non-specific migration of the adoptively transferred in vitro activated T cells to non-target tissue sites might predispose to cardiovascular damages and systemic inflammatory responses. Anecdotal evidence of a cardiovascular hazard has emerged and abundant data point to exacerbation of cytokine release syndrome associated with T cell immunotherapy. We undertook this study to address critical knowledge gaps regarding the molecular mechanisms that determine the function and fate of the adoptively transferred in vitro-generated T cells, and cardiovascular toxicity associated with sequestration of the therapeutic T cells at non-tumor-bearing tissues after intravenous transfer. Through several lines of evidence from our preliminary study, we propose that autologous T cells undergo significant molecular and cellular reprogramming during ex-vivo manufacturing process. We predict that the intrinsic changes are important for the robust T cell activation and expansion, but fail to derive T cell migration toward the target tumor, and thus serve to increase toxicity. We discovered that a decrease in ?II-spectrin expression during in vitro T cell activation results in decreased cell stiffness and a dramatic change in spontaneous T cell migration pattern upon intravenous transfer. Moreover, screening of a key intracellular protein associated with the altered T cell migration revealed a novel Rab13-mediated endosomal redistribution pattern that mediates the non-specific T cell migration. We will, (1) determine the causes of cardiovascular cytotoxicity and cytokine release syndrome associated with non-specific migration of in vitro activated T cells, (2) determine the molecular mechanisms that prevent specific migration toward the target tissue site, and (3) test whether we can generate T cells with an improved tissue-specific homing property and a reduced cardiovascular side-effects. These studies will combine differential perturbations of novel mechanisms that regulate activated T cell migration, in vivo mouse models, state of the art intravital multiphoton imaging, high-resolution singles cell assays, and analysis defining vascular inflammatory responses to understand a potentially serious risk of adoptively T cell transfer immunotherapy. We shall also explore novel alternative approaches that might promote the anti-cancer efficacy and minimize the cardiovascular risk of the T cell immunotherapy.

Public Health Relevance

T cell immunotherapy has emerged as a promising therapeutic option with complete and durable responses in several disease conditions such as viral infection, autoimmune disease, atherosclerosis, and cancer. However, a concern has been that prolong circulation and/or non-specific migration of the adoptively transferred in vitro activated T cells to non-target tissue sites might predispose to cardiovascular damages and systemic inflammatory responses. We will investigate the molecular and cellular mechanism of chemokine-mediated migration of the therapeutic CD8 T cells. These studies will combine differential perturbations of novel mechanisms that regulate activated T cell migration, in vivo mouse models, state of the art intravital multiphoton imaging, high-resolution singles cell assays, and analysis defining vascular inflammatory responses to understand a potentially serious risk of adoptively T cell transfer immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI147362-02
Application #
9981638
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jiang, Chao
Project Start
2019-07-22
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627