Targeting CD276 (B7-H3) Positive Solid Tumors by 4SCAR-276

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Recruiting
participants needed

100
sponsor

Shenzhen Geno-Immune Medical Institute

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Updated on 19 February 2024

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blood transfusion

platelet count

metastasis

neutrophil count

solid tumor

monoclonal antibodies

growth factor

ejection fraction

immunohistochemistry

serum bilirubin

tyrosine

solid neoplasm

kidney function test

antibody therapy

recurrent solