# CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2021 · $172,309

## Abstract

Multiple myeloma (MM) is a neoplasm of bone marrow (BM) resident long-lived plasma cells (LLPC) that
comprises 20% of all hematologic malignancies - second only to non-Hodgkin’s lymphoma. Despite new
chemotherapeutic agents, MM remains incurable. Although initially sensitive to chemotherapy, the primary
cause of treatment failure is the development of progressively more chemo-refractory disease whose
resistance is due to upregulation of pro-survival mechanisms. Thus defining the specific mechanisms of
myeloma cell survival/drug resistance is essential for the development of curative treatment approaches in
MM. It is now clear that myeloma cells are critically dependent on interactions with BM microenvironment (ME)
for their survival, just like their normal LLPC counterparts, and these interactions play a major role in MM
resistance to chemotherapy. Despite their central importance in myeloma survival however, the specific
molecular and cellular components involved in these interactions remain poorly characterized. In our original
proposal, we hypothesized that CD28 was playing significant pro-survival role in myeloma. Although it has
been primarily characterized as the prototype T cell costimulatory receptor involved in T cell activation and
survival, CD28 is also expressed on normal PC and MM. Work accomplished during the last funding cycle has
demonstrated that CD28 activation through two downstream signaling pathways plays an essential role in the
survival of both normal LLPC and MM cells, and that therapeutically blocking CD28 activation leads to MM cell
death/resensitization to chemotherapy in preclinical in vivo models. Based on these findings and initial
evidence for clinical efficacy, we have just opened a phase II clinical trial of blocking CD28 activation in
refractory/relapsed MM (NCT02334865) More recently, we have found that CD28 activation substantially
enhances the metabolic fitness of MM cells, which plays a major role in its pro-survival effect. In addition to
directly supporting MM survival, we have found that MM CD28 also modulates the MM ME. CD28 engagement
of its ligands CD80 and CD86 on stromal dendritic cells (DC) initiates CD80/CD86 “backsignaling” that induces
DC production of the pro-MM survival cytokine IL-6 and the immunosuppressive tryptophan (Trp)-catabolizing
enzyme indoleamine 2, 3 dioxygenase (IDO). We have also shown that CD86 expressed on MM cells has
independent pro-survival function. More recently we have determined that kynurenine (Kyn, produced by IDO
degradation of Trp) is an endogenous ligand for the aryl-hydrocarbon receptor (AhR), and AhR activation has a
significant but previously unrecognized pro-survival role in MM. The Specific Aims of this proposal are: 1).
Characterize the effect of blocking CD28 activation on myeloma chemoresistance in a Phase 2 clinical trial in
MM patients, 2). Define how CD28 activation enhances the metabolic fitness of myeloma cells, and 3).
Determine the role of MM CD28-media...

## Key facts

- **NIH application ID:** 10085205
- **Project number:** 5R01CA121044-14
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** KELVIN P. LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $172,309
- **Award type:** 5
- **Project period:** 2007-09-12 → 2021-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085205

## Citation

> US National Institutes of Health, RePORTER application 10085205, CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival (5R01CA121044-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10085205. Licensed CC0.

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