Third-Generation CAR-T-cell Therapy in Individuals With HIV-1 Infection (TCTIWHI)

A Phase I Trial Using Third-Generation CAR-T-cell Therapy in Individuals With HIV-1 Infection

To evaluate the safety of autologous CAR-T-cell therapy in individuals lived with HIV-1 infection, CAR T cells are infused after ex vivo expansion and transduction with lentiviral vectors encoding a broadly neutralizing HIV-1 scFv antibody.

Study Overview

• Status: Unknown
• Conditions: HIV-1
• Intervention / Treatment: Biological: CAR-T cells

Detailed Description

This study is a prospective, single-center, single-arm, open-label and phase I clinical trial. Subjects with CD4+T cell counts greater than 350/μl and viral loads of <50 copies/ml over 1 year by antiviral treatment are enrolled. T cells are stimulated with CD3 and CD28, transduced with lentiviral vectors encoding a broadly neutralizing HIV-1 scFv antibody and expanded for approximately 2 weeks. Then, patients are infused with CAR T cells at a dosage of 1×10^5 CAR-T cells/kg body weight. If this dose is well tolerated, dosing will be increased to 5×10^5 CAR T cells/kg body weight. After infusion, adverse events, and HIV-1 latent reservoir size and CAR levels in peripheral blood will be monitored to assess the safety of CAR-T-cell treatment, potential therapeutic efficacy and kinetics of CAR T cells.

• Study Type: Interventional
• Enrollment (Anticipated): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100039
    • 302 Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Aged 18 to 70 years
2. HIV-1 infection by confirmed test;
3. Receiving antiviral treatment ≥ 1 years;
4. Current CD4+ T cell count > 350 cells/μl;
5. HIV-1 RNA levels of < 50 copies/ml for at least a year;
6. Patients who agrees to use two effective methods of contraception to avoid pregnancy during the study period.
7. Patients who sign the informed consent form prior to inclusion in the study.

Exclusion Criteria:

1. Patients with concomitant HAV, HBV, HCV, HDV, HEV, EBV, CMV or syphilis infection;
2. A history of AIDS-related opportunistic infections and tumors within 1 year prior to enrollment;
3. A History of corticosteroids or immunosuppressive drugs for autoimmune diseases by physicians within the last 2 years;

4. Participants with clinically significant laboratory abnormalities as follows:

   • Hemoglobin ≤ 10 gm/dl (female), <11g/dl (male)
   • Absolute neutrophil count ≤ 1×10^9/L
   • Platelet count ≤100×10^9/L
   • Alanine aminotransferase (ALT)≥ 2.5 x ULN
   • Aspartate aminotransferase (AST) ≥ 2.5 x ULN
   • Total bilirubin > 1.5 ULN
   • Serum creatinine >110 μmol/L
   • International normalized ratio (INR) >1.5 or activated partial thromboplastin time (APTT) >45 s
5. Patients with severe psychiatric illness, drugs or alcohol abuse;
6. A woman who is in pregnancy or lactation;
7. A history of central nervous system disease, such as cerebral hemorrhage, dementia, epilepsy and autoimmune diseases;
8. Patients with a non-AIDS-related serious underlying disease;
9. Patients who participate in another clinical study currently which may affect the results of this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CAR-T-cell therapy; Four patients with plasma HIV RNA <50 copies/ml and CD4+T cell count more than 350 cells/μl receiving at least one-year antiviral treatment are injected intravenously with 1×10^5 CAR-T cells/kg body weight. If the dosage of 1×10^5 CAR-T cells/kg body weight is well tolerated, 5×10^5 CAR-T cells/kg body weight will be infused for another 4 subjects who meet the inclusion and exclusion criteria.

