NexCAR19 (Talikabtagene Autoleucel) in Relapsed/Refractory B-Cell Malignancies (NexCAR19)

Inclusion Criteria

1. All participants must meet Inclusion Criteria 1-13.

   Additionally:
2. High-grade lymphoma subjects must meet Criteria 14-18.
3. Other B-cell lymphoma subjects must meet Criteria 19-24.
4. B-ALL subjects must meet Criteria 25-29.

General Inclusion Criteria (Applicable to All Cohorts)

1. Age ≥18 years.
2. Patients approved for leukapheresis by the CAR-T cell treatment council.
3. ECOG performance status \<2.
4. Life expectancy ≥12 weeks.
5. Renal Function: Estimated creatinine clearance ≥60 mL/min (Cockcroft-Gault) → fludarabine/cyclophosphamide lymphodepletion.

   In lymphoma cohort patients with creatinine clearance 30-60 mL/min, bendamustine may be used as an alternative due to cumulative fludarabine toxicity and neurotoxicity risk.
6. Liver Function:

   1. ALT and AST ≤3 × ULN unless attributable to underlying malignancy.
   2. Total bilirubin ≤2 × ULN except in Gilbert syndrome, isolated unconjugated hyperbilirubinemia, or if attributable to underlying malignancy.
7. Hemodynamically stable with LVEF ≥45% (confirmed by echocardiography or MUGA scan).
8. Baseline oxygen saturation \>92% on room air.
9. ANC ≥500/µL (may be waived if cytopenia due to underlying malignancy at investigator discretion).
10. Platelet count ≥50,000/µL (may be waived if cytopenia due to underlying malignancy at investigator discretion).
11. Negative serum or urine pregnancy test (within 24 hours prior to conditioning therapy) in women of childbearing potential; also negative prior to leukapheresis.
12. Sexually active patients (women of childbearing potential and all men) must use highly effective contraception for ≥12 months after CAR-T infusion.
13. Written informed consent provided.

    High-Grade Lymphoma - Additional Inclusion Criteria (14-18)
14. Histologically confirmed previously treated:

    1. Diffuse large B-cell lymphoma (DLBCL)
    2. Primary mediastinal B-cell lymphoma
    3. Transformed indolent B-cell lymphoma
    4. Follicular lymphoma Grade 3B
    5. High-grade B-cell lymphoma
15. Chemotherapy-refractory disease defined as:

    1. Primary refractory disease
    2. Best response to last chemotherapy = PD or SD (biopsy confirmed)
    3. Progression/relapse ≤12 months after autologous SCT
    4. Relapse ≤12 months after first-line CR (biopsy confirmed)
    5. Relapse beyond 12 months if auto-SCT not feasible
16. Not eligible for or unwilling to undergo autologous SCT.
17. Must have received anti-CD20 monoclonal antibody and anthracycline-containing regimen. Transformed lymphoma subjects must have received ≥2 prior systemic lines.
18. Measurable disease per International Working Group (IWG) criteria.

    Other B-Cell Lymphomas - Additional Inclusion Criteria (19-24)
19. Histologically confirmed:

    1. Mantle Cell Lymphoma (Cyclin D1 overexpression or t(11;14))
    2. Follicular Lymphoma Grade I-IIIA
    3. Marginal Zone Lymphoma
20. Relapsed or refractory disease:

    1. MCL: ≤5 prior regimens including:

       * Anthracycline or bendamustine
       * Anti-CD20 antibody
       * BTK inhibitor (ibrutinib or acalabrutinib; intolerance allowed)
    2. FL/MZL: Progression after ≥2 combination chemoimmunotherapy regimens (single-agent CD20 or splenectomy not counted).
21. Radiologically measurable disease at screening

    1. per revised IWG (Cheson 2007): ≥1 measurable lesion
    2. Previously irradiated lesions measurable only if progression documented
    3. If only nodal disease: ≥1 node ≥2 cm
22. No known active CNS lymphoma involvement.
23. Prior therapy toxicities resolved to ≤Grade 1 (except alopecia).
24. Prior autologous HCT, POD24 status, and prior PI3K inhibitor therapy allowed.

    B-Cell Acute Lymphoblastic Leukemia (B-ALL) - Additional Inclusion Criteria (25-29)
25. Relapsed/Refractory B-ALL meeting one of:

    1. Primary refractory disease
    2. First relapse ≤12 months
    3. ≥2 prior systemic lines
    4. Post-allogeneic SCT relapse (≥100 days post-transplant; off immunosuppression ≥4 weeks)
    5. Ph+ disease:

       * TKI intolerance
       * Relapsed/refractory after ≥2 TKIs
       * No alternative TKI option
    6. Ineligible for allogeneic SCT due to

       * comorbidity,
       * conditioning contraindication,
       * no donor,
       * prior SCT,
       * or refusal (documented).
26. Morphological bone marrow disease.
27. CD19 tumor expression documented within 3 months (BM or PB by flow cytometry).
28. Absolute lymphocyte count ≥100/µL.
29. ≥3 half-lives elapsed since prior immune checkpoint inhibitor or stimulatory therapy

Exclusion Criteria

1. All participants must meet Exclusion Criteria 1-14.

   Additionally:
2. High-grade lymphoma: 15-22
3. Low-grade lymphoma: 23-24
4. B-ALL: 25

General Exclusion Criteria (All Cohorts)

1. Uncontrolled life-threatening infection (e.g., positive blood culture ≤72h before infusion).
2. HIV positive.
3. Active HBV replication or active HCV (RNA positive).
4. Unstable angina or MI within 6 months.
5. Uncontrolled cardiac arrhythmia.
6. Concurrent malignancy except adequately treated non-melanoma skin cancer, in situ carcinoma (≥3 years disease-free), or completely resected malignancy in CR ≥3 years.
7. Pregnant or breastfeeding.
8. Hypersensitivity to CAR-T product excipients.
9. Active autoimmune/inflammatory neurologic disorders.
10. Primary immunodeficiency.
11. Short-acting leukemia/lymphoma therapies must be stopped \>72h before leukapheresis and infusion.
12. Burkitt lymphoma/leukemia.
13. Steroids must be discontinued \>72h prior (\<12 mg/m²/day hydrocortisone equivalent allowed).
14. Investigator deems subject unable to comply.

    High-Grade Lymphoma - Additional Exclusion (15-22)
15. Active CNS involvement.
16. Prior allogeneic HSCT.
17. Systemic immunosuppressives not discontinued ≥1 weeks before leukapheresis/infusion.
18. Anti-proliferative therapy not stopped ≥1 weeks prior.
19. Cytotoxic drugs not stopped ≥1 week prior.
20. A minimum interval of ≥4 weeks is required between donor lymphocyte infusion (DLI) and leukapheresis, and ≥4 weeks between DLI and CAR-T cell infusion. This requirement applies to prior antibody-based therapies, including anti-CD20, anti-CD22, anti-CD79a, and similar agents.
21. CNS prophylaxis not stopped \>1 week prior.
22. Radiation not stopped ≥2 days before leukapheresis and ≥1 week before infusion.

    Low-Grade Lymphoma - Additional Exclusion (23-24)
23. Live vaccine ≤6 weeks before conditioning.
24. Tumor mass effect requiring urgent treatment.

    B-ALL - Additional Exclusion (25)
25. Acute graft-versus-host disease (GVHD) of Grade II-IV according to the Glucksberg criteria or Grade B-D according to the IBMTR index; or acute or chronic GVHD requiring systemic treatment within 4 weeks prior to enrollment.