CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

For Diffuse Large B-Cell Lymphoma (DLBCL) Cohort:

* Diagnosis of DLBCL that is refractory to first-line chemoimmunotherapy, relapses within 12 months of first-line chemoimmunotherapy, relapses after 12 months in a transplant-ineligible patient, or is relapsed/refractory after two or more lines of systemic therapy. Eligible histologies include DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from indolent lymphoma (follicular lymphoma, marginal zone lymphoma, or chronic lymphocytic leukemia)
* Age ≥18 years
* ECOG performance status ≤2
* Measurable disease on PET/CT or CT per Lugano Criteria
* Adequate organ function: ANC ≥1000 cells/mm³; platelet count ≥75,000 cells/mm³; creatinine clearance or eGFR ≥45 mL/min; total bilirubin ≤2.0x ULN; AST or ALT ≤3.0x ULN; left ventricular ejection fraction \>40%

For Multiple Myeloma (MM) Cohort:

* Relapsed or refractory multiple myeloma after ≥1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, with disease refractory to lenalidomide (progression within 60 days of last lenalidomide dose)
* Age ≥18 years
* ECOG performance status ≤2
* Adequate organ function: ANC ≥1000 cells/mm³; platelet count ≥75,000 cells/mm³; creatinine clearance or eGFR ≥30 mL/min; total bilirubin ≤2.0x ULN; AST or ALT ≤3.0x ULN; left ventricular ejection fraction \>40%

Exclusion Criteria:

For DLBCL Cohort:

* History of previous total body irradiation
* Prior CAR T-cell therapy
* Clonal cytopenia of uncertain significance (CCUS)
* Prior history of myeloid malignancies (MDS/AML or MPN), T-cell lymphoblastic lymphoma/leukemia, or B-cell acute lymphoblastic leukemia
* Current or prior CNS involvement by lymphoma
* Significant cardiovascular impairment (CHF greater than NYHA Class II, uncontrolled hypertension, unstable angina, MI or stroke within 6 months, or cardiac ventricular arrhythmia)
* Decompensated cirrhosis
* Active HIV, hepatitis B, or hepatitis C infection
* Active uncontrolled systemic fungal, bacterial, or viral infection
* Pregnancy

For MM Cohort:

* History of previous total body irradiation
* History of myelodysplastic syndrome, CCUS, or concurrent active hematological malignancy with bone marrow involvement
* Active HIV, hepatitis B, or hepatitis C infection
* Active uncontrolled systemic fungal, bacterial, or viral infection
* Prior CAR T-cell therapy
* Active or history of CNS myeloma or leptomeningeal infiltration
* Pregnancy

主要终点：Incidence of Dose-Limiting Toxicities (DLTs) · This outcome measures the number of participants experiencing a dose-limiting toxicity (DLT) at each LD-TBI dose level, within 28 days following CAR T-cell infusion. This measure is used to assess the safety and tolerability of the treatment regimen across escalating radiation dose levels and to determine the maximum tolerated dose (MTD). · Through Day 28 post-CAR T cell infusion
次要终点：Incidence and Severity of Cytokine Release Syndrome (CRS)；Incidence and Severity of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)；Incidence and Severity of Immune Effector Cell-Associated Hemophagocytic Syndrome (IEC-HS)；Incidence of Delayed Immune Effector Cell-Associated Hematotoxicity (ICAHT)；Incidence and Severity of Treatment-Related Adverse Events；Overall Response Rate (ORR)；Overall Survival (OS)；Progression-Free Survival (PFS)

• Part 1: LBCL: Dose Level -1 (0.5 Gy) · EXPERIMENTAL · Participants with relapsed/refractory LBCL receive lymphodepletion followed by LD-TBI 0.5 Gy on Day 0, ≥4 hours before infusion of commercial CD19-directed CAR T-cell therapy. Used if de-escalation from Dose Level 0 is required due to dose-limiting toxicity.
• Part 1: LBCL: Dose Level 0 (1.0 Gy, Starting Dose) · EXPERIMENTAL · Participants with relapsed/refractory LBCL receive lymphodepletion followed by LD-TBI 1.0 Gy (starting dose) on Day 0, ≥4 hours before infusion of commercial CD19-directed CAR T-cell therapy.
• Part 1: LBCL: Dose Level +1 (2.0 Gy) · EXPERIMENTAL · Participants with relapsed/refractory LBCL receive lymphodepletion followed by LD-TBI 2.0 Gy on Day 0, ≥4 hours before infusion of commercial CD19-directed CAR T-cell therapy. Used if Dose Level 0 is tolerated.
• Part 1: MM: Dose Level -1 (0.5 Gy) · EXPERIMENTAL · Participants with relapsed/refractory multiple myeloma receive lymphodepletion followed by LD-TBI 0.5 Gy on Day 0, ≥4 hours before infusion of commercial BCMA-directed CAR T-cell therapy. Used if de-escalation from Dose Level 0 is required.
• Part 1: MM: Dose Level 0 (1.0 Gy, Starting Dose) · EXPERIMENTAL · Participants with relapsed/refractory multiple myeloma receive lymphodepletion followed by LD-TBI 1.0 Gy (starting dose) on Day 0, ≥4 hours before infusion of commercial BCMA-directed CAR T-cell therapy.
• Part 1: MM: Dose Level +1 (2.0 Gy) · EXPERIMENTAL · Participants with relapsed/refractory multiple myeloma receive lymphodepletion followed by LD-TBI 2.0 Gy on Day 0, ≥4 hours before infusion of commercial BCMA-directed CAR T-cell therapy. Used if Dose Level 0 is tolerated.
• Part 2: LBCL: Expansion Cohort at MTD · EXPERIMENTAL · Expansion-cohort participants with relapsed/refractory LBCL are randomized 1:1 to LD-TBI at the MTD or one dose level below. This arm receives LD-TBI at the MTD (single dose, Day 0), preceded by lymphodepletion and followed ≥4 hours later by commercial CD19-directed CAR T-cell therapy.
• Part 2: LBCL: Expansion Cohort Below MTD · EXPERIMENTAL · Expansion-cohort participants with relapsed/refractory LBCL are randomized 1:1 to LD-TBI at the MTD or one dose level below. This arm receives LD-TBI one dose level below the MTD (single dose, Day 0), preceded by lymphodepletion and followed ≥4 hours later by commercial CD19-directed CAR T-cell therapy.

This is a clinical trial to evaluate the safety of combining CAR T-cell therapy with low-dose total body irradiation (LD-TBI) in patients with previously treated large B-cell lymphoma (LBCL) or multiple myeloma (MM). The investigators' hypothesis is that the combination will make the immune system more active in fighting cancer by increasing the display of antigens and activating pathways that lead to cell death, including death receptors like FAS and TRAIL2. This approach is expected to help the CAR T cells grow and last longer, leading to stronger anti-tumor effects and more cancer cell deaths. Participants will receive LDTBI treatment before their CAR T cell therapy and will be followed up for 2 years.