# Therapeutic use of T cells engineered to produce radiation-inducible cytokines

> **NIH NIH R21** · UNIVERSITY OF CHICAGO · 2020 · $211,410

## Abstract

Project Summary: We propose to use genetically-engineered T cells to deliver cytotoxic cytokines under the
control of a radio-inducible promoter. When the genetically engineered T cells localize to the tumor bed,
activation of the cytokine is achieved by radiotherapy (RT), thereby exposing the tumor to the therapeutic effects
of both RT and cytokine therapy. This “molecular switch” strategy was pioneered by our laboratory, employing
recombinant adenoviral vectors. In this concept, RT activates a chimeric gene with a radio-inducible promoter
linked to a cytokine gene. Furthermore, the direct anti-tumor effects of RT have the potential to synergize with
the anti-tumor effects of adoptively-transferred T cells.
HYPOTHESIS: The ability to exogenously control the production of cytokines by tumor-infiltrating T cells will (i)
counteract the immunosuppressive effects of the tumor, affecting a critical anti-tumor T cell effector function, (ii)
minimize systemic toxicity due to controlled local activation of cytokine production, (iii) potentiate the synergy
between RT and adoptive transferred T cells, and therefore (iv) improve the therapeutic ratio of RT.
Specific Aims: 1) Cloning of T cell-specific radio-inducible promoters in retroviral vectors driving expression of
a reporter gene for transduction of T cells, and in vivo analysis of gene induction by RT using longitudinal tumor
imaging; 2) Cloning of T cell-specific radio-inducible promoters in retroviral vectors to drive expression of
therapeutic cytokines in T cells and treatment of murine primary and oligometastatic tumors with radio-inducible
cytokines-expressing T cells plus local RT.
 Our imaging technology uniquely allows us to examine the same tumor, and an identical area of the tumor,
hours or days after each RT dose, and measure the increase in EGFP expression compared to levels before
RT. This will allow in vivo comparison and validation of radio-induction of T cell-specific promoters identified in
Aim 1. Furthermore, anti-tumor effects of T cells will be visible as destruction of cancer cells and vessels, thereby
providing us with mechanistic data. Other cutting-edge technologies in our proposal include a CT-scan image-
guided small animal irradiator for irradiation of mouse cancer tissues with millimetric precision.
 Our proposed combination of RT, gene therapy and adoptive T-cell therapy for treatment of locally advanced
or metastatic cancer is dramatically new, and therefore has the potential to move beyond traditional approaches
in the treatment of cancer. The initial clinical application of our new paradigm is the treatment of refractory solid
tumors and oligometastases with the combined effects of adoptively-transferred T cells carrying radio-inducible
cytokine cargo and RT, since RT has been shown to be an immunostimulatory modality; therefore, it is likely
that translation of our approach would result in increased cures and significantly lower toxicities for
cancer patients. Of not...

## Key facts

- **NIH application ID:** 9930549
- **Project number:** 5R21CA226582-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** RALPH R WEICHSELBAUM
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $211,410
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930549

## Citation

> US National Institutes of Health, RePORTER application 9930549, Therapeutic use of T cells engineered to produce radiation-inducible cytokines (5R21CA226582-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9930549. Licensed CC0.

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