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.
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 Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
100
infusion, for 1x10\^6\~1x10\^7 cells/kg via IV
Guangdong Zhujiang Hospital of Southern Medical University
Guangzhou, Guangdong, China
RECRUITINGShenzhen Children's Hospital
Shenzhen, Guangdong, China
RECRUITINGShenzhen Geno-Immune Medical Institute
Shenzhen, Guangzhou, China
RECRUITINGNumber of patients with adverse events
Determine the toxicity profile the GD2, PSMA and CD276 4SCAR-T cells with Common Toxicity Criteria for Adverse Effects version 4.0
Time frame: 3 year
Anti-tumor effects
Complete response/remission (CR), Very good partial response/remission (VGPR) will be assessed by the image scan
Time frame: 3 year
The expansion of CAR-T cells
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.
Time frame: 3 year
The anti-tumor activity after CAR-T infusions
The anti-tumor activity of lymphocytes will be assessed
Time frame: 1 year
The cytokine secretion profile after CAR-T infusions
The cytokine secretion profile of lymphocytes will be assessed.
Time frame: 1 year
Survival time of the patients
The overall survival time of the patients treated with CAR-T cells
Time frame: 3 year
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Shandong Cancer Hospital
Jinan, Shandong, China
RECRUITING