Biological: CAR-T cells; The presence of latent infected cells remains a key barrier to HIV-1 functional cure. Current approach to reducing the latent HIV reservoir is to reactivate virus-containing cells to make them be detected and eliminated by host defense. Endogenous cytotoxic T-lymphocytes (CTL) may not be adequate because of cellular exhaustion and immune escape of virus. We have designed a kind of CAR-T cell based on CTL engineered to express a scFv of a broadly neutralizing anti-HIV antibody. According to our preclinical studies, CAR-T cells strongly eradicated HIV-1-infected target cells making them a particularly suitable candidate to reach a functional HIV cure. In this clinical trial, we mainly intend to evaluate the safety of CAR-T-Cell therapy on HIV patients whose plasma HIV has been successfully suppressed after antiviral therapy.; Other Names: HIV-1 specific chimeric antigen receptor T cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation the safety of CAR-T-cell treatment	To assess the adverse events of CAR-T-cell therapy in HIV-1 infected individuals by measuring liver function, blood routine, and cytokine and so on in this clinical trial	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment the potential therapeutic efficacy of CAR-T cell therapy	To evaluate the change of HIV-1 latent reservoir in peripheral blood after CAR-T-cell therapy by RT-PCR	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cellular kinetics of CAR-T cells	To measure the cellular kinetics of CAR-T cells after infusion by RT-PCR and flow cytometry	3 months

Collaborators and Investigators

• Sponsor: Beijing 302 Hospital
• Collaborators: Tsinghua University
• Investigators: Principal Investigator: Fu-Sheng Wang, MD, Beijing 302 Hospital of China

Publications and helpful links

General Publications

• Walker RE, Bechtel CM, Natarajan V, Baseler M, Hege KM, Metcalf JA, Stevens R, Hazen A, Blaese RM, Chen CC, Leitman SF, Palensky J, Wittes J, Davey RT Jr, Falloon J, Polis MA, Kovacs JA, Broad DF, Levine BL, Roberts MR, Masur H, Lane HC. Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood. 2000 Jul 15;96(2):467-74.
• Mitsuyasu RT, Anton PA, Deeks SG, Scadden DT, Connick E, Downs MT, Bakker A, Roberts MR, June CH, Jalali S, Lin AA, Pennathur-Das R, Hege KM. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood. 2000 Aug 1;96(3):785-93.
• Abdel-Mohsen M, Richman D, Siliciano RF, Nussenzweig MC, Howell BJ, Martinez-Picado J, Chomont N, Bar KJ, Yu XG, Lichterfeld M, Alcami J, Hazuda D, Bushman F, Siliciano JD, Betts MR, Spivak AM, Planelles V, Hahn BH, Smith DM, Ho YC, Buzon MJ, Gaebler C, Paiardini M, Li Q, Estes JD, Hope TJ, Kostman J, Mounzer K, Caskey M, Fox L, Frank I, Riley JL, Tebas P, Montaner LJ; BEAT-HIV Delaney Collaboratory to Cure HIV-1 infection. Recommendations for measuring HIV reservoir size in cure-directed clinical trials. Nat Med. 2020 Sep;26(9):1339-1350. doi: 10.1038/s41591-020-1022-1. Epub 2020 Sep 7.
• Liu B, Zou F, Lu L, Chen C, He D, Zhang X, Tang X, Liu C, Li L, Zhang H. Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4+ T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy. J Virol. 2016 Oct 14;90(21):9712-9724. doi: 10.1128/JVI.00852-16. Print 2016 Nov 1.
• Maldini CR, Claiborne DT, Okawa K, Chen T, Dopkin DL, Shan X, Power KA, Trifonova RT, Krupp K, Phelps M, Vrbanac VD, Tanno S, Bateson T, Leslie GJ, Hoxie JA, Boutwell CL, Riley JL, Allen TM. Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo. Nat Med. 2020 Nov;26(11):1776-1787. doi: 10.1038/s41591-020-1039-5. Epub 2020 Aug 31.

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2021
• Primary Completion (Anticipated): June 15, 2022
• Study Completion (Anticipated): October 1, 2022

Study Registration Dates

• First Submitted: December 7, 2020
• First Submitted That Met QC Criteria: April 25, 2021
• First Posted (Actual): April 28, 2021

Study Record Updates

• Last Update Posted (Actual): April 28, 2021
• Last Update Submitted That Met QC Criteria: April 25, 2021
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: safety; HIV-1 infection; CAR T cells; HIV latent reservoir
• Additional Relevant MeSH Terms: Infections
• Other Study ID Numbers: 2020-HIV-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No