Sequential Infusion of Anti-CD19 and Anti-CD20 CAR-T Cells Against Relapsed and Refractory B-cell Lymphoma

Sequential Infusion of Anti-CD19 and Anti-CD20 Chimeric Antigen Receptor(CAR) T Cells Against Relapsed and Refractory B-cell Lymphoma

Cluster of differentiation antigen 19(CD19) specifically presents in B lymphocyte cell lines steadily,while not in most normal tissue,including pluripotent hematopoietic stem cells.Cluster of differentiation antigen 20(CD20) presents in 90% of B-cell lymphomas.CD19 antigen is a well-established target for B-cell lymphomas treatment as well as CD20 antigen.Both CD19-targeting CAR T Cells and CD20-targeting CAR T Cells can be used as adoptive cellular immunotherapies for B-cell lymphomas.Though two kinds of single target treatments were proved can induce recession of B-cell lymphomas, the risk of cancer cells to escape and tumor recurrence are still existed. There are no report about combination transfer of two kinds of single target treatments.This research aimed emphasis on safety and therapeutic efficacy evaluation,as well as if combination transfer can decrease recurrence rate.

Study Overview

• Status: Unknown
• Conditions: Recurrent or Refractory B Cell Malignancy
• Intervention / Treatment: Biological: Mixed CD19/CD20 CAR-T Transfer

Detailed Description

To determine:

Primary Outcome Measure:

The Overall complete remission rate and one-year survival rate of combination transfer of CD19-targeting CAR T Cells and CD20-targeting CAR T Cells is superior to or at least not worse than two kinds of single target treatments in the treatment of CD19+/CD20+ B-cell lymphomas.

The risk of cancer recurrence in a year of combination transfer of CD19-targeting CAR T Cells and CD20-targeting CAR T Cells is inferior to two kinds of single target treatments.

Secondary Outcome Measures:

Evaluate the initial effect time, time to disease progression, and life quality improvement of combination transfer compare to single target treatments.

Evaluate the safety and tolerability of combination transfer compare to single target treatments by observation of high fever duration in patients and testing related cell factor level in peripheral blood.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Jingan
    • Shanghai, Jingan, China, 200072
      • Recruiting
      • Shanghai Longyao Biotechnology Inc., Ltd.
      • Contact: Wang Xin, M.D.; Phone Number: +86 185-1602-2625; Email: wangxin928@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 Years to 70 Years, Male and female
• Survival time>12 weeks
• B cell lymphomas diagnosed by Physical examination,pathological examination,Laboratory tests and imaging tests
• Chemotherapy failure or recurrent B cell lymphomas
• Creatinine< 2.5mg/dl
• Glutamic-pyruvic transaminase, glutamic oxalacetic transaminase< 3 fold of normal level
• Bilirubin<2.0mg/dl
• Karnofsky Performance Status>50% at the time of screening
• Adequate pulmonary, renal, hepatic, and cardiac function
• Fail in autologous or allogenic haemopoietic stem cell transplantation
• Free of leukocytes removal contraindications
• Voluntarily join CAR-T clinical trial
• Understand and sign written informed consent

Exclusion Criteria:

• Pregnant or nursing women or women with pregnancy plan in half a year
• Any infectious disease (HIV, active tuberculosis, ect.)
• Active hepatitis B, active hepatitis C infection
• Feasibility assessment proves that the efficiency of transduction of lymphocyte is below 10% or the lymphocyte amplification is below 5 fold with the costimulation of cluster of differentiation 3(CD 3)and cluster of differentiation 8(CD 8)
• Abnormal vital signs or cannot cooperate with the inspectors
• mental or psychological disease cannot cooperate with treatment and curative effect evaluation
• Highly allergic constitution or history of severe allergies, especially allergy to interleukin-2(IL-2)
• General infection or local severe infection, or other infection that is not controlled
• Dysfunction in lung, heart, kidney and brain
• Severe autoimmune diseases
• Other symptoms that are not applicable for CAR-T

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mixed CD19/CD20 CAR-T Transfer; Subjects with CD19+/CD20+ B-cell lymphomas will be infused with CD19-targeting CAR T Cells and CD20-targeting CAR T Cells in one time or in parts	Biological: Mixed CD19/CD20 CAR-T Transfer; Autologous CD19 CAR-T cells and CD20 CAR-T cells with average 1-5*10^6 cells/kg body weight,separately.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall complete remission rate	The complete remission rate will be evaluated by routine methods.	Half a year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The initial effect time	The initial effect time will be recorded.	1 year
The one-year survival rate	The one-year survival rate will be recorded.	1 year
The safety and the tolerability(incidence of treatment-emergent adverse events defined as dose-limited toxicity)	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0.	1 month
The time to disease progression	The time to disease progression will be counted after complete remission.	1 year
The one-year recurrence	The one-year recurrence will be counted after complete remission.	1 year
The life quality improvement	The life quality improvement will be evaluated by appetite,sleep,pain and mental state.	1 year

Collaborators and Investigators

• Sponsor: Shanghai Longyao Biotechnology Inc., Ltd.
• Collaborators: Xuzhou Medical University; Shanghai Jiao Tong University School of Medicine
• Investigators: Principal Investigator: Shengqin Ye, M.D., Shanghai Longyao Biotechnology Inc., Ltd.

Publications and helpful links

General Publications

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
• Wang Y, Zhang WY, Han QW, Liu Y, Dai HR, Guo YL, Bo J, Fan H, Zhang Y, Zhang YJ, Chen MX, Feng KC, Wang QS, Fu XB, Han WD. Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. Clin Immunol. 2014 Dec;155(2):160-75. doi: 10.1016/j.clim.2014.10.002. Epub 2014 Oct 16.
• Witkowska M, Smolewski P. Emerging immunotherapy and strategies directly targeting B cells for the treatment of diffuse large B-cell lymphoma. Immunotherapy. 2015;7(1):37-46. doi: 10.2217/imt.14.93.
• Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH, Gea-Banacloche JC, Pavletic SZ, Hickstein DD, Lu TL, Feldman SA, Iwamoto AT, Kurlander R, Maric I, Goy A, Hansen BG, Wilder JS, Blacklock-Schuver B, Hakim FT, Rosenberg SA, Gress RE, Kochenderfer JN. Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease. J Clin Oncol. 2016 Apr 1;34(10):1112-21. doi: 10.1200/JCO.2015.64.5929. Epub 2016 Jan 25.
• Hay KA, Turtle CJ. Chimeric Antigen Receptor (CAR) T Cells: Lessons Learned from Targeting of CD19 in B-Cell Malignancies. Drugs. 2017 Mar;77(3):237-245. doi: 10.1007/s40265-017-0690-8.
• Sang W, Shi M, Yang J, Cao J, Xu L, Yan D, Yao M, Liu H, Li W, Zhang B, Sun K, Song X, Sun C, Jiao J, Qin Y, Sang T, Ma Y, Wu M, Gao X, Cheng H, Yan Z, Li D, Sun H, Zhu F, Wang Y, Zeng L, Li Z, Zheng J, Xu K. Phase II trial of co-administration of CD19- and CD20-targeted chimeric antigen receptor T cells for relapsed and refractory diffuse large B cell lymphoma. Cancer Med. 2020 Aug;9(16):5827-5838. doi: 10.1002/cam4.3259. Epub 2020 Jul 1.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Anticipated): February 28, 2019
• Study Completion (Anticipated): February 28, 2020

Study Registration Dates

• First Submitted: June 23, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): July 2, 2017
• Last Update Submitted That Met QC Criteria: June 29, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Other Study ID Numbers: LYCT-1701

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