Evaluation of Chimeric Antigen Receptor Design To Identify Affinity and Spatial Binding Requirements
Tuesday, June 4, 2024
12:00 PM-2:00 PM
BIOMED PhD Thesis Defense
Title:
Evaluation of Chimeric Antigen Receptor Design To Identify Affinity and Spatial Binding Requirements for Optimal T Cell Effector Function
Speaker:
Nicholas W. Mazzanti, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University
Senior Associate Scientist
Johnson & Johnson Innovative Medicine
Advisors:
Madhusudhanan Sukumar, PhD
Associate Director of Cell Therapy
Johnson & Johnson Innovative Medicine
Kara L. Spiller, PhD
URBN Professor of Biomedical Innovation
School of Biomedical Engineering, Science and Health Systems
Drexel University
Details:
Chimeric antigen receptors (CARs) are artificial immunoreceptors that drive T cell-mediated tumor destruction. CAR-modified T cells have demonstrated unprecedented clinical success, leading to six FDA-approved CAR T cell therapies targeting hematological malignancies. In many cases, however, CARs elicit suboptimal T cell effector function. CAR T cell therapies have been less impactful in patients with solid tumors, yielding no current FDA-approved treatments for these indications. While CAR T cells have positively disrupted the landscape of medicine, many structural modifications are needed to improve the modality.
Antigen binding affinity and spacer length are important biophysical properties of CAR design that directly impact T cell effector function. These parameters play a critical role in determining a CAR’s clinical performance, yet optimal affinity and spacer characteristics remain unclear. Furthermore, it’s unknown whether ideal CAR design parameters are universal or target specific. Here, we describe our strategy to assess the influence of antigen binding affinity and spacer length on T cell effector function. We explore multiple tumor models to understand whether our results may be widely applied or restricted to individual indications. First, we identified high affinity tumor-specific antibodies that represent both hematological and solid tumor models. Each parental antibody was sequence-manipulated and then recombinantly expressed to evaluate tumor binding strength. Affinity variant antibodies were then reformatted as CARs containing varied-length spacer domains. Genetically modified T cells expressing each CAR were evaluated for effector function, in vitro. The results of our studies indicated, for both tumor models, that antigen binding affinity and spacer length impact tumor killing and T cell expansion. These biophysical properties also influenced cellular avidity, suggesting an impact on synapse formation, T cell differentiation and persistence.
Collectively, our findings suggest applicable thresholds for rational CAR design. Further evaluation is required to optimize CAR design for each indication. However, the principles identified in this study may be used to improve clinical outcomes for patients in need.
Contact Information
Natalia Broz
njb33@drexel.edu