Haplo-Identical Non-Gene Editing CD7 CAR T-Cells Induced Bone Marrow and Extramedullary Remission in a Pediatric Patient with TP53 Mutated Relapsed and Refractory Early T-Cell Precursor Lymphoblastic Leukemia/Lymphoma after Haploidentical Hematopoietic Stem Cell Transplantation

Patients with relapsed/refractory early T-cell precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) respond poorly to traditional therapy and have dismal prognosis. CD7 expresses in almost all blasts of T-cell lymphoma/leukemia and represents one of the most promising therapeutic targets for T-ALL/LBL by CD7 targeted chimeric antigen receptor modified T cell therapy (CD7-CART). Because of shared CD7 expression in the majority of normal T-cell surfaces, we utilized an non-gene editing strategy by co-transducing CAR-T cells with a CD7 protein expression blocker (PEBL), and successfully overcame the fratricide as well as maintain the proliferation and cytotoxicity of CD7-CART-cells. Here, we presented the efficacy and safety results of CD7-CART therapy in a pediatric patient with TP53 mutated ETP-ALL/LBL. The patient was diagnosed with ETP-ALL/LBL at 2016, achieved and maintained complete remission (CR) for 2 years with traditional chemotherapy. The disease relapsed at a month after discontinuation of chemotherapy. He underwent haploidentical HSCT at the second CR, but suffered relapse again 2 years post haplo-HSCT. TP53 mutation（VAF:96.5%） and extensive extramedullary infiltration was detected at relapse. The patient was resistant to venetoclax combined with decitabine, homoharringtonine, aclarubicin, cytarabine and granulocyte colony stimulating factor (G-CSF), high-dose cytarabine combined with cladribine, G-CSF, chidamide and CD38 CART therapy. Nanobody derived CD7-CART cells were manufactured from lymphocytes of the donor. The CART cells were negative for CD7, CD223 and CD279. 70.5% of blasts in the bone marrow aspirates were observed prior to CAR T-cells infusion. A total of 5×10 ⁶/kg CD7-CART-cells were infused. CR was confirmed at day 30 bone marrow evaluation and maintained at the last followup at day 91. Partial remission was achieved as evaluated by PET-CT scan at day 93. Persistence of CD7-CART-cells can be detected with flowcytometry until day 96 post CAR T-cells infusion. Grade 3 cytokine release syndrome with high fever and hypotension were observed, which was relived by tocilizumab and dexamethosone. No organ dysfuction and immune effector cell-associated neurotoxicity syndrome were observed. In general, we showed for the first time that the nanobody derived CD7-CART with PEBL technology was a potent and safe salvage therapy in a relapsed/refractory ETP-ALL/LBL patient with high tumor burden.