DESCRIPTION:

T-cell engaging CD20xCD3 bispecific antibodies (BsAbs) have changed the treatment of relapsed/refractory B-cell lymphoma, but responses are often limited. Loss of the CD20 antigen and T-cell exhaustion explain only part of this resistance. In "cold" lymphomas escaping BsAb, I found selective pressure on the CXCR4-CXCL12 axis, which governs the microanatomical positioning of germinal center large B-cell lymphoma. In a preclinical large B-cell lymphoma model, giving the CXCR4 antagonist plerixafor as a short "priming dose" 1-2 hours before BsAb significantly improves survival, while CXCR4 antagonism given alone has minimal response. I hypothesize that CXCR4 priming transiently impairs lymphoma retention in immune-cold niches, making them more susceptible to killing mediated by T-cell engagers. I will share my research program to define the optimal priming schedule, visualize T-cell: lymphoma interactions in situ, identify the critical cellular targets of CXCR4 antagonism, and test whether biomarkers can predict which lymphomas preferentially benefit from CXCR4-antagonist priming of BsAb.

LEARNING OBJECTIVES

• Describe the mechanisms currently invoked for bispecific T-cell engager failure
• Explain why microanatomical access is a distant and modifiable determinant of engager efficacy, separate from antigen expression and T-cell exhaustion.
• Evaluate CXCR4 antagonism given as a ‘priming dose” as a novel intervention to improve T-cell engager efficacy.