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DOI: 10.1055/s-0035-1550266
What we learned from bench to bedside with the neuroblastoma targeting CD171-specific CAR
Introduction: Despite efficacy of chimeric antigen receptor (CAR) T cell therapy in leukemia and lymphoma patients, similar clinical responses in solid tumor patients is an unrealized objective. We developed a CAR specific for CD171, an antigen expressed in several solid tumors including neuroblastoma.
Methods: Since CD171 is also expressed in healthy tissues, we performed a safety study in non-human primates. Further, we analyzed influence of CAR extracellular spacer and cytoplasmic signaling domain variants on magnitude of cytotoxic CD8+T lymphocyte (CTL) activation for tumor cell cytolysis and cytokine secretion.
Results: CARs displaying the highest in vitro activity displayed the lowest in vivo anti-tumor activity, whereas CARs tuned for moderate signaling potency mediated tumor eradication. Recursively triggering hyperactive CARs rendered CTLs susceptible to activation-induced cell death (AICD), indicating that AICD is a critical parameter for achieving clinical efficacy against solid tumors.
Conclusion: Our results assisted the design of a clinical trial comparing two CARs with different cytoplasmic signaling domains in patients with refractory or relapsed neuroblastoma.