# Combinatorial application of nanoscale technologies to target a novel mechanism of immune evasion by cancer cells

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $690,825

## Abstract

PROJECT SUMMARY
Immunotherapy holds the promise of a cure for cancer. However, only a subset (<20%) of patients
exhibit durable response to immunotherapy. This is because immune checkpoint inhibitors need
immune cells in the tumor. However, many tumors are found to be immunologically barren or cold,
i.e. lack tumor infiltrating lymphocytes (TILs). Overcoming this barrier is key to a cure for cancer.
We recently discovered that cancer cells form physical nanoscale tentacles (tunneling nanotubes)
to connect with and harvest mitochondria from immune cells, which depletes the immune cells.
Recent evidence show mitochondria-harvesting tumors have poor clinical outcomes. There is is
an unmet need to target this novel mechanism of immune evasion. There are two distinct and
complementary strategies to achieve this goal: (1) Engineer CAR-Ts or TILS with extra
mitochondria (augmented T cells) such that any loss of mitochondria to cancer cells doesn’t not
fully deplete the immune cells of their metabolic capacity; and (2) Disable the ability of a cancer
cell to form nanotubes to harvest immune cell mitochondria. In this proposal, we aim to develop
an immunotherapeutic regimen that combines these two strategies with an immune checkpoint
inhibition. Specifically, We will evaluate different organelle transplantation technologies for
delivering mitochondria, a nanoscale structure, to a T cell ex vivo prior to infusion as cell therapy
(Aim 1); (2) Test the antitumor efficacy of these mitochondria-augmented T cells in combination
with a drug that inhibits the capability of cancer cells to form nanotubes and an immune checkpoint
inhibitor (Aim 2); and Dissect the mechanisms underlying mitochondrial harvesting (Aim 3). These
studies can lead to paradigm shift in immunotherapy and generate fundamental insights into
cancer-immune cell communications at the nanoscale.

## Key facts

- **NIH application ID:** 10978903
- **Project number:** 1R01CA293908-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Shiladitya Sengupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $690,825
- **Award type:** 1
- **Project period:** 2024-06-21 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978903

## Citation

> US National Institutes of Health, RePORTER application 10978903, Combinatorial application of nanoscale technologies to target a novel mechanism of immune evasion by cancer cells (1R01CA293908-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10978903. Licensed CC0.

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