Abstract Presenter: Parmeshwar Amatya, PhD, MPH, scientist in the Oncology Division at Washington University School of Medicine

Abstract Title: Mechanism of CRS: Critical Roles of IFN-γ, CD40L, and CD4 Cells.

Session: Welcome, Awards & Best Abstracts, 8:15 – 10:15 a.m. on Feb. 14, Ballroom B

Presentation Time: 9:15 – 9:30 a.m.

What is your presentation/abstract about?

“Our abstract is about the mechanism of cytokine release syndrome (CRS). We developed an in vitro CRS model in which we cocultured effector cells, i.e., CAR T-cells, tumor, and cytokine-primed myeloid cells. We used two different approaches to study CRS. The first was to screen a small-molecule kinase inhibitor library, and the second was to perform a custom CRISPR knock-out screen of genes expressed in and on activated T cells. Those approaches helped us to identify different pathways relevant to CRS and determine whether blocking those pathways would result in a drastic reduction in secretion of CRS-associated cytokines such as IL-6 and minimal impact on CAR T-cell antitumor activity.

“Our research reports that interferon gamma, CD40L, and CD4+ CART19 have key potential roles in CRS, which can be mitigated by blocking the PI3K delta gamma kinase pathway by duvelisib or the Janus kinase (JAK) 1/2 pathway by ruxolitinib.”

How did you first become interested in this topic?

“Despite remarkable clinical efficacy, CAR T-cell therapy for hematological malignancies is limited by life-threatening toxicity in over 50% of patients. This information inspired us to look for ways to improve treatment outcomes by reducing CRS toxicities without compromising CAR T-cell-mediated anti-tumor efficacy in the clinic.”

What are you working on next related to this topic?

“We need to verify the role of CD40L in an in vivo mouse model and eventually test this concept in humans with relapsed refractory non-Hodgkin lymphoma (NHL) receiving CAR T-cell therapy.  We are also pursuing additional CRISPR screens to identify new and novel genes and pathways for future CRS mitigation strategies, but also to identify genes that may enhance CAR T-cell therapy function in vitro and in vivo.”

How do you hope your work influences the field?

“On the basis of our research, clinical trials testing a JAK1 inhibitor, itacitinib, and a PI3K delta gamma inhibitor, duvelisb, for CRS prophylaxis are underway. This may improve efficacy of CAR T-cell therapy for different hematological malignancies in the future. Future studies combining PI3K delta gamma inhibitors and JAK1/2 kinase inhibitors, or combining CD40L plus gamma interferon neutralizing antibodies together, may have the strongest impact on mitigating CRS and potentially immune effector cell-associated neurotoxicity syndrome (ICANS).”

What excites you most about transplantation and cellular and gene therapy today?

“Novel discoveries and improvement in treatment outcomes offer more hope and will continue to drive progress in this field.”

Is there anything else you would like Tandem Meetings attendees to know about your abstract?

“We need to keep making improvements in this field for cost effectiveness and better treatment outcomes.”