Roswell Park Team Provides First Direct Evidence of CD28 Effects on CAR T-Cell Therapy | Roswell Park Comprehensive Cancer Center

BUFFALO, N.Y. — For patients with multiple myeloma, a cancer that often returns even after successful initial treatment, a new study from Roswell Park Comprehensive Cancer Center offers a potential path toward more durable responses to CAR T-cell therapy. Researchers have identified a key protein, CD28, that influences how effectively this emerging immunotherapy works and have pinpointed a way to potentially mitigate its negative effects.

Understanding CAR T-Cell Therapy and the Challenge of Relapse

Chimeric antigen receptor (CAR) T-cell therapy has significantly improved survival rates for individuals with multiple myeloma. However, 30-60% of patients experience relapse. The study, reported in Blood Cancer Discovery, investigated factors contributing to this relapse and potential strategies to overcome it.

The Role of the CD28 Protein

Led by Scott Olejniczak, PhD, Associate Professor of Oncology at Roswell Park, the research team discovered that the CD28 protein – found on both T cells and some multiple myeloma cells – impacts the effectiveness of CAR T-cell therapy. CAR T-cell therapy works by modifying a patient’s own T cells to recognize and destroy cancer cells.

Did You Know? Roswell Park Comprehensive Cancer Center was founded in 1898 and is one of the first NCI-designated comprehensive cancer centres in the country.

Addressing Immune Overreaction and Cytokine Release Syndrome

Sometimes, CAR T-cell therapy can trigger an overreaction of the immune system, releasing excessive proteins called cytokines. This can lead to cytokine release syndrome (CRS), a potentially serious inflammatory response. The study found that interactions between ligands and the CD28 protein on CAR T cells may contribute to this overreaction in multiple myeloma and other blood cancers.

Abatacept as a Potential Solution

Researchers found that the FDA-approved drug abatacept (brand name Orencia) may help control CRS by preventing CD28 from interacting with the CD86 ligand. Blocking CD28 signaling may also improve how well CAR T therapy works in some patients, as CD28 can promote the survival of myeloma cells when present on those cancer cells.

Expert Insight: The identification of CD28 as a key factor influencing CAR T-cell therapy response represents a significant step toward refining this promising immunotherapy. The potential to modulate the immune response with an existing drug like abatacept offers a relatively rapid pathway to clinical translation.

Looking Ahead: Clinical Trials and Collaborative Research

Dr. Olejniczak, in collaboration with Ehsan Mahlek, MD and Kelvin Lee, MD, PhD, is developing an early-phase clinical trial to evaluate this strategy in multiple myeloma patients undergoing CAR T-cell therapy. Mackenzie Lieberman, a former researcher in Dr. Olejniczak’s lab, was the study’s first author, and the research team also included members from McMaster University in Hamilton, Ontario.

Frequently Asked Questions

What is CAR T-cell therapy?

CAR T-cell therapy involves removing a patient’s T cells and inserting genes to enable them to target and destroy cancer cells. These modified T cells are then multiplied and returned to the patient.

What is cytokine release syndrome (CRS)?

CRS is a potentially serious inflammatory response that can occur when the immune system overreacts during CAR T-cell therapy, releasing too many cytokines.

What is abatacept and how might it help?

Abatacept is an FDA-approved medication that can prevent CD28 from interacting with the CD86 ligand, potentially controlling CRS and improving CAR T therapy responses.

As research continues, will these findings translate into more effective and less toxic treatment options for individuals battling multiple myeloma?