# NanoOptogenetic immunotherapy for B cell lymphoma

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $437,693

## Abstract

Project Summary/Abstract:
Chimeric antigen receptors (CARs) are engineered recombinant receptors composed of
key signaling modules from both the T cell receptor (TCR) and co-stimulatory receptors
to mount effective anti-tumor immunity. Engineered CAR-T cells be reinfused into the
patient to recognize and attack cancer cells. CAR-T cell therapy has shown very
promising results in clinical trials. However, owing to a lack of precise control of the dose,
location, and timing of T cell activity, this method involves some significant safety
challenges to be overcome. For example, cytokine release syndrome (CRS), occurred
due to a large and uncontrolled release of cytokines in response to CAR-T, may cause
symptoms ranging from fever to potentially fatal organ destructions. In addition,
conventional CAR T cells are also associated with the targeted destruction of normal
tissue, which is known as “on-target, off-tumor” effects since tumor antigens are also
expressed at a certain level in several normal tissues. Therefore, the uncontrolled
aggressively amplified CAR-T cells cross-react with cells in the heart, lung or liver and
cause devastating consequences in patients. To address this challenging issue, we
propose to develop non-invasive methodologies that allow for the spatiotemporal control
of chimeric antigen receptor (CAR) T cells for cancer treatment by using B cell
lymphoma as a test case. This proposal is based on two key discoveries made by the
members of the team. First, we have created a way to optogenetically modulate the
function of calcium signaling by conferring visible light sensitivity to stromal interaction
molecule 1 (STIM1), activating the ORAI1 calcium channel in T cells to mount effector
immune responses. The second is our development of upconversion nanoparticles
(UCNPs), more specifically their use as in vivo relay nodes to capture and convert low
power, deep tissue-penetrant, and near infrared radiation (NIR) into visible light for in
vivo optogentic applications. In our preliminary results, we have demonstrated that the
use of ex vivo UCNPs and optogentic dual engineering approach can indeed
optogenetically instruct immune cells (i.e,, dentritic cells) to attack melanoma in mice,
and that NIR light therapy effectively suppresses melanoma growth and metastasis to
lungs. We propose three specific aims. For Aim 1, we will develop photo-tunable CARs
in engineered therapeutic T cells. In Aim 2, we will devise new generations of UCNPs
with improved compatibility with OptoCARs. In Aim 3, we will determine the efficacy of
nano-optogenetic CAR-T platforms in vitro and in vivo. This new strategy will overcome
many of the limitations of current CAR-T based approaches, and will enable new
applications in both fundamental science and human health.

## Key facts

- **NIH application ID:** 10144404
- **Project number:** 5R01CA232017-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Gang Han
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $437,693
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144404

## Citation

> US National Institutes of Health, RePORTER application 10144404, NanoOptogenetic immunotherapy for B cell lymphoma (5R01CA232017-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144404. Licensed CC0.

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