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Summary: Background: Thus far, all approved chimeric antigen receptor (CAR)-T products are manufactured using modified viruses, which increases the risk of tumorigenesis, costs and production time. We aimed to evaluate the safety and efficacy of a kind of virus-free CAR-T cells (PD1-19bbz), in which an anti-CD19 CAR sequence is specifically integrated at the PD1 locus using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, in adults with relapsed/refractory (r/r) B cell non-Hodgkin’s lymphoma (B-NHL). Methods: This single-arm phase I dose-escalation clinical trial evaluated PD1-19bbz in adult patients with r/r B-NHL from May 3rd 2020 to August 10th 2021. The patients were recruited and treated at the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Patients underwent leukapheresis and lymphodepleting chemotherapy before PD1-19bbz infusion. After the dose-escalation phase including three cohorts: 2 × 106/kg, 4 × 106/kg, 6 × 106/kg with three patients at each dose level, the optimal biological dose was determined to be 2 × 106/kg, which was then applied to an extended cohort of nine patients. The primary endpoint was the incidence of dose-limiting toxicities (DLT). The secondary endpoint was the response and survival. This trial was registered at www.clinicaltrials.gov as #NCT04213469. Findings: Twenty-one patients received PD1-19bbz infusion. Among all treated patients, 19 (90%) patients were diagnosed with stage III or IV disease. Meanwhile, 19 (90%) were stratified as intermediate risk or worse. Of note, four participants had >50% programmed death ligand-1 (PD-L1) expression in pre-treatment tumour sample, including two with extremely high levels (∼80%). There was no DLT identified. Fourteen patients had low-grade (1–2) cytokine release syndrome and two patients received tocilizumab. Four patients experienced immune effector cell-associated neurotoxicity syndrome of grade 1–2. The most common adverse events were hematologic toxicities, including anaemia (n = 6), lymphocyte count decreased (n = 19), neutrophil count decreased (n = 17), white blood cell count decreased (n = 10), and platelet count decreased (n = 2). All patients had objective response and 18 patients reached complete response. At a median follow-up of 19.2 months, nine patients remained in remission, and the estimated median progression-free survival duration was 19.5 months (95% confidence interval: 9.9–infinity), with the median overall survival not reached. Interpretation: In this first-in-human study of non-viral specifically integrated CAR-T products, PD1-19bbz exhibited promising efficacy with a manageable toxicity profile. A phase I/II trial of PD1-19bbz in a larger patient cohort is underway. Funding: National Key R&D Program of China, National Natural Science Foundation of China, Key Project of Science and Technology Department of Zhejiang Province, Shanghai Zhangjiang National Independent Innovation Demonstration Area, Key Projects of Special Development Funds.

Rituximab is a widely used anti-CD20 monoclonal antibody with a high incidence of infusion-related reactions (IRRs) during administration. Reducing the incidence of IRRs remains problematic in hematological practices. In the present study, a novel strategy of a prednisone pretreatment regimen was designed similar to the combination of rituximab, cyclophosphamide, epirubicin, vincristine and prednisone (R-CHOP) with the aim of exploring the effect on the incidence of IRRs to rituximab in patients with diffuse large B-cell lymphoma (DLBCL). A prospective, randomized (1:1) and controlled study was conducted in three regional hospitals in two groups (n=44 for each group): i) A control group treated with standard R-CHOP-like regimen; and ii) a group receiving a prednisone-pretreatment, modified R-CHOP-like protocol for newly diagnosed patients with DLBCL. The primary endpoint was to assess the incidence of IRRs to rituximab, as well as the association of IRRs with the efficacy of treatment. The second endpoint involved clinical outcomes. The total incidence of IRRs to rituximab in the treatment group was significantly lower compared with that in the control group (15.9 vs. 43.2%; P=0.0051). The different grade incidence of IRRs was lower in the treatment group compared with that in the control group (P=0.0053). In total, 29.5% of patients (26/88) experienced >1 IRR episode. The incidence of IRRs in the pre-treatment group was decreased compared with that in the control group in the 1st cycle (15.9 vs. 43.2%; P=0.0051) and 2nd cycle (6.8 vs. 27.3%; P=0.0107). The overall response rate was similar between the two groups (P>0.05). Median progression-free survival and median overall survival time were not statistically distinct between the two groups (P=0.5244 and P=0.5778, respectively). Grade ≥III toxicities mainly included vomiting and nausea (<20%), leukopenia and granulocytopenia (<20%), and alopecia (<25%). No death events were reported. Apart from IRRs to rituximab, the incidence of other adverse events was similar in both groups. The novel prednisone-pretreatment R-CHOP-like protocol in the present study significantly decreased the total and different grade incidences of IRRs to rituximab among newly diagnosed patients with DLBCL. This clinical trial was retrospectively registered with the Chinese Clinical Trial Registry (registration number, ChiCTR2300070327; date of registration, 10 April 2023). [ABSTRACT FROM AUTHOR]