# Optimizing systemic immunotherapy for personalized brain metastasis treatment

> **NIH NIH U54** · STANFORD UNIVERSITY · 2021 · $352,061

## Abstract

ABSTRACT – PROJECT 3
By definition, when patients develop brain metastasis (BM) from their systemic cancer, they become stage IV
and their prognosis drops to under a year. While the mechanism behind brain-tropism of different tumors (Project
1) and the role of resident immune cells in supporting brain metastasis (Project 2) need to be elucidated, there
is also a gap in our understanding of how brain tumors represent an inflection point in patient survival and anti-
tumor response. We have previously observed evidence of intracranial metastases dampening the immune
response mounted by cytotoxic T lymphocytes. Understanding the mechanism by which tumor-associated
macrophages (TAMs) recruited to BMs exert said immunosuppression is crucial for the successful treatment of
brain metastasis. We propose to study the role of TAMs in dampening T cell priming via a TGF-β mediated
pathway. We hypothesize that TGF-β released by TAMs in the BM act at the level of the draining lymph nodes
to induce global immunosuppression. We believe that blockade of TGF-β at the lymph nodes will augment an
antitumor immune response induced by checkpoint-blockade or vaccination strategies (such as with induced
pluripotent stem cells or iPSCs). To test our hypothesis, we will investigate the: i) migration of TAMs to BMs and
tumor draining lymph nodes and its effects on T cell priming, ii) role of TGF-β secreted by the TAMs in mediating
said immunosuppression at the level of the draining lymph nodes, and iii) synergy of inhibiting TGF-β signaling
and iPSC vaccines to treat BMs. We expect that the data generated from these studies will provide novel insights
into a previously unexplored mechanism by which BM-infiltrating TAMs exert systemic immunosuppression and
open new avenues for the design of future therapeutic strategies to treat patients with brain metastasis.

## Key facts

- **NIH application ID:** 10272361
- **Project number:** 1U54CA261717-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Michael Lim
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,061
- **Award type:** 1
- **Project period:** 2021-09-21 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10272361

## Citation

> US National Institutes of Health, RePORTER application 10272361, Optimizing systemic immunotherapy for personalized brain metastasis treatment (1U54CA261717-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10272361. Licensed CC0.

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