# B cell depletion to prevent autoimmunity

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $397,099

## Abstract

PROJECT SUMMARY
Immune related adverse events (IRAEs) remain a major obstacle to optimal application of combination
checkpoint blockade in human cancer. Deeper understanding of the mechanisms underlying these IRAEs, and
in particular underlying cellular and genomic pathways and antigenic targets is essential to develop optimal
strategies to prevent and treat these AEs. This application represents a collaborative effort between two
investigators with experience in cancer immunology (KD) and human autoimmunity (IS) to investigate the role of
B cells in IRAEs. It builds directly on our prior studies evaluating early immunologic changes in patients
undergoing immune checkpoint blockade, as well studies of altered B cell differentiation and function underlying
human autoimmune disorders. In these studies, we have observed that CCB therapy leads to a distinct pattern
of changes in B cells, particularly involving CD21lo B cell subset and plasmablasts. We have also identified
distinct epigenetic and transcriptional signatures of B cells in autoimmune disorders such as lupus. Our
hypothesis is that preexisting changes in autoreactive B cells will identify patients at risk for early IRAEs. We
further posit that CCB-induced expansion of pathogenic B cells is mediated by the engagement of epigenetic
and transcriptomic programs akin to those observed in naturally occurring autoimmunity. B cells have been
proposed to play both a pro- and anti-tumor role in cancer. In order to specifically isolate the effect of B cells in
IRAEs, we will evaluate changes in pathogenic B cells and plasmablasts in the context of a randomized clinical
trial to specifically deplete B cells in melanoma patients undergoing CCB. The specific aims of the project are:
Aim 1. To assess whether pre-existing transcriptional and epigenetic alterations in B cell subsets identify
patients at risk for CCB-induced irAEs and are normalized by Rituxan
Aim 2. To evaluate Rituxan-mediated depletion of pathogenic B cells and their contribution to irAEs
following CCB.
Aim 3. To evaluate whether depletion of B cells leads to alterations in circulating or tumor-infiltrating T
cells in patients undergoing CCB.
Together these studies will provide direct insights into the relative contribution of B cells in patients undergoing
CCB, both in terms of favorable as well as adverse impact on tumor-immune interactions and patient outcome.
Understanding these cellular interactions directly in humans is essential for developing rational approaches to
prevent IRAEs.

## Key facts

- **NIH application ID:** 10439680
- **Project number:** 5R01AR077926-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Kavita Madhav Dhodapkar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $397,099
- **Award type:** 5
- **Project period:** 2020-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439680

## Citation

> US National Institutes of Health, RePORTER application 10439680, B cell depletion to prevent autoimmunity (5R01AR077926-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10439680. Licensed CC0.

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