# Targeting Lag-3 and PD -1 in Myeloid Cells of GBM

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $402,791

## Abstract

Glioblastoma (GBM) is the most aggressive type of primary malignant brain tumor in
adults. GBM has a bleak prognosis of approximately 12-15 months, despite continuing
advances to the standard of care. Immunotherapy has demonstrated the significant
potential to boost immune responses against many cancer types; inhibitors of checkpoint
molecules, such as CTLA-4 and PD-1, have been used to treat many solid tumors with
varying success. While it has demonstrated efficacy in treating some tumors with an
inflammatory milieu and high degree of infiltration by anti-tumor T cells, it has shown little
to no response in treating tumors such as GBM. This tumor type is characterized by a
particularly immunosuppressive microenvironment with a notable paucity of T cells.
Targeted approaches designed to reduce immunosuppression in the tumor and increase
anti-tumor T cell activity are crucial to successfully treat GBM. Recent preclinical data from
our laboratory and preliminary findings from a Phase I clinical trial have shown promising
signs of efficacy with co-blockade of PD-1 and the alternative checkpoint LAG-3. We have
observed long-term survivors and radiographic responses in trial patients. We have noted
improved T cell responses against the tumor and a reduction in myeloid-derived
suppressor cells (MDSCs), following dual therapy of patients. We propose to study the
mechanism by which the immune system is enhanced against GBM via PD-1/LAG-3
blockade. We hypothesize that dual therapy recruits cells of the myeloid compartment in
order to boost anti-cancer T cell activity, and reduces the presence of immunosuppressive
myeloid cells in the tumor itself. To test our hypothesis, we will investigate the: i) priming
of T cells by antigen presenting myeloid cells in response to dual therapy in murine models
of GBM, ii) role of soluble product generated from cleavage of surface LAG-3 molecule in
inducing myeloid-mediated immunosuppression in the tumor (using both murine models
and patient samples), and iii) expansion of anti-tumor T cells and reduction in MDSCs
levels in patients following dual therapy. We will correlate our findings with overall survival
and progression free survival of the trial patients. We expect that the data generated from
these studies will provide novel insights into a previously unexplored mechanism by which
dual immune checkpoint blockade therapy can modulate the myeloid response against
tumors. The knowledge obtained from this study will contribute to improving the design of
future therapeutic strategies to treat GBM patients.

## Key facts

- **NIH application ID:** 10367804
- **Project number:** 1R01NS121404-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Michael Lim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,791
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367804

## Citation

> US National Institutes of Health, RePORTER application 10367804, Targeting Lag-3 and PD -1 in Myeloid Cells of GBM (1R01NS121404-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10367804. Licensed CC0.

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