Journal
MOLECULAR THERAPY
Volume 25, Issue 8, Pages 1933-1945Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2017.04.017
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Categories
Funding
- AIRC, Molecular Clinical Oncology 5 per mille, Innate immunity in cancer: Molecular targeting and cellular therapy [9962]
- IG, Novel leukemia treatment by the use of chimeric antigen receptors (CARs) [17248]
- Libera Le Ali project, Fondazione Just Italia
- SNF [310030 166445]
- Oncosuisse [KFS-3728-08-2015]
- S.T.'s fellowship
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Chimeric antigen receptor (CAR)-redirected T lymphocytes are a promising immunotherapeutic approach and object of pre-clinical evaluation for the treatment of acute myeloid leukemia (AML). We developed a CAR against CD123, overexpressed on AML blasts and leukemic stem cells. However, potential recognition of low CD123-positive healthy tissues, through the on-target, off-tumor effect, limits safe clinical employment of CAR -redirected T cells. Therefore, we evaluated the effect of context-dependent variables capable of modulating CAR T cell functional profiles, such as CAR binding affinity, CAR expression, and target antigen density. Computational structural biology tools allowed for the design of rational mutations in the anti-CD123 CAR antigen binding domain that altered CAR expression and CAR binding affinity without affecting the overall CAR design. We defined both lytic and activation antigen thresholds, with early cytotoxic activity unaffected by either CAR expression or CAR affinity tuning but later effector functions impaired by low CAR expression. Moreover, the anti-CD123 CAR safety profile was confirmed by lowering CAR binding affinity, corroborating CD123 is a good therapeutic target antigen. Overall, full dissection of these variables offers suitable anti-CD123 CAR design optimization for the treatment of AML.
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