# Engineered and Encapsulated Stem Cells for Resected Brain Tumors

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $386,033

## Abstract

SUMMARY
Glioblastoma (GBM) is the most common primary brain tumor in adults with a very poor prognosis. Given, the
central role tumor resection plays in GBM therapy clinical care, understanding the specific influence of tumor
resection on immune response in the tumor microenvironment offers a new platform for developing effective
immune based therapies for GBM. We have recently developed syngeneic orthotopic mouse GBM-model of
tumor resection and shown that tumor debulking results in substantial reduction of myeloid-derived suppressor
cells (MDSCs) and simultaneous recruitment of CD4/CD8 T cells into the resection cavity. In this proposal, we
will first generate GBM resection models from genetically distinct currently available mouse GBM lines and
analyze profiles of immune cells infiltrated into tumor microenvironment pre- and post-tumor debulking. While
resection of primary tumor has shown clinical benefit, systemically delivered or direct injection of therapeutic
agents in tumor resection cavities has provided limited additional benefit. In our previous studies, we have
extensively demonstrated that locally delivered receptor targeted engineered adult stem cells have therapeutic
benefits and synthetic extracellular matrix (sECM) encapsulation of stem cells is necessary to prevent their rapid
“wash- out” post-transplantation in mouse GBM tumor resection cavity. In our recently published studies, we
have shown that sECM encapsulated mesenchymal stem cell (MSC) mediated local delivery of bifunctional,
immunomodulatory and cytotoxic protein, interferon (IFN) β enhances selective post-surgical infiltration of CD8 T
cells and directly induces cell-cycle arrest in tumor cells. However, IFN has been known to upregulate program
cell death ligand 1 (PD-L1) expression on tumor cells, thus hindering the immunomodulatory function of IFN.
Based on the recent findings that: blocking PD-L1 induced by IFNβ treatment eradicates established tumors;
tumor suppressor, phosphatase and tensin homolog (PTEN) loss promotes immune resistance; and our exciting
preliminary data on: MSC-IFNβ mediated upregulation of PD-L1 in vivo; and local delivery of ScFv-PDL1, we will
create bimodal MSC expressing ScFv-PDL1 and IFNβ and test them in syngeneic PTEN wild type (wt.) and
mutant GBM models of resection. To ease clinical translation and ensure safety of our approach, we will
ultimately engineer clinical grade human MSC to co-express ScFv-PDL1/IFN β and HSV-thymidine kinase (TK)
and test our approach in GBM tumors generated from patient derived GBM lines in humanized NSG mice. The
incorporation of genetically engineered imaging markers markers into MSC and GBMs will allow us to follow
MSC fate and efficacy in vivo and thus to fine tune the proposed approaches. The overall goal of this proposal is
thus to immune profile genetically distinct GBM resection models and to assess rationale based therapeutic
efficacy of immunomodulatory agents. Once validated, we will initiate a c...

## Key facts

- **NIH application ID:** 10129437
- **Project number:** 5R01NS107857-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Khalid A Shah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,033
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129437

## Citation

> US National Institutes of Health, RePORTER application 10129437, Engineered and Encapsulated Stem Cells for Resected Brain Tumors (5R01NS107857-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10129437. Licensed CC0.

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