Efficacy and Safety of CD19-CAR.p40-T in Patients With Relapsed/Refractory CD19-Positive Hematologic Malignancies

CD19-directed CAR-T cell therapy has demonstrated significant antitumor activity in B-cell hematologic malignancies; however, relapse, insufficient persistence, and limited durability of response remain important clinical challenges. CD19-CAR.p40-T is a genetically modified autologous T-cell product designed to target CD19-positive malignant cells while incorporating autocrine p40 expression, with the aim of enhancing T-cell expansion, persistence, and antitumor activity in vivo.

This study is a prospective, single-arm, Phase I/II clinical trial in patients with relapsed or refractory CD19-positive hematologic malignancies. After screening and leukapheresis, eligible participants will undergo manufacture of autologous CD19-CAR.p40-T cells. Before infusion, participants will receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide to promote in vivo expansion and activity of the infused CAR-T cells. CD19-CAR.p40-T cells will then be administered as a single intravenous infusion.

Following infusion, participants will undergo close safety monitoring, including evaluation for cytokine release syndrome, immune effector cell-associated neurotoxicity, hematologic toxicity, infections, and other treatment-emergent adverse events. Disease assessments will be performed according to applicable disease-specific response criteria. In addition, serial blood samples will be collected to characterize the pharmacokinetic and cellular kinetic profile of CD19-CAR.p40-T cells, including expansion and persistence over time.

The purpose of this study is to characterize the safety profile of CD19-CAR.p40-T, evaluate its preliminary antitumor activity, and generate clinical and translational data to support further development of this investigational cell therapy in CD19-positive hematologic malignancies.

Inclusion criteria

Subjects must meet all of the following criteria to be enrolled:

• • Aged 18 to 75 years, male or female;
• • Histologically or cytologically diagnosed with relapsed/refractory CD19-positive hematologic malignancy according to the 2022 World Health Organization (WHO) diagnostic criteria;
• • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
• • Life expectancy of at least 3 months;
• • No contraindications to peripheral blood leukapheresis;
• • CD19 expression on tumor cells confirmed by flow cytometry and/or immunohistochemistry;
• • No severe cardiac, pulmonary, hepatic, or renal dysfunction;
• • Able to understand and willing to provide written informed consent. Exclusion Criteria

Subjects who meet any of the following criteria should be excluded from enrollment:

• History of allergy to any component of the cellular product;
• Complete blood count meeting any of the following criteria: white blood cell count (WBC) ≤1 × 10⁹/L, absolute neutrophil count (ANC) ≤0.5 × 10⁹/L, absolute lymphocyte count (ALC) ≤0.5 × 10⁹/L, or platelet count (PLT) ≤25 × 10⁹/L;
• Laboratory abnormalities including, but not limited to, serum total bilirubin ≥1.5 mg/dL; serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 times the upper limit of normal; or serum creatinine ≥2.0 mg/dL;
• Class III or IV cardiac insufficiency according to the New York Heart Association (NYHA) functional classification, or left ventricular ejection fraction (LVEF) <50% by echocardiography;
• Abnormal pulmonary function, with oxygen saturation <92% on room air;
• History of myocardial infarction, cardiac angioplasty or stent placement, unstable angina, or other clinically significant severe cardiac disease within 12 months prior to enrollment;
• Grade 3 hypertension with poor blood pressure control despite medication;
• History of traumatic brain injury, disturbance of consciousness, epilepsy, severe cerebral ischemia, or cerebral hemorrhagic disease;
• Autoimmune disease, immunodeficiency, or other conditions requiring treatment with immunosuppressive agents;
• Uncontrolled active infection;
• Prior treatment with any CAR-T cell product or other genetically modified T-cell therapy;
• Receipt of a live vaccine within 4 weeks prior to enrollment;
• Positive test results for HIV, HBV, HCV, or TPPA/RPR, or HBV carrier status;
• History of alcohol abuse, drug abuse, or psychiatric illness;
• Participation in any other clinical study within 3 months prior to enrollment in this clinical study;
• Female subjects who meet any of the following conditions:

• Pregnant or breastfeeding;
• Planning to become pregnant during the study; or
• Of childbearing potential and unwilling or unable to use effective contraception;
• Any other condition that, in the investigator's opinion, makes the subject unsuitable for participation in this study.