Adaptive Dual-Target CAR-T Cells for Relapsed or Refractory Hematologic Malignancies

Summary

Phase 1/2 umbrella study evaluates biomarker-selected dual-target CAR-T cell modules for adults with relapsed or refractory hematologic malignancies. After central antigen co-expression screening, participants are assigned to the most appropriate active dual-target module: CD19/CD22, CD19/CD20, BCMA/CD19, BCMA/CD38, BCMA/GPRC5D, CD33/CD123, CD33/CLL1, or CD5/CD7. Phase 1 determines safety, dose-limiting toxicities, and the recommended phase 2 dose for each module; phase 2 estimates preliminary antitumor activity, including overall response rate and MRD-negative response. Lymphodepletion with fludarabine/cyclophosphamide precedes infusion. The design is intended to reduce antigen escape by matching disease biology and target co-expression to a rational dual-target strategy.

Eligibility

Inclusion Criteria:

* Age 18 to 75 years at the time of consent.
* Pathologically or cytologically confirmed eligible disease: B-ALL; B-cell NHL/CLL/SLL; multiple myeloma/plasma cell leukemia; AML/high-risk MDS/BPDCN; or T-ALL/T-LBL/peripheral T-cell lymphoma.
* Relapsed or refractory disease after at least 2 prior lines of therapy, or no curative/approved standard option judged appropriate by the investigator.
* Central laboratory confirmation that at least one active dual-target module is suitable based on malignant-cell antigen co-expression and safety review.
* Measurable or otherwise evaluable disease by disease-specific response criteria.
* ECOG performance status 0 to 2.
* Adequate organ function: LVEF \>= 45%; creatinine clearance \>= 40 mL/min; AST/ALT \<= 3 x ULN; total bilirubin \<= 1.5 x ULN unless due to Gilbert syndrome; oxygen saturation \>= 92% on room air.
* Adequate hematologic reserve unless cytopenia is clearly disease-related.
* Ability to undergo leukapheresis and willingness to comply with study procedures and follow-up.
* If prior allogeneic HSCT: at least 100 days from transplant, no uncontrolled GVHD, and no systemic immunosuppression above physiologic steroid replacement.
* Negative pregnancy test for participants of childbearing potential and agreement to use effective contraception during protocol-defined risk periods.
* Written informed consent obtained before any study-specific procedure.

Exclusion Criteria:

* \- Active uncontrolled infection, including uncontrolled bacterial, fungal, or viral infection, or clinical sepsis.
* Active symptomatic CNS involvement requiring escalating therapy; previously treated/stable CNS disease may be allowed if defined prospectively in the final protocol.
* Prior gene-modified cellular therapy within 12 weeks before leukapheresis, or unresolved \>= Grade 3 toxicity from prior anticancer therapy
* Need for urgent cytoreduction such that manufacturing delay would create unacceptable clinical risk.
* Active autoimmune disease requiring systemic immunosuppression, except limited replacement-dose steroids or protocol-permitted topical/inhaled therapy.
* Prior solid organ transplant.
* Clinically significant cardiovascular disease, uncontrolled arrhythmia, decompensated heart failure, myocardial infarction within 6 months, or recent stroke within 6 months.
* Uncontrolled HIV, HBV, or HCV viremia.
* Pregnancy or breastfeeding.
* Another active malignancy requiring systemic therapy, unless low-risk and definitively treated per protocol-defined exceptions.
* Known hypersensitivity to fludarabine, cyclophosphamide, or critical product excipients.
* Inability to manufacture a releaseable CAR-T product or failure to meet module-specific product-release criteria.
* Any medical, psychiatric, or social condition that, in the investigator's judgment, would increase risk, impair compliance, or confound interpretation of study results.

Conditions8

Interventions8

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