Clinical Study of CAIX-targeted CAR-T Cells in the Treatment of Advanced Renal Cell Carcinoma

Study Overview
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Brief Summary
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This is an experimental study to evaluate the safety and efficacy of CAR T cells targeting CAIX in the treatment of advanced renal cancer.

Detailed Description
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We designed a clinical study and divided the trial into two phases. Phase 1 (climbing test) : 12 patients were randomly divided into 4 groups (n=3). 12 patients were treated with cyclophosphamide at the dose of 60mg/kg/d 8-7 days before CAR-T cell infusion, and fludalabine at the dose of 25mg/m^2/d 6-2 days before CAR-T cell infusion. 5 mg anti-human CAIX monoclonal antibody (G250) was injected into the hepatic artery of each patient by an interventional catheter on the day before CAR-T cells infusion. On Day 0, CAR T cells were injected into patients in group 1, 2, 3 or 4 at the dose of 1x10^7/ person, 1*10^8/ person, 1*10^9/ person or 1*10^10/ person, respectively. The infusion time is about 15-30min. On day 0-14, IL-2 (75000IU/kg) was injected subcutaneously once a day. From day 15-28, IL-2 (75000IU/kg) was subcutaneously injected into the patients three times a week. The purpose of this study is to assess subjects' MTD (maximum tolerated dose) against CAR T cells. Phase 2: After determining the appropriate therapeutic dose for patients with renal cell carcinoma, 8 patients received the same pre-treatment of chemotherapy and G250 antibody. Then, the appropriate therapeutic dose of CAR T cells according to the results of phase 1 was infused on Day 0. On day 0-14,IL-2 (75000IU/kg) was given subcutaneously once a day. On day 15-28, IL-2 (75000IU/kg) was given subcutaneously three times a week. Peripheral blood was collected every 4 weeks to evaluate proliferation and survival of CAR-T cells. After 6 months of close follow-up, subjects will undergo a medical history evaluation, physical examination, and blood tests quarterly for 2 years. After this assessment, subjects will be enrolled in an annual telephone follow-up and questionnaire study for up to five years to evaluate treatment for long-term health problems, such as recurrence of malignant tumors.

Official Title
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Clinical Study of CAIX-targeted CAR-T Cells in the Treatment of Advanced Renal Cell Carcinoma

Conditions
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Immunotherapy

Intervention / Treatment
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* Biological: CAR-T cell immunotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged from 18 to 70 years old; The patient's ECOG score is ≤ 2; Patients with advanced or metastatic renal cell carcinoma: (1) have received first-line and second-line targeted therapy in the past; (2) Previous immunization with PD-1/L1 and ≤2 regimens; (3) Unable to tolerate targeted therapy or immunotherapy. 4.There are measurable or evaluable lesions; 5.The main tissues and organs of patients function well: liver function: ALT/AST< 3 times the upper limit of normal value (ULN); Renal function: creatinine < 220 μmol/L; Lung function: indoor oxygen saturation ≥ 95%; Cardiac function: Left ventricular ejection fraction (LVEF)≥40% 6.Patients or their legal guardians voluntarily participate and sign informed consent. Exclusion Criteria: Infectious diseases (such as HIV, active hepatitis B or C infection, active tuberculosis, etc.); Feasibility assessment and screening showed that the transfection of targeted lymphocytes was less than 10% or the amplification was insufficient (< 5 times) under the co-stimulation of CD3/CD28. The vital signs are abnormal, and those who cannot cooperate with the examination; Those who have mental or psychological diseases can not cooperate with treatment and efficacy evaluation; Highly allergic constitution or severe allergic history, especially those who are allergic to IL-2; Subjects with systemic infection or severe local infection who need anti-infection treatment; Complicated with dysfunction of heart, lung, brain, liver, kidney and other important organs; Patients with other tumors; Doctors believe that there are other reasons that can not be included in the treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: CAR-T cell immunotherapy<br>The registered patients will received CAR-T cell immunotherapy for the new specific chimeric antigen receptor of CAIX antigen by infusion. | Biological: CAR-T cell immunotherapy<br>* This CAR-T cell immunotherapy with a novel specific Chimeric antigen receptor aiming at CAIX antigen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety evaluation:Incidence and severity of adverse events | To evaluate the incidence and severity of possible adverse events within one month after targeted CAIX CAR-T infusion, including cytokine release syndrome and on-target toxicity. | First 1 month after CAR-T cells infusion | 
| Effectiveness evaluation | In order to observe the efficacy of CAR-T cells after infusion, total remission rate (ORR), complete remission (CR), partial remission (PR), disease stability (SD) or progression (PD) will be used for evaluation. | 3 months after CAR-T cells infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Progression-free survival (PFS) time | 24 months after CAR-T cells infusion | 
| Overall survival (OS) | Overall survival (OS) time | 24 months after CAR-T cells infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carbonic anhydrase, advanced renal cell carcinoma, CAR-T, Chimeric antigen receptor, T cell, CAIX