Autologous CD19-CD20-NKG2D-nsBicephali CAR-T for Relapsed/Refractory Central Nervous System Lymphoma

Inclusion Criteria:

* Age 18-75 years, male or female.
* Good performance status: ECOG 0-2 or Karnofsky Performance Status (KPS) ≥70.
* Diagnosis of relapsed/refractory primary CNS lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL).

  * PCNSL: prior treatment with at least 2 lines and unsuitable for autologous hematopoietic stem cell transplantation; or prior treatment with at least 3 lines; or disease progression/relapse within 12 months after autologous transplantation. Participants must previously have received at least 1 line of HD-MTX-based CNS-directed therapy (intravenous dose ≥2500 mg/m²) and have documented progression, relapse, or intolerance.
  * SCNSL: relapse or refractory disease after at least 1 line of CNSL-directed therapy; if systemic lymphoma is also present, the systemic component must have relapsed after treatment including an anti-CD20 monoclonal antibody and an anthracycline.
* Presence of measurable CNS disease (at least one enhancing lesion ≥1 cm on contrast-enhanced brain MRI, or positive CSF by flow cytometry and/or cytology).
* Positive expression of CD19 and/or CD20 in tumor biopsy tissue or malignant CSF cells. Participants with prior failure of single-target CD19- or CD20-directed therapy are allowed, provided the washout period since the last treatment is at least 6 months.
* Estimated life expectancy ≥12 weeks.
* Adequate organ function:

  * Bone marrow and immune function: peripheral blood absolute CD3 count ≥50/mm³ and absolute lymphocyte count ≥0.2×10\^9/L; ANC ≥1000/μL; platelets ≥50,000/μL, without recent red blood cell or platelet transfusion.
  * Hepatic and renal function: creatinine clearance (Cockcroft-Gault) ≥45 mL/min; if relaxed to 30-45 mL/min, fludarabine dose must be reduced strictly; AST and ALT ≤3×ULN; total bilirubin and alkaline phosphatase ≤1.5×ULN.
  * Cardiopulmonary function: LVEF ≥50% (NYHA class I-II); oxygen saturation on room air \>92%.
* Prior-treatment washout: anti-B-cell chemotherapy/immunotherapy stopped for at least 3 weeks; intrathecal CNS therapy stopped for at least 1 week; systemic corticosteroids (except physiologic replacement) stopped for at least 1 week; short-acting cytotoxic drugs stopped for at least 3 days.
* Negative pregnancy test for women of childbearing potential; participants with partners of childbearing potential must agree to use effective contraception during treatment and for 24 months after infusion.
* Voluntary participation and signed informed consent.

Exclusion Criteria:

* High-risk CNS status: imaging showing high-risk brain herniation or uncontrollable intracranial pressure elevation risk (large subcortical mass effect with significant cerebral edema), or severe status epilepticus or poorly controlled seizures within 14 days.
* Prior severe CAR-T toxicity: prior CD19/CD20-targeted therapy (including CAR-T or bispecific antibodies) with grade IV CRS or ICANS, or grade III CRS/ICANS without full recovery after treatment.
* Uncontrolled serious active infection requiring systemic intravenous therapy.
* Positive virology: active hepatitis B (HBsAg positive and peripheral blood HBV DNA ≥10\^3 copies/mL); hepatitis C (HCV RNA positive); positive syphilis screening with titer ≥1:8; HIV antibody positive.
* Toxicity from prior antitumor therapy not recovered to CTCAE v5.0 grade ≤2, except alopecia or fatigue.
* Severe cardiovascular or respiratory disease, including myocardial infarction, unstable angina, or severe arrhythmia within the past 6 months; moderate-to-severe pulmonary arterial hypertension; or need for ventilatory support or oxygen reservoir mask assistance.
* Prior history of, or concurrent, other active malignancy, except cured carcinoma in situ or basal cell skin cancer.
* History of major solid organ transplantation.
* Active tuberculosis at screening, or latent tuberculosis without systematic prophylaxis.
* Live vaccine received within 6 weeks before lymphodepleting conditioning.
* Pregnancy or breastfeeding; severe allergy to any lymphodepleting drug or any component of the CAR-T product.
* Severe psychiatric disease, major depression, suicidal tendency, or any other condition that, in the investigator's judgment, makes the participant unsuitable for enrollment.