# Targeted activation of autoimmune checkpoints in B cell malignancies

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $410,875

## Abstract

Targeted therapy of cancer typically focuses on agents that suppress oncogenic signaling below a minimum
threshold needed for survival and proliferation. Here, we propose a novel strategy to overcome drug-resistance
in B cell malignancies based on targeted activation of an autoimmunity checkpoint (AIC) for removal of
autoreactive B cells. Owing to the necessity of the B cell repertoire to censor autoreactive clones, B cells
fundamentally differ in their signaling requirements from other cell types. Unlike other types of cancer, B cell
malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive
B cell receptor (BCR). Three recent studies from our group showed that targeted AIC-activation is achievable
by pharmacological hyperactivation of BCR-signaling above a maximum threshold (Chen et al., Nature 2015;
Shojaee et al., Cancer Cell 2015; Shojaee et al., Nature Med 2016). Hence, targeted AIC-activation can be
leveraged for eradication of drug-resistant B cell leukemia and lymphoma clones.
Based on these and other findings, we propose three Aims to validate targeted autoimmunity checkpoint (AIC)-
activation as new concept for the treatment of human B cell malignancies:
1. This proposal includes a mechanistic Aim based on the novel observation that checkpoints to safeguard
from autoimmunity disease are still functional in B cell malignancies. This Aim explores how AIC-activation
can be reliably achieved in B cell malignancies and how AIC-activation leads to cell death.
2. The stratification Aim will identify disease subtypes and groups of patients that may be most responsive to
AIC-activation and elucidate the biological basis of different treatment responses.
3. A therapeutic Aim will refine the treatment concept by prioritizing targeted hyperactivation of specific
components of the BCR pathway and by exploring combinations with established treatment agents.

## Key facts

- **NIH application ID:** 9844450
- **Project number:** 5R01CA157644-11
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Markus Muschen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $410,875
- **Award type:** 5
- **Project period:** 2017-04-04 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844450

## Citation

> US National Institutes of Health, RePORTER application 9844450, Targeted activation of autoimmune checkpoints in B cell malignancies (5R01CA157644-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9844450. Licensed CC0.

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