Keynote Presentation: Outsmarting the Escape Artist: Resistance in CAR T-Cell Therapy for Hematologic Cancers w/ Live Q&A

Despite remarkable success in relapsed or refractory B-cell malignancies, CAR T-cell therapy faces significant challenges: primary resistance, relapse, and treatment-related toxicities. This talk reviews clinical outcomes of FDA-approved CAR T products and highlights emerging mechanisms of resistance—including tumor-intrinsic factors such as CD58 loss, host microenvironmental barriers, and T-cell exhaustion. Dr. Ruella will present pre-clinical and clinical data on novel strategies to overcome these obstacles: engineering PD-1:intracellular-CD2 switch receptors to restore CD2–CD58 co-stimulation; leveraging metabolic modulation with the ketogenic diet and β-hydroxybutyrate to enhance CAR T oxidative phosphorylation and persistence; and applying CD5-knockout CAR T cells to treat T-cell lymphomas while preserving immune competence. Attendees will gain a translational perspective on next-generation CAR T design and how these innovations may broaden indications, improve durability of response, and reduce toxicity in hematologic cancers.

Learning Objectives:

1. Analyze clinical and biologic mechanisms that drive primary and acquired resistance to CAR T-cell therapy in B-cell malignancies.

2. Analyze clinical and biologic mechanisms that drive primary and acquired resistance to CAR T-cell therapy in B-cell malignancies.

3. Discuss translational approaches for expanding CAR T therapy to T-cell lymphomas and autoimmune diseases while mitigating toxicity.