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4SCAR-T Therapy Targeting GD2, PSMA and CD276 for Treating Neuroblastoma

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ClinicalTrials.gov Identifier: NCT04637503
Recruitment Status : Recruiting
First Posted : November 19, 2020
Last Update Posted : November 19, 2020
Sponsor:
Collaborator:
Shenzhen Children's Hospital
Information provided by (Responsible Party):
Shenzhen Geno-Immune Medical Institute

Brief Summary:
The purpose of this clinical trial is to assess the feasibility, safety and efficacy of multiple 4SCAR-T cell therapy which targets GD2, PSMA and CD276 surface antigens in patients with relapsed and refractory neuroblastoma (NB). Another goal of the study is to understand the function of the multi-CAR-T cells and their persistency in the patients.

Condition or disease Intervention/treatment Phase
Neuroblastoma Biological: GD2, PSMA and CD276 CAR-T cells Phase 1 Phase 2

Detailed Description:

Neuroblastoma is one of the most aggressive childhood tumors arising from neural crest cells. Nearly 50% of patients with high risk disease have poor long-term survival even after multimodal treatments. Novel immunotherapy targeting tumor-specific antigens has been developed to meet the desperate need.

Disialoganglioside (GD2) is a well-studied tumor associated antigen which is expressed uniformly in NB but restrictedly in normal tissue. Over the past few years, CAR-T therapy against GD2 in NB has achieved encouraging but modest outcomes. Only a fraction of patients achieved measurable responses. Like for many other solid tumors, CAR-T therapy for NB is not as effective as for hematologic malignancies.

In this study, the investigators use "multiple targeting" approach as the strategy to overcome the challenge in treating NB. Prostate-specific membrane antigen (PSMA) is expressed in normal prostate but is upregulated in prostate tumor. However, PSMA expression is not restricted to prostate cancer. By immunohistochemistry (IHC) staining, the investigators confirmed that PSMA is expressed in a variety of solid tumors, including brain tumor, neuroblastoma and some lymphoma tumor tissues. Therefore, PSMA could potentially serve as a promising target for antigen-specific immunotherapy in patients with NB. In addition, CD276 (B7-H3) is an immune checkpoint molecule highly expressed on many solid tumors including NB. CD276 has been characterized to be involved in tumor evasion and thus its expression is correlated with poor prognosis. These characteristics make CD276 an attractive candidate for immunotherapy. Given the significant variation of tumor antigen expression among patients, the investigators aim to examine GD2, PSMA and CD276 expression in each patient's tumor sections by IHC staining, and combine two or three highly-expressed targets for the 4SCAR-T therapy. This individualized and multi-antigen-targeted approach is a new strategy to overcome the limited clinical outcome in the 4SCAR-T therapy against NB.

The purpose of this clinical study is to assess the feasibility, safety and efficacy of the combinational GD2, PSMA and CD276 4SCAR-T cell therapy against NB. Another goal of the study is to learn more about the function of the multi-4SCAR-T cells and their persistency in the patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multi-center Phase I/II Clinical Trial of 4SCAR-T Therapy Targeting GD2, PSMA and CD276 for Treating Neuroblastoma
Estimated Study Start Date : November 18, 2020
Actual Primary Completion Date : November 19, 2020
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma Scars

Arm Intervention/treatment
Experimental: effectiveness of CAR-T cells targeting GD2, PSMA and CD276
Gene-modified T cells are designed to kill tumor cells through specific recognition of GD2, PSMA and CD276. This study will evaluate the side effects and effective doses of GD2, PSMA and CD276 CAR-T cells in treating refractory and recurrent NB
Biological: GD2, PSMA and CD276 CAR-T cells
infusion, for 1x10^6~1x10^7 cells/kg via IV




Primary Outcome Measures :
  1. Number of patients with adverse events [ Time Frame: 3 year ]
    Determine the toxicity profile the GD2, PSMA and CD276 4SCAR-T cells with Common Toxicity Criteria for Adverse Effects version 4.0


Secondary Outcome Measures :
  1. Anti-tumor effects [ Time Frame: 3 year ]
    Complete response/remission (CR), Very good partial response/remission (VGPR) will be assessed by the image scan

  2. The expansion of CAR-T cells [ Time Frame: 3 year ]
    The investigators will monitor the expansion of GD2, PSMA and CD276 CAR-T cells in the peripheral blood of patients and the correlation with antitumor effects.

  3. The anti-tumor activity after CAR-T infusions [ Time Frame: 1 year ]
    The anti-tumor activity of lymphocytes will be assessed

  4. The cytokine secretion profile after CAR-T infusions [ Time Frame: 1 year ]
    The cytokine secretion profile of lymphocytes will be assessed.

