clinical study of caix-targeted car-t cells in the treatment of advanced renal cell carcinoma

Conditions: Immunotherapy

Summary: this is an experimental study to evaluate the safety and efficacy of car t cells targeting caix in the treatment of advanced renal cancer.

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.

Eligibility criteria:
inclusion criteria: 1. male or female patients aged from 18 to 70 years old; 2. the patient's ecog score is ≤ 2; 3. 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: 1. liver function: alt/ast\< 3 times the upper limit of normal value (uln); 2. renal function: creatinine \< 220 μmol/l; 3. lung function: indoor oxygen saturation ≥ 95%; 4. cardiac function: left ventricular ejection fraction (lvef)≥40% 6.patients or their legal guardians voluntarily participate and sign informed consent. exclusion criteria: 1. infectious diseases (such as hiv, active hepatitis b or c infection, active tuberculosis, etc.); 2. 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. 3. the vital signs are abnormal, and those who cannot cooperate with the examination; 4. those who have mental or psychological diseases can not cooperate with treatment and efficacy evaluation; 5. highly allergic constitution or severe allergic history, especially those who are allergic to il-2; 6. subjects with systemic infection or severe local infection who need anti-infection treatment; 7. complicated with dysfunction of heart, lung, brain, liver, kidney and other important organs; 8. patients with other tumors; 9. doctors believe that there are other reasons that can not be included in the treatment.

Keywords: carbonic anhydrase advanced renal cell carcinoma car-t chimeric antigen receptor t cell caix