# T cell migration and cardiovascular toxicity in immunotherapy

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $569,426

## Abstract

PROJECT SUMMARY/ABSTRACT
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 βII-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.

## Key facts

- **NIH application ID:** 10192644
- **Project number:** 5R01AI147362-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Minsoo Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $569,426
- **Award type:** 5
- **Project period:** 2019-07-22 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10192644

## Citation

> US National Institutes of Health, RePORTER application 10192644, T cell migration and cardiovascular toxicity in immunotherapy (5R01AI147362-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10192644. Licensed CC0.

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