# Project 1: Active immunotherapy combined with checkpoint modulation for glioblastoma

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $345,823

## Abstract

Project 1: Active immunotherapy combined with checkpoint modulation for glioblastoma 
SUMMARY/ABSTRACT 
The lack of effective treatments for glioblastoma (GBM) patients remains a significant health problem and 
highlights the need for novel and innovative approaches. Immunotherapy is an appealing strategy because of 
the potential ability for immune cells to traffic to and destroy infiltrating tumor cells in the brain. Pre-clinical studies 
and clinical trials of dendritic cell (DC) vaccination for GBM have shown some promising results, but also some 
treatment failures. The broad overall goals of this research project are to investigate mechanisms of immune 
evasion following active immunotherapy, and to develop rational combinations of immunotherapeutic strategies 
to overcome the immunosuppressive milieu of the brain tumor microenvironment. Our new preliminary data 
strongly suggests that active immunotherapy with DC vaccination may create a pro-inflammatory tumor 
microenvironment that induces the immigration of immunosuppressive antigen presenting cells (iAPC), which 
express high levels of PD-L1 and IL-10. We show that these cells are phenotypically similar to the iAPC that 
dominantly influence the T-cell response to chronic viral infection, and may act to counteract effective T-cell 
responses induced by DC vaccination via a mechanism involving PDL1/PD-1. Furthermore, inhibition of iAPC 
using an anti-PD1 mAb (Nivolumab, BMS) or a CNS penetrant inhibitor of CSF-1R (PLX-3397, Plexxikon), in 
conjunction with tumor lysate-pusled DC vaccination (DC-Vax-L), resulted in significantly prolonged survival in 
tumor-bearing animals with well-established intracranial (i.c.) gliomas. We therefore postulate that clinically 
relevant anti-tumor immunity to glioblastoma (GBM) must have two cellular components: 1) significant infiltration 
of tumor-specific tumor-infiltrating lymphocytes (TIL); and 2) blockade of immune-regulatory antigen presenting 
cell (iAPC) function within the tumor microenvironment. As such, our hypothesis is that the local cellular 
interactions between iAPC and T lymphocytes within the brain tumor microenvironment is a critical factor 
influencing the efficacy of immunotherapies in glioblastoma patients. A better understanding of the biology of 
these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune 
responses for this deadly type of brain tumor. In Aim 1, we will study the mechanisms by which iAPC limit glioma- 
specific anti-tumor immune responses in vitro and in vivo. In Aim 2, we will evaluate the efficacy of combining 
tumor lysate-pulsed DC vaccination (to induce T-cell infiltration into tumors) with immune checkpoint inhibition 
and other novel immunoregulatory targets (to block iAPC function) in pre-clinical syngeneic animal models of 
glioblastoma, and explore the use of a novel PET tracers as non-invasive imaging biomarkers of immune 
response. Finally, in Aim ...

## Key facts

- **NIH application ID:** 10225550
- **Project number:** 5P50CA211015-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Linda M Liau
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,823
- **Award type:** 5
- **Project period:** 2017-08-11 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225550

## Citation

> US National Institutes of Health, RePORTER application 10225550, Project 1: Active immunotherapy combined with checkpoint modulation for glioblastoma (5P50CA211015-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10225550. Licensed CC0.

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