# Temporal analysis of the GBM tumor microenvironment during myeloid cell activating therapy

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $557,266

## Abstract

ABSTRACT
The tumor microenvironment (TME) in glioblastome multiforme (GBM) is often complex, overall
immunosuppressive, and can change quickly in response to different therapeutic interventions. The reason for
our limited understanding of the highly dynamic network is largely because i) current transcriptomic analyses
nearly always represent single time point data from surgical resection specimen, ii) the TME can change
rapidly during treatment and iii) the fact that peripheral immune cell composition generally does not reflect what
occurs inside tumors. In order to design more effective GBM therapies, we will i) require new therapeutic
approaches (drugs, carriers and combinations); ii) tools to serially interrogate TME changes over time so that
emerging compensatory mechanisms of resistance and immunosuppression can be identified. The goals of
this project are to i) test the novel myeloid cell targeted CANDI IL-12 activating therapies as they have shown
remarkable efficacy in preclinical GBM[Lugani et al., 2022, Adv Mat, in review] and other cancer models[Koch
et al., 2020, Cell Chem Biol, 27, 94-104.e5; Rodell et al., 2018, Nat Biomed Eng, 2, 578-588] and ii) improve
our temporal understanding of the GBM TME by performing serial multiplexed analyses. This proposal builds
on three recent novel technologies to address the above problems in new ways: i) FAST-FNA[Ko et al., 2020,
Angew Chem Weinheim Bergstr Ger, 132, 6906-6913; Oh et al., 2021, Clin Cancer Res] to perform serial,
deep multiplexed analyses of GBM, ii) multiplexed SAFE-intravital microscopy (IVM)[Ko et al., 2022, Adv Sci
(Weinh), e2200064; Ko et al., 2022, Nat Biotechnol] to analyze GBM drug distribution and cellular effects at
single cell resolution in vivo and iii) CANDI[Lugani et al., 2022, Adv Mat, in review; Rodell et al., 2018, Nat
Biomed Eng, 2, 578-588], a novel myeloid cell targeted dual immunostimulatory approach to efficiently
jumpstart a GBM immune response. We propose three aims: i) serial analysis of the TME in two murine
models (CT2A and 005) using the new bioorthogonal approaches (“baseline study”); ii) determine the efficacy
of CANDI myeloid activating therapies in GBM and iii) perform mechanistic studies to gain further insight into
the effects of CANDI and how to enhance this therapy in GBM. Findings from these mechanistic studies will be
important because they could reveal at a mechanistic level the treatment's mechanisms of action, and from a
clinical perspective, define which TME components that should be studied clinically. Ultimately, we hope to
improve our temporal understanding of the GBM TME and apply the gained knowledge to the design of future
trials.

## Key facts

- **NIH application ID:** 10850692
- **Project number:** 5R01CA281735-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** RALPH WEISSLEDER, MD, PhD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $557,266
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850692

## Citation

> US National Institutes of Health, RePORTER application 10850692, Temporal analysis of the GBM tumor microenvironment during myeloid cell activating therapy (5R01CA281735-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10850692. Licensed CC0.

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