  5. Survival time of the patients [ Time Frame: 3 year ]
    The overall survival time of the patients treated with CAR-T cells



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with tumors have received standard first-line therapy and been judged to be non-resectable, metastatic, progressive or recurrent.
  • The expression status of GD2, PSMA and CD276 antigens of the tumor will be determined for eligibility. Positive expression is defined by GD2, PMSA and CD276 antibody staining results based on immunohistochemistry or flow cytometry analyses.
  • Body weight greater than or equal to 10 kg.
  • Age: ≥1 year and ≤ 65 years of age at the time of enrollment.
  • Life expectancy: at least 8 weeks.
  • Prior Therapy:

    1. There is no limit to the number of prior treatment regimens. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or less.
    2. Participant must not have received hematopoietic growth factors for at least 1 week prior to mononuclear cells collection.
    3. At least 7 days must have elapsed since the completion of therapy with a biologic agent, targeted agent, tyrosine kinase inhibitor or a metronomic non-myelosuppressive regimen.
    4. At least 4 weeks must have elapsed since prior therapy that included a monoclonal antibody.
    5. At least 1 week since any radiation therapy at the time of study entry.
  • Karnofsky/jansky score of 60% or greater.
  • Cardiac function: Left ventricular ejection fraction greater than or equal to 40/55 percent.
  • Pulse Ox greater than or equal to 90% on room air.
  • Liver function: defined as alanine transaminase (ALT) <3x upper limit of normal (ULN), aspartate aminotransferase (AST) <3x ULN; serum bilirubin and alkaline phosphatase <2x ULN.
  • Renal function: Patients must have serum creatinine less than 3 times upper limit of normal.
  • Marrow function: White blood cell count ≥1000/ul, Absolute neutrophil count ≥500/ul, Absolute lymphocyte count ≥500/ul, Platelet count ≥25,000/ul (not achieved by transfusion).
  • Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria, and the marrow disease not evaluable for hematologic toxicity.
  • For all patients enrolled in this study, their parents or legal guardians must sign an informed consent and assent.

Exclusion Criteria:

  • Existing severe illness (e.g. significant cardiac, pulmonary, hepatic diseases, etc.) or major organ dysfunction, with the exception of grade 3 hematologic toxicity.
  • Untreated central nervous system (CNS) metastasis: Patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible.
  • Previous treatment with other genetically engineered GD2, PSMA and CD276 CART cells.
  • Active HIV, Hepatitis B virus (HBV), Hepatitis C virus (HCV) infection or uncontrolled infection.
  • Patients who require systemic corticosteroid or other immunosuppressive therapy.
  • Evidence of tumor potentially causing airway obstruction.
  • Inability to comply with protocol requirements.
  • Insufficient CART cells availability.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04637503


Contacts
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Contact: Lung-Ji Chang, PhD +86-8672-5195 c@szgimi.org

Locations
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China, Guangdong
Guangdong Zhujiang Hospital of Southern Medical University Recruiting
Guangzhou, Guangdong, China, 510282
Contact: Lihua Yang, M.D, PhD    86-13580532469    dryanglihua@163.com   
Contact: Lihua Yu, M.D    86-13414125621    eveylhyu@gmail.com   
Shenzhen Children's Hospital Recruiting
Shenzhen, Guangdong, China, 518000
Contact: Xiuli Yuan, M.D    86-18938690212    18938690212@163.com   
China, Guangzhou
Shenzhen Geno-Immune Medical Institute Recruiting
Shenzhen, Guangzhou, China, 518000
Contact: Lung-Ji Chang, PhD    +86-13671121909    c@szgimi.org   
China, Shandong
Shandong Cancer Hospital Recruiting
Jinan, Shandong, China, 250022
Contact: Jingfu Wang, M.D, Ph.D    86-13821271562    wangjingfu666@163.com   
Sponsors and Collaborators
Shenzhen Geno-Immune Medical Institute
Shenzhen Children's Hospital
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Responsible Party: Shenzhen Geno-Immune Medical Institute
ClinicalTrials.gov Identifier: NCT04637503    
Other Study ID Numbers: GIMI-IRB-20010
First Posted: November 19, 2020    Key Record Dates
Last Update Posted: November 19, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Shenzhen Geno-Immune Medical Institute:
CART
chimeric antigen receptor
adoptive T cell transfer
GD2, PSMA, CD276, B7-H3
Additional relevant MeSH terms:
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Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue