In this single-center, single-arm,prospective, open-label, phase 1/2 study, the safety and efficacy of autologous CD70 targeted chimeric antigen receptor modified T (CAR-T) cell therapy will be evaluated in patients with CD70 antigen positive Relapsed/Refractory Lymphoma . In this clinical trial, at least 12 eligible patients in dose escalation period will be enrolled to receive 3 doses of CD70-CAR cell therapy according to the "3+3" principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD70-CAR-T cell therapy at dose of recommended phase 2 dose(RP2D).
CAR-T cell therapy has been identified as a breakthrough therapy in hematologic malignancies,especially anti-CD19 CAR-T cell therapy in the treatment of r/r B-NHL has achieved remarkable efficacy.However, relapse with CD19-negative tumor after treatment with anti-CD19 CAR-T cells has been reported in different types of B-cell lymphoid malignancies, with a percentage up to 38% in patients with non-Hodgkin lymphoma (NHL).At present, the CAR-T cell treatment for HL is mainly confined to CD30 antigen,with an objective response rate (ORR) only 38%\~62%. Therefore, a more effective treatment strategy is needed for these patients. CD70, the membrane-binding ligand of the CD27 (a tumor necrosis factor receptor superfamily), has been reported to mediate tumour cell proliferation and be expressed on the malignant cells of diffuse large B-cell lymphoma (DLBCL),mantle cell lymphoma (MCL) and follicular lymphomas (FL), as well as Hodgkin lymphoma, etc,but rarely on normal B cells or T cells,indicating CD70 targeted treament has emerged as potentialnovel immunotherapeutic strategy.Preclinical study demonstrated CD70-CAR-T cells represent a new therapeutic option for the treatment of patients with CD19-negative recurrence of lymphoma.Based on the preclinical data, we conduct this clinical trial in order to test the the safety profiles and anti-tumor activities of CD70-CAR-T cells in vivo. In dose escalation period, at least 12 eligible patients will be enrolled and receive 3 doses of CD70-CAR-T cell therapy (1 × 10\^6 cells/kg, 3 × 10\^6 cells/kg, 1 × 10\^7 cells/kg) according to the "3+3" principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD70-CAR-T cell infusion at dose of RP2D, which is determined by data from dose escalation period, including occurrence of dose limiting toxicities(DLT), pharmacokinetics/pharmacodynamics, efficacy and other parameters, to furtherly evaluate the safety and efficacy profiles of CD70-CAR-T cell therapy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Dose escalation: Dose1 (1×10\^6 cells/kg) ,Dose 2(3×10\^6 cells/kg) ,Dose 3 (1×10\^7 cells/kg) Doseexpansion: RP2D Drug: Fludarabine Intravenous fludarabine 25-30 mg/m\^2/day on days 5, -4, and -3. Drug: Cyclophosphamide Intravenous cyclophosphamide 300-500 mg/m\^2/day on days -5, -4, and -3.
China
Beijing, Biotherapeutic Department of Chinsese PLA Gereral Hospital, China
RECRUITINGIncidence of treatment related adverse events(AEs)
AE is defined as any adverse medical event from the date of randomization to 12 months after CD70-CAR-T cells infusion. Among them, CRS and ICANS were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0.
Time frame: Up to 12 months since the initiation of CD70-CAR-T cell therapy.
Incidence of dose limiting toxicities (DLTs)
DLT was defined as CD70-CAR-T cells-related events with onset within first 28 days following infusion: Thedevelopment of Grade (G) 3 or higher grade CRS lasting \> 2 weeks; All G4 non-hematologic toxicities.
Time frame: Up to 28 days since the initiation of CD70-CAR-T cell therapy
Maximum tolerated dose (MTD)
MTD is defined as the highest dose level of less than or equal to 2 DLT among the 6 subjects finally determined.
Time frame: Up to 28 days since the initiation of CD70-CAR-T cell therapy
Number and copy number of CD70-CAR-T cells
Number and copy number of CD70-CAR-T cells are evaluated by number in peripheral blood and tumor tissue.
Time frame: Up to 3 years
Objective response rate (ORR)
The incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as the best response to treatment assessed by investigators and based on the Lugano 2014. assessment criterion
Time frame: Up to 3 years
Progression Free Survival (PFS)
Progression Free Survival is defined as the time from the initiation of CD70-CAR-T cell therapy to documented disease progression or death.
Time frame: Up to 3 years
Time to response (TTR)
TTR is defined as the time from CD70-CAR-T cell infusion to first assessed CR or PR by investigators and based on the Lugano 2014 assessment criterion.
Time frame: Up to 3 years
Duration of response (DOR)
Duration of response is defined as the time from objective response until documented tumor progression among responders.
Time frame: Up to 3 years
Overall Survival (OS)
Overall Survival is defined as the time from the initiation of CD70-CAR-T cell therapy to documented disease progression or death.
Time frame: Up to 3 years
Pharmacodynamics: Peak level of cytokines in serum (phase 1 and phase 2)
The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), C reactive protein (CRP), ferritin. Peak was defined as the maximum post-baseline level of the cytokine.
Time frame: Up to 28 days since the initiation of CD70-CAR-T cell therapy
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