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

Efficacy and Safety of Autocrine p40-Expressing CD19-Targeted Chimeric Antigen Receptor T Cells (CD19-CAR.p40-T) in Patients With Relapsed/Refractory CD19-Positive Hematologic Malignancies

1. Study Title:

   A Study on the Efficacy and safety of Autocrine p40-Expressing CD19-Targeted Chimeric Antigen Receptor T Cells (CD19-CAR.p40-T) in Patients With Relapsed/Refractory CD19-Positive Hematologic Malignancies

2. Study Objectives:

   2.1.1 Primary Objective To evaluate the safety of autocrine p40-expressing CD19-targeted chimeric antigen receptor T cells (CD19-CAR.p40-T) in the treatment of patients with relapsed/refractory CD19-positive hematologic malignancies.

   2.1.2 Secondary Objective To evaluate the efficacy of autocrine p40-expressing CD19-targeted chimeric antigen receptor T cells (CD19-CAR.p40-T) in the treatment of patients with relapsed/refractory CD19-positive hematologic malignancies.

   2.1.3 Exploratory Objective To evaluate the in vivo expansion and persistence of CD19-CAR.p40-T cells.

3. Participant Intervention:

Participants will receive lymphodepleting chemotherapy (FC regimen: Fludarabine + Cyclophosphamide) on Days -5, -4, and -3 relative to the planned CD19-CAR.p40-T cell infusion. The CD19-CAR.p40-T cell infusion will be administered 72 hours after the completion of the FC chemotherapy.

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:

1. • Aged 18 to 75 years, male or female;
2. • Histologically or cytologically diagnosed with relapsed/refractory CD19-positive hematologic malignancy according to the 2022 World Health Organization (WHO) diagnostic criteria;
3. • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
4. • Life expectancy of at least 3 months;
5. • No contraindications to peripheral blood leukapheresis;
6. • CD19 expression on tumor cells confirmed by flow cytometry and/or immunohistochemistry;
7. • No severe cardiac, pulmonary, hepatic, or renal dysfunction;
8. • 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:

1. History of allergy to any component of the cellular product;

2. 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;

3. 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;

4. 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;

5. Abnormal pulmonary function, with oxygen saturation <92% on room air;

6. History of myocardial infarction, cardiac angioplasty or stent placement, unstable angina, or other clinically significant severe cardiac disease within 12 months prior to enrollment;

7. Grade 3 hypertension with poor blood pressure control despite medication;

8. History of traumatic brain injury, disturbance of consciousness, epilepsy, severe cerebral ischemia, or cerebral hemorrhagic disease;

9. Autoimmune disease, immunodeficiency, or other conditions requiring treatment with immunosuppressive agents;

10. Uncontrolled active infection;

11. Prior treatment with any CAR-T cell product or other genetically modified T-cell therapy;

12. Receipt of a live vaccine within 4 weeks prior to enrollment;

13. Positive test results for HIV, HBV, HCV, or TPPA/RPR, or HBV carrier status;

14. History of alcohol abuse, drug abuse, or psychiatric illness;

15. Participation in any other clinical study within 3 months prior to enrollment in this clinical study;

16. Female subjects who meet any of the following conditions:

    1. Pregnant or breastfeeding;
    2. Planning to become pregnant during the study; or
    3. Of childbearing potential and unwilling or unable to use effective contraception;

17. Any other condition that, in the investigator's opinion, makes the subject unsuitable for participation in this study.