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

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

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

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

Locations

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

More Information

• Responsible Party: Shenzhen Geno-Immune Medical Institute
• ClinicalTrials.gov Identifier: NCT04637503
• Other Study ID Numbers: GIMI-IRB-20010
• First Posted: November 19, 2020
• Last Update Posted: November 19, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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