Purpose: Since CD7 may represent a potent target for T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) immunotherapy, this study aimed to investigate safety and efficacy of autologous CD7-chimeric antigen receptor (CAR) T cells in relapsed and refractory (R/R) T-ALL/LBL patients, as well as its manufacturing feasibility. Experimental Design: Preclinical phase was conducted in NPG{trade mark, serif} mice injected with Luc+ GFP+CCRF-CEM cells. Open label phase I clinical trial (NCT04004637) enrolled patients with R/R CD7-positive T-ALL/LBL who received autologous CD7-CAR T cells infusion. Primary endpoint was safety, secondary endpoints included efficacy, pharmacokinetic and pharmacodynamic parameters. Results: CD7 blockade strategy was developed using tandem CD7 nanobody VHH6 coupled with an ER/Golgi-retention motif peptide to intracellularly fasten CD7 molecules. In preclinical phase CD7 blockade CAR T-cells prevented fratricide and exerted potent cytolytic activity, significantly relieving leukemia progression and prolonged the median survival of mice. In clinical phase, the complete remission (CR) rate was 87.5% (7/8) three months after CAR T cells infusion; one leukemia patient achieved minimal residual disease negative CR and one lymphoma patient achieved CR for more than 12 months. Majority of patients (87.5%) only had grade 1 or 2 cytokine release syndrome with no T-cell hypoplasia or any neurological toxicities observed. The median maximum concentration of CAR T cells was 857.2 cells/µL at approximately 12 days and remained detectable up to 270 days. Conclusions: Autologous nanobody-derived fratricide-resistant CD7-CAR T cells demonstrated a promising and durable antitumor response in R/R T-ALL/LBL with tolerable toxicity, warranting further studies in highly aggressive CD7-positive malignancies.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin’s lymphoma with strong heterogeneity and high invasiveness. The high-throughput sequencing of peripheral blood T cell receptor (TCR) can analyze the individual's immune response and directly reflect the immune status. This study aimed to detect the TCR β chain in peripheral blood of DLBCL patients and the control group, and also to analyze the characteristics of the TCR CDR3 immune repertoire of DLBCL patients before and after chemotherapy. We found that the diversity of the baseline TCR repertoire in DLBCL samples were significantly reduced than those in the control group, while there was no difference in diversity before and after chemotherapy. Patients with 53.5 years or older, stage III-IV, high IPI score and ECOG performance showed a limited TCR CDR3 repertoire. The baseline TCR diversity of patients who achieved complete remission (CR) was higher than that of the non-remission (Non-CR) group. Comparing the V gene and J gene of the CR group and the Non-CR group, it was found that the two Vβ genes have the potential to predict the therapeutic effect. In addition, standard first-line chemotherapy regimen caused changes in the frequency of T cell clones in DLBCL patients. The similarity index of CR group was lower, indicating that more changes in TCR clones occurred after chemotherapy. This study revealed the unique TCR CDR3 immune repertoire of DLBCL patients and its relationship with clinical characteristics. Dynamic monitoring of TCR diversity can more accurately predict clinical benefit.
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