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

Immunotherapy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04969354
• Other study ID #: XYFY2021-KL092-02
• Status: Recruiting
• Phase: Phase 1
• Start date: October 1, 2021
• Est. completion date: September 30, 2026

Study information

• Verified date: July 2021
• Source: The Affiliated Hospital of Xuzhou Medical University
• Contact: Hailong Li, M.D/Ph.D
• Phone: 0086-17798835021
• Email: Justinlee719[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: September 30, 2026
• Est. primary completion date: September 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Immunotherapy

Intervention

Biological:
• CAR-T cell immunotherapy
This CAR-T cell immunotherapy with a novel specific Chimeric antigen receptor aiming at CAIX antigen.

Locations

Country	Name	City	State
China	Affiliated Hospital of Xuzhou Medical University	Xuzhou	Jiangsu

Sponsors (2)

Lead Sponsor	Collaborator
The Affiliated Hospital of Xuzhou Medical University	Xuzhou Medical University

Country where clinical trial is conducted

China, 

References & Publications (12)

Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, Borquez-Ojeda O, Qu J, Wasielewska T, He Q, Bernal Y, Rijo IV, Hedvat C, Kobos R, Curran K, Steinherz P, Jurcic J, Rosenblat T, Maslak P, Frattin — View Citation

Kawalekar OU, O' Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, Patel PR, Guedan S, Scholler J, Keith B, Snyder NW, Blair IA, Milone MC, June CH. Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Devel — View Citation

Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R, Gratama JW. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management — View Citation

Lamers CH, Willemsen R, van Elzakker P, van Steenbergen-Langeveld S, Broertjes M, Oosterwijk-Wakka J, Oosterwijk E, Sleijfer S, Debets R, Gratama JW. Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. — View Citation

Linehan WM, Ricketts CJ. Kidney cancer in 2016: RCC - advances in targeted therapeutics and genomics. Nat Rev Urol. 2017 Feb;14(2):76-78. doi: 10.1038/nrurol.2016.260. Epub 2016 Dec 29. Review. — View Citation

Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, Smith JP, Walker AJ, Kohler ME, Venkateshwara VR, Kaplan RN, Patterson GH, Fry TJ, Orentas RJ, Mackall CL. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chim — View Citation

Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissi — View Citation

Sadelain M, Rivière I, Riddell S. Therapeutic T cell engineering. Nature. 2017 May 24;545(7655):423-431. doi: 10.1038/nature22395. Review. — View Citation

Song C, Sadashivaiah K, Furusawa A, Davila E, Tamada K, Banerjee A. Eomesodermin is required for antitumor immunity mediated by 4-1BB-agonist immunotherapy. Oncoimmunology. 2014 Jan 1;3(1):e27680. Epub 2014 Feb 27. — View Citation

Weinkove R, George P, Dasyam N, McLellan AD. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations. Clin Transl Immunology. 2019 May 11;8(5):e1049. doi: 10.1002/cti2.1049. eCollection 2019. Review. — View Citation

Xu J, Tian K, Zhang H, Li L, Liu H, Liu J, Zhang Q, Zheng J. Chimeric antigen receptor-T cell therapy for solid tumors require new clinical regimens. Expert Rev Anticancer Ther. 2017 Dec;17(12):1099-1106. doi: 10.1080/14737140.2017.1395285. Epub 2017 Oct — View Citation

Zhang Q, Li H, Yang J, Li L, Zhang B, Li J, Zheng J. Strategies to improve the clinical performance of chimeric antigen receptor-modified T cells for cancer. Curr Gene Ther. 2013 Feb;13(1):65-70. Review. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Progression-free survival (PFS)	Progression-free survival (PFS) time	24 months after CAR-T cells infusion
Secondary	Overall survival (OS)	Overall survival (OS) time	24 months after CAR-T cells infusion