GD2/PSMA Bi-specific CAR-T Cell Therapy

Официальное название

GD2/PSMA Bi-specific CAR-T Cells For the Treatment of GD2 and PSMA Positive Solid Tumors

Обзор

The purpose of this clinical trial is to assess the feasibility, safety and efficacy of anti-GD2/PSMA bi-specific CAR-T cell therapy in patients with GD2 and PSMA positive tumor. Another goal of the study is to learn more about the function of the anti-GD2/PSMA bi-specific CAR-T cells and their persistency in patients.

Подробное описание

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 anti-GD2/PSMA bi-specific chimeric antigen receptor (bi-4SCAR-GD2/PSMA). The chimeric antigen receptor (CAR) molecules enable the T cells to recognize and kill tumor cells through the recognition of a surface antigen, GD2 or PSMA, which is expressed at high levels on tumor cells but not at significant levels on normal tissues.

Disialoganglioside (GD2) is a well-studied tumor associated antigen which is expressed uniformly in nervous system-related tumors but at low levels in normal tissues. Over the past few years, CAR-T therapy against GD2 in tumor has achieved encouraging but modest outcomes. Only a fraction of patients achieved measurable responses. In solid tumors, GD2 CAR-T therapy alone may not as effective as CAR-T cell therapy in hematological malignancies.

Prostate-specific membrane antigen (PSMA) is expressed in normal prostate and upregulated in prostate tumor. Therefore, PSMA is a promising target for immunotherapy of prostate cancer. However, PSMA is not restricted to prostate cancer and it is known that PSMA is enriched in the tumor stromal environment. Based on immunostaining, it is confirmed that PSMA is expressed in a variety of solid tumors, including brain tumor, neuroblastoma and some lymphomas.

To overcome tumor escape of single target antigen and enhance in vivo CAR-T efficacy, a novel bi-specific GD2/PSMA CAR-T therapy regimen is developed to include booster and consolidation CAR-T applications to target highly-refractory cancer. The aim is to evaluate safety and long term efficacy of the bi-CAR-T therapy strategy in GD2 and/or PSMA positive cancer patients.

Вмешательства

• Биопрепарат bi-4SCAR GD2/PSMA T cells
  Infusion of bi-4SCAR GD2/PSMA T cells at 10\^6 cells/kg body weight via IV

Первичные конечные точки

• Number of patients with adverse events. [Срок оценки: 6 months]

Вторичные конечные точки (6)

• Anti-tumor effects [Срок оценки: 1 year]
• Anti-tumor effects [Срок оценки: 1 year]
• The persistence of bi-4SCAR GD2/PSMA T cells [Срок оценки: 1 year]
• The expansion bi-4SCAR GD2/PSMA T cells [Срок оценки: 1 year]
• Survival time of the patients [Срок оценки: 3 years]
• Survival time of the patients [Срок оценки: 3 years]

Критерии участия

Критерии включения

• Patients with tumors have received standard first-line therapy and have been judged to be non-resectable, metastatic, progressive or recurrent.
• The expression status of GD2 or PSMA antigens in the tumor tissue will be determined for eligibility. Positive expression is defined by GD2 and PMSA antibody staining results based on immunohistochemistry or flow cytometry analyses.
• Body weight greater than or equal to 10 kg.
• Age: ≥1 year and ≤ 75 years of age at the time of enrollment.
• Life expectancy: at least 8 weeks.
• Prior Therapy:

There is no limit to the number of prior treatment regimens. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must be resolved to grade 2 or less.

• Participant must not have received hematopoietic growth factors for at least 1 week prior to mononuclear cells collection.
• At least 7 days must have elapsed since the completion of therapy with a biologic agent, selected targeted agent or a metronomic non-myelosuppressive regimen.
• At least 4 weeks must have elapsed since prior therapy that included a monoclonal antibody.
• 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 does not have hematologic toxicity.
• For all patients enrolled in this study, themselves or their parents or legal guardians must sign an informed consent and assent.

Критерии исключения

• Existing severe illness (e.g. significant cardiac, pulmonary, hepatic diseases, etc.) or major organ dysfunction, or greater than grade 2 hematologic toxicity.
• Untreatable 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 or PSMA-specific CAR T cells or antibody therapy.
• 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 CAR T cells availability.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Shenzhen Geno-immune Medical Institute — Шэньчжэнь

Идентификаторы

NCT: NCT05437315 · GIMI-IRB-22003

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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