# Targeting metastatic tumors with engineered cellular therapies

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $385,097

## Abstract

SUMMARY
Metastatic brain tumors are the most commonly observed intracranial tumors. Patients with advanced breast
cancer have a high propensity to metastasize to the brain with human epidermal growth factor receptor (EGFR)
positive and triple-negative breast cancer (TNBC; estrogen and progesterone receptor and Her2 negative)
subtypes showing the highest incidence of brain metastases. To effectively treat multiple highly aggressive brain
metastatic breast tumors (BMBT), there is an urgent need to develop therapeutics that target aberrant signaling
pathways in tumor cells and the immune cells in the tumor microenvironment (TME) of BMBT. Recently, we have
shown that intrathecal (IT) and intracarotid artery (ICA) injection of adult allogeneic “off the shelf” mesenchymal
stem cells (MSC) expressing bifunctional protein simultaneously targeting EGFR and (DR)4/5), EvDRL have
therapeutic efficacy in mouse models of BMBT that mimic clinical settings. These findings although promising,
have raised fundamental questions on the potential of combining MSC released EvDRL induced tumor cell killing
with therapeutic agents that simultaneously activate immune effector functions against BMBT. Our recently
published studies indicate that DRL (TRAIL) component of EVDRL is the key driver of EVDRL mediated cell death
in patient derived BMBT cells. Previous studies have shown that in addition to tumor cells, DRL induces
apoptosis in myeloid derived suppressor cells (MDSC) and CD4+ CD25+ FoxP3+ Tregs and simultaneously
increases recruitment of CD8+ T cells in the TME. Furthermore, clinical and pre-clinical studies using combined
cytotoxic therapy and immune checkpoint (ICI) blockade have shown increased efficacy in breast metastatic
tumors thus offering the potential to combine of MSC-EVDRL with immunomodulatory agents to treat BMBT. In
this proposal, we will first evaluate the efficacy and influence of MSC-EVDRL induced tumor cell death in the TME
in humanized (hu) NSG breast to brain metastatic tumor models generated from BMBT cells that have varying
response to EVDRL mediated apoptosis. Next, we will create bimodal MSC releasing EVDRL and anti-
programmed cell death protein (PD)-1 nanobodies (Nb-PD1) and evaluate the mechanism combined efficacy of
engineered MSC in huNSG breast to brain metastatic tumor models. We hypothesize that human MSC-EvDRL
will lead to specific killing of local and widely disseminated BMBT cells and Nb-PD1 will target T cells recruited to
the TME. To ease clinical translation, we will incorporate activatable kill switch/PET imaging agent, herpes
simplex virus-thymidine kinase (HSV-TK) into MSC and assess their fate by PET imaging and selective
eradication mediated by HSV-TK activation. Given that engineered MSC are in phase I clinical trial in non-small
cell lung cancer patients; a phase I/II trial using IT of anti-PD-1 antibody is currently ongoing in leptomeningeal
metastatic patients; and our MSC-DRL therapy in primary brain tumor (GBM) pat...

## Key facts

- **NIH application ID:** 10931641
- **Project number:** 5R01CA285519-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Khalid A Shah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,097
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931641

## Citation

> US National Institutes of Health, RePORTER application 10931641, Targeting metastatic tumors with engineered cellular therapies (5R01CA285519-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10931641. Licensed CC0.

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