Six authors were selected to present their work in the Feb. 14 Best Abstracts session. Summaries of their presentations appear below. The entire session is available for on-demand viewing for registered attendees of the 2025 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT® and CIBMTR®.

Enhancing the Persistence and Anti-Tumor Efficacy of CAR-T and CAR-NK Cells through Genetic Disruption of Death Receptors

Tal Cohen, MD, research fellow at Memorial Sloan Kettering Cancer Center, discussed her work on enhancing the persistence and anti-tumor efficacy of chimeric antigen receptor T-cell (CAR T) therapy and CAR natural killer (CAR NK) cells through genetic disruption of death receptors.

The research demonstrated that FAS ligand (FAS-L) was predominantly expressed on endogenous CAR-engineered T and NK cells and that CAR T and CAR NK cells co-engineered with delta FAS had enhanced persistence and antitumor efficacy compared to their controls. Further, CAR T-cell-derived FAS-L was dispensable for both in vitro and in vivo antitumor efficacy.

“Overall, CAR-engineered lymphocyte persistence is mediated by the FAS-L and FAS autoregulatory circuit. Impairment of FAS in CAR T and CAR NK cells establishes a potential novel gene therapy strategy that could enhance the persistence of anti-tumor efficacy of cellular immunotherapies,” Cohen said.

Comparative Analysis of CRISPR-Cas9, Lentiviral Transduction, and Base Editing for Sickle Cell Disease Therapy in a Murine Model

Henna Butt, MD, hematology/oncology fellow, Children’s National Hospital, discussed a comparative analysis of CRISPR-Cas9, lentiviral transduction, and base editing for sickle cell disease.

The research demonstrated that base editing created fewer double-stranded breaks, allowed for gentler editing, and reduced the risk of deleterious insertions and deletions. Investigators found no differences in stem cell quality, proliferation, differentiation, or signaling frequency across therapies ex vivo.

“However, in a competitive transplantation setting, we do see the Makassar base editing and BB305 transduction outcompete CRISPR-Cas9 BCL11A editing,” Butt said. “We also see that CRISPR-Cas9 editing results in lower signaling reduction and lower editing in GPA+ cells.”

Gene Therapy with Reduced-Intensity Conditioning for Sickle Cell Disease

Stella Davies, MBBS, PhD, MRCP, director of the Division of Bone Marrow Transplantation and Immune Deficiency and co-executive director of the Cancer and Blood Disease Institute, Cincinnati Children’s Hospital Medical Center, and professor at the University of Cincinnati, discussed results from a gene therapy protocol for sickle cell disease using reduced-intensity conditioning.

Seven patients were included in the study, which met its primary endpoint of a greater than 80% reduction in veno-occlusive events. Six patients had sustained hemoglobin F (HbF^G16D) levels and robust F-cell generation. Time to platelet recovery and neutrophil engraftment was 16 days. One patient had lower engraftment of transduced cells. Patients had an average length of hospital stay of 24 days. Grade 4 thrombocytopenia was present for a median of five days, and grade 4 neutropenia was present for a median of eight days.

“I am hopeful that our reduced intensity conditioning and study execution entirely within an academic space will allow our next planned study to focus on cost reduction and exportability,” Davies said.

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

Parmeshwar Amatya, PhD, MPH, scientist in the Oncology Division at Washington University School of Medicine, discussed his findings regarding the mechanism of cytokine release syndrome (CRS) from an in vitro model.

“We developed an in vitro assay of CRS. A high-throughput kinase inhibitor screen identified Janus kinase (JAK) 1/2, and therefore interferon gamma and phosphoinositide 3-kinase (PI3K) delta and gamma, as key targets for CRS mitigation without impacting CAR T-cell function,” Amatya said.

In their assay, researchers found that interleukin-6 (IL-6) was exclusively secreted by a pMC1 cluster of myeloid cells in response to activated CD19 CAR T cells. A CRISPR knockout screen identified CD40L as a key mediator of CRS. They also found that CD40L was selectively expressed on activated CD4 cells, but not on CD8 or NK cells. Cytotoxic activity was primarily mediated through CD8 CAR T cells, but CD4 CAR T cells were the main driver of CRS and IL-6.

Accelerated Brain Aging and Cognitive Decline in Hematologic Cancer Survivors Post-Transplant: Insights from Brain Age Gap and White Matter Hyperintensities

Noha Sharafeldin, MD, MSc, PhD, assistant professor in the Hematology and Oncology Division and Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, discussed accelerated brain aging and cognitive decline in hematologic cancer survivors post-transplant.

“Bone marrow transplant (BMT) survivors do experience significant cognitive decline following transplant with evidence of brain age acceleration compared to healthy controls,” Sharafeldin said.

Further, she found that accelerated brain age was associated with worse neurocognitive scores. She believes this supports the potential clinical utility of MRI-based markers of brain aging. These promising predictors of declining cognitive function could help identify patients at high risk of decline to potentially target them for early intervention in the future.

A Randomized Phase II Study Comparing Cyclosporine and Sirolimus Combined with MMF or Post-Transplant Cyclophosphamide As Gvhd Prophylaxis after HLA-Matched or -Mismatched Unrelated Mobilized Blood Cell Transplantation Using Nonmyeloablative or Reduced-Intensity Conditioning

Masumi Ueda Oshima, MD, associate professor in the Clinical Research Division, Fred Hutchinson Cancer Center, and associate professor, University of Washington School of Medicine, discussed results from a randomized phase 2 trial comparing cyclosporine and sirolimus combined with mycophenolate mofetil (MMF) or post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis after HLA-matched or -mismatched unrelated mobilized blood cell transplantation using nonmyeloablative or reduced-intensity conditioning.

“The combination of PTCy with cyclosporine and sirolimus improved CRFS (chronic GVHD-free relapse-free survival) and reduced the chronic GVHD rate to a significantly low level,” Oshima said. “However, this came with the increased risk of infections as we have seen in prior prospective studies with PTCy.”

There was no increase in non-relapse mortality or relapse with PTCy, cyclosporine, and sirolimus.