# Targeting macrophages to sensitize myeloma to immune checkpoint blockade

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2020 · $335,113

## Abstract

Project Summary
Immune checkpoint blockade has emerged as a promising approach to treat cancer by restoring T cell effector
function and breaking a tumor-permissive microenvironment. Remarkable clinical efficacy, durable response,
and low toxicity of PD-1 checkpoint blockade have been observed in various malignancies including
hematological cancers. However, in a phase 1 study of nivolumab (anti-PD-1 antibody; BMS-936558), none of
27 patients with multiple myeloma (MM) experienced a partial or complete response, whereas objective
responses were observed in about 40% of patients with follicular lymphoma or diffuse large B cell lymphoma.
As we and others have shown that MM cells express high levels of PD-L1, that bone marrow (BM)-infiltrating T
cells are largely PD-1 positive, and more importantly MM cells carry somatic mutations in amounts similar to as
B-cell lymphomas, the absence of response to PD-1 antibody therapy for MM cannot be explained by a lack of
tumor-infiltrating T cells or PD-L1 or neoantigen expression by MM cells or immune cells. We speculated that
PD-1/PD-L1 checkpoint blockade alone is insufficient to break the permissive microenvironment in MM
because BM-infiltrating immunosuppressive cells, such as tumor-associated MΦs, myeloid-derived suppressor
cells (MDSCs), and/or regulatory T cells (Tregs) could still inhibit the function of MM-specific effector T cells
restored by the checkpoint blockade. Indeed, our preliminary studies showed that, similar to human MM, PD-1
mAbs had no significant therapeutic effect against established MM in murine models. However, to our surprise,
in vivo depletion of MΦs, but not MDSCs or Tregs, resulted in significant anti-MM effects following PD-1
checkpoint blockade. This application will test our hypothesis is that MΦs, as one of the major BM-infiltrating
cell types, are crucial in suppressing T-cell immunity in the tumor microenvironment, and targeting these cells
will significantly improve the therapeutic efficacy of checkpoint blockade in patients with MM. Aim 1 will
determine the role and mechanism of MΦs in the primary resistance to PD-1 checkpoint blockade therapy in
MM. Aim 2 will elucidate the mechanisms of MΦ-mediated immune suppression, and Aim 3 will determine the
translational potential of combining MΦ-targeting and PD-1 antibodies to treat human MM. Accomplishing
these aims will provide the justification and tools to clinically target BM-infiltrating MΦs to sensitize MM patients
to PD-1 checkpoint inhibitors. The proposed studies will also lead to a better understanding of the fundamental
mechanisms underlying the primary resistance to PD-1 checkpoint blockade and could pave the way to the first
substantial improvements in the treatment in MM and other hematological malignancies by way of targeting
MΦs and PD-1 inhibition.

## Key facts

- **NIH application ID:** 9634041
- **Project number:** 5R01CA214811-04
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Qing Yi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,113
- **Award type:** 5
- **Project period:** 2017-03-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9634041

## Citation

> US National Institutes of Health, RePORTER application 9634041, Targeting macrophages to sensitize myeloma to immune checkpoint blockade (5R01CA214811-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9634041. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*