# Proj. 2: Combining immune checkpoint blockade with T cell activation

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $485,132

## Abstract

Summary Project 2
Immune Checkpoint blockade (CPB) has revolutionized the care for many cancers, but clinical trials using anti-
PD-1 ICB have not had significant efficacy in GBM. GBM has a profoundly immunosuppressive tumor
microenvironment (TME) promoted by immunosuppressive cell types, pathways and mediators. Thus, it is not
surprising that single CPB did not meet therapeutic expectations. The goal of Project 2 is to improve patient
outcomes following anti-PD-1/ CTLA-4 therapy in GBM by identifying rational combination therapy approaches.
We hypothesize that combining therapies to improve T cell priming and activation with anti-PD-1/ CTLA-4 therapy
will significantly increase response rates in GBM, converting these immunologically “cold” tumors into “hot”
tumors. Based on our preliminary data showing that selective loss of PD-1 at different stages of T cell
differentiation can either promote or antagonize effector and memory differentiation, we further hypothesize that
the timing of PD-1/ CTLA-4 blockade in combinatorial regimens may critically influence protective anti-tumor T
cell responses. Project 2 will test these hypotheses using three complementary approaches that evaluate timing
of PD-1 blockade combined with vaccination, oncolytic virus vaccine therapy, or targeted therapies in the
following aims: 1- Determine the effect of peptide vaccination combined with anti-PD-1/ CTLA-4 therapy
on the establishment of anti-tumor immune responses and development of immunological memory; 2-
Test if addition of an oncolytic virus boost to GBM cell vaccine further increases sensitivity to anti-PD-
1/ CTLA-4; and 3- Evaluate the ability of small molecule CDK4/6 targeted therapies to enhance therapeutic
benefit of anti-PD-1/ CTLA-4 in GBM models. Interactions with all Projects and utilization of all Cores are
described in the Proposal. Our findings will provide optimal ways to combine therapies and insights into the
immunosuppressive GBM microenvironment. These data will directly inform the rationale design of combination
therapies for future clinical trials for GBM patients.

## Key facts

- **NIH application ID:** 10210220
- **Project number:** 5P01CA236749-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** E. Antonio Chiocca
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $485,132
- **Award type:** 5
- **Project period:** 2020-07-03 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210220

## Citation

> US National Institutes of Health, RePORTER application 10210220, Proj. 2: Combining immune checkpoint blockade with T cell activation (5P01CA236749-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10210220. Licensed CC0.

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