Allogeneic γ9δ2 T Cells Treatment of Recurrent Hematologic Tumors

Study Overview
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Brief Summary
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This is an open single-arm clinical study aimed at evaluating the safety and tolerance of allogeneic γ9δ2 T cell injection in the treatment of patients with recurrent hematologic tumors after allogeneic hematopoietic stem cell transplantation.

Detailed Description
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To evaluate the safety and in vivo dynamics of allogeneic γ9δ2 T cell in the treatment of recurrent hematologic tumors after allogeneic hematopoietic stem cell transplantation patients, and to explore the appropriate therapeutic dose.

Official Title
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Allogeneic γ9δ2 T Cells for the Treatment of Recurrent Hematologic Tumors After Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Hematologic Diseases

Intervention / Treatment
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* Biological: allogeneic γ9δ2 T Cells
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Zoredronic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 12-65 (inclusive)； Patients with recurrent hematologic tumors after allogeneic hematopoietic stem cell transplantation； Basically normal liver and kidney function (as demonstrated by the following laboratory tests prior to initial γ9δ2 T cell therapy) Alanine transaminase/aspartate transaminase < 2.5×ULN； serum creatinine < 1.5×ULN； total bilirubin level < 1.5×ULN； No obvious hereditary disease; Normal cardiac function, cardiac ejection index above 55%; Women of reproductive age (15 to 49 years) must undergo a pregnancy test within 7 days before starting treatment and the result is negative, and use contraception during the clinical trial period and within 3 months after the last cell transfusion; Sign informed consent. Exclusion Criteria: Patients with simple extramedullary recurrence; Pregnant and lactating women; Organ failure; Heart: Ⅲ level and Ⅳ level; Liver: reach the grade C Child - Turcotte liver function; Kidney, renal failure and uremia period; Lung: symptoms of severe respiratory failure; Brain: consciousness disorder. Patients with a history of solid organ transplantation; Uncontrollable infectious diseases or other serious diseases, including but not limited to infections (such as HIV positive), congestive heart failure, unstable angina, arrhythmia, psychosis, or restricted social circumstances or those that the attending physician considers to pose unpredictable risks; Patients with systemic autoimmune diseases or primary immunodeficiency; Patients with allergic constitution; Use of systemic steroid drugs; Chronic diseases requiring the use of immunological agents or hormone herapy; Prior treatment with any other immune cells; Participated in similar clinical trials within 30 days; Received radiation therapy within 4 weeks from the time of enrollment; Researchers don't think clinical trials are appropriate for other reasons.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with recurrent hematologic tumors after allogeneic hematopoietic stem cell transplantation<br>A conditional chemotherapy regimen of fludarabine and cyclophosphamide will be administered, zoredronic acid depending on the patient's status, followed by investigational therapy, allogeneic γ9δ2 T Cells | Biological: allogeneic γ9δ2 T Cells<br>* dose escalation (3+3) : dose 1 (5 × 10^7cells/kg) ,dose 2 (1 × 10^8 cells/kg) ,dose 3 (2 × 10^8cells/kg)<br>Drug: Fludarabine<br>* Intravenous fludarabine on days-5 and -4,the infusion dose is adjusted according to the subject's condition<br>* Other names: Fludarabine Phosphate for Injection;Drug: Cyclophosphamide<br>* Intravenous cyclophosphamide on days -5、-4、and -3, the infusion dose is adjusted according to the subject's condition<br>* Other names: Cyclophosphamide for Injection;Drug: Zoredronic acid<br>* Intravenous zoredronic acid 50ug/kg 24 hours before cell infusion（or according to the dosage of the instruction）（If applicable）<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) | AE is defined as any adverse medical event from the date of leukapheresis to 12 months after allogeneic γ9δ2 T cells infusion. Among them, cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria, graft-versushost disease (GVHD) according to criteria defined by the Mount Sinai Acute GVHD International Consortium. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0 | 12 months | 
| Incidence of Dose-Limiting Toxicities (DLTs) | DLT was defined as allogeneic γ9δ2 T Cells-related events with onset within first 14 days following infusion: The development of Grade (G) III-IV acute GVHD according to the Mount Sinai Acute GVHD International Consortium criteria; The development of G3 or higher grade CRS lasting > 2 weeks; Any allogeneic γ9δ2 T cells-related AE requiring intubation; All G4 non-hematologic toxicities. Symptoms of GVHD include but are not limited to skin rash, enterocolitis with diarrhea, liver dysfunction with jaundice, fever, weight loss, etc. | First infusion date of allogeneic γ9δ2 T cells to 14 days end cell infusion | 
| 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. | 14 days | 
| Recommended phase 2 dose (RP2D) | The recommended dose for phase 2 was determined through phase 1 study | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from allogeneic γ9δ2 T cells infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date. | 12 months | 
| Progression Free Survival (PFS) | PFS is defined as the time from the allogeneic γ9δ2 T cells infusion date to the date of disease progression assessed by investigators assessment, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. | 12 months | 
| Pharmacokinetics: Persistence of the allogeneic γ9δ2 T cells | Persistence of the allogeneic γ9δ2 T cells assessed by number in peripheral blood. | 14 days | 
| Pharmacodynamics: Peak level of cytokines in serum | The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α) etc. Peak was defined as the maximum post-baseline level of the cytokine. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent hematologic tumors, Allogenic γδT Cell