Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Symptoms and General Pathology

Prostatic Neoplasms

Cicatrix

Infusion of 4SCAR-PSMA T cells at 10\^6 cells/kg body weight via IV

4SCAR-PSMA T cells

Sixi Liu, MD

Xiuli Yuan, MD

Lung-Ji Chang, PhD

Jie Mao, MD

Bo Wang, MD

The purpose of this clinical trial is to assess the feasibility, safety and efficacy of PSMA-specific CAR-T cell therapy in patients with PSMA positive tumor. Another goal of the study is to learn more about the function of the PSMA CAR-T cells and their persistency in the patients.

Prostate-specific membrane antigen (PSMA) is expressed in normal prostate and is upregulated in prostate tumor. Therefore, PSMA is a promising target for antigen-specific immunotherapy in patients with prostate cancer. However, it has been reported that PSMA expression is not restricted to prostate cancer and PSMA is often enriched in the tumor stromal environment. By immunostaining, we found that PSMA is expressed in a variety of solid tumors, including brain tumor, neuroblastoma and some lymphoma tumor tissues.

This study aims to use T cells obtained directly from the patient, which can be genetically modified to express PSMA-specific chimeric antigen receptor (CAR). The CAR molecules enable the T cells to recognize and kill tumor cells or tumor stromal tissues through the recognition of a surface antigen, PSMA. This study will evaluate the side effects and the best dose of anti-PSMA CAR-T cells to target PSMA positive tumors and tumor microenvironment.

PSMA-specific CAR-T Cell Therapy

Phase I/II Clinical Trial of 4SCAR-PSMA T Cell Therapy Targeting PSMA Positive Malignancies

Determine the toxicity profile the 4SCAR-PSMA cells with Common Toxicity Criteria for Adverse Effects version 4.0

Objective responses (complete response (CR) + partial response (PR)) are assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

Scale of CAR copies and tumor burden (for efficacy)

The survival time of the patients treated with the 4SCAR-PSMA T cells, including progression free survival (PFS) and overall survival (OS) will be evaluated.

Shenzhen Children's Hospital

The Seventh Affiliated Hospital of Sun Yat-sen University

Shenzhen Hospital of Southern Medical University

Shenzhen Geno-Immune Medical Institute

President

Rare Diseases

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Gaucher Disease Type 2

Neuroepithelioma

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

infusion, for 1x10\^6\~1x10\^7 cells/kg via IV

GD2, PSMA and CD276 CAR-T cells

Lihua Yang, M.D, PhD

Lihua Yu, M.D

Xiuli Yuan, M.D

Jingfu Wang, M.D, Ph.D

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.

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

Multi-center Phase I/II Clinical Trial of 4SCAR-T Therapy Targeting GD2, PSMA and CD276 for Treating Neuroblastoma

Determine the toxicity profile the GD2, PSMA and CD276 4SCAR-T cells with Common Toxicity Criteria for Adverse Effects version 4.0

Complete response/remission (CR), Very good partial response/remission (VGPR) will be assessed by the image scan

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.

The anti-tumor activity of lymphocytes will be assessed

The cytokine secretion profile of lymphocytes will be assessed.

The overall survival time of the patients treated with CAR-T cells

The 4SCAR-GD2-modified T cells can recognize and kill tumor cells through the recognize of GD2 .This study will evaluate the side effects and effective doses of 4SCAR-GD2 T cells in treating refractory and recurrent solid tumors

4SCAR-GD2

Lung-Ji Chang, PhD.

Lung-Ji Chang

Patients with refractory and/or recurrent solid tumor have poor prognosis despite complex multimodel therapy and therefore, novel approaches are urgently needed. The investigators are attempt to treat these diseases using T cells genetically modified with a 4th generation lentiviral chimeric antigen receptor (4SCAR fused with an inducible apoptotic caspase 9 domain) targeting GD2 (4SCAR-GD2). The 4SCAR-GD2-modified T cells can recognize and kill tumor cells through the recognition of GD2, a surface protein expressed at high levels on many types of tumors but not on normal tissues. This study will evaluate the side effects and effective doses of 4SCAR-GD2 T cells in treating refractory and/or recurrent tumors.

Background:

Patients with refractory and/or recurrent solid tumors have poor prognosis despite complex multimodal therapy; therefore, novel curative approaches are needed. The investigators are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a 4th generation GD2-specific chimeric antigen receptor (4SCAR-GD2). The chimeric antigen receptor (CAR) molecules enable the T cells to recognize and kill tumor cells through the recognition of a surface antigen, GD2, which is expressed at high levels on tumor cells but not at significant levels on normal tissues. This study will evaluate the side effects and the best dose of a novel 4th generation anti-GD2 CAR T cells to refractory and/or recurrent solid tumors.

Design:

Participants will be screened through physical exam and medical history. Blood and urine samples will be collected. Imaging studies or bone marrow aspirates may be performed.

Peripheral blood mononuclear cells (PBMC) will be obtained by apheresis, and T cells will be activated and modified to express the 4SCAR-GD2 gene.

On Day -5 to -7, PBMC will be activated and enriched for T cells, which will be followed by 4SCAR-GD2 lentiviral transduction. The total culture time is approximately 5-7 days.

Participants will receive a preparative conditioning regimen comprising cyclophosphamide/fludarabine to prepare their immune system to accept the modified CAR T cells.The preparative regimen will be based on patient immune condition and consistent with standard chemotherapy conditioning regimen.

Study on GD2 Positive Solid Tumors by 4SCAR-GD2

Multicenter Trial of Phase I/II Studies on GD2 Positive Solid Tumors by 4SCAR-GD2

Determine the toxicity profile the 4SCAR-GD2-modified T cells with Common Toxicity Criteria for Adverse Effects version 4.0

Disease status is defined by the biochemical markers and image scan to get the outcomes such as Complete response/remission (CR) , Very good partial response/remission (VGPR) , etc

The investigators will monitor the expansion and functional persistence of 4SCAR-GD2 T cells in the peripheral blood of patients and the correlation with antitumor effects

assessment of lymphocyte phenotypes and anti-tumor activity

Evaluate the survival time of the patients treated with the 4SCAR-GD2 T cells, including progression free survival (PFS) and overall survival (OS)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
PSMA-specific CAR-T Cell Therapy	NCT04429451	PSMA Positive T...	4SCAR-PSMA T ce...	1 Year - 75 Years	Shenzhen Geno-Immune Medical Institute
4SCAR-T Therapy Targeting GD2, PSMA and CD276 for Treating Neuroblastoma	NCT04637503	Neuroblastoma	GD2, PSMA and C...	1 Year - 65 Years	Shenzhen Geno-Immune Medical Institute
Study on GD2 Positive Solid Tumors by 4SCAR-GD2	NCT02992210	Solid Tumor	4SCAR-GD2	1 Year - 65 Years	Shenzhen Geno-Immune Medical Institute
4SCAR-T Therapy Targeting GD2, PSMA and CD276 for Treating Neuroblastoma	NCT04637503	Neuroblastoma	GD2, PSMA and C...	1 Year - 65 Years	Shenzhen Geno-Immune Medical Institute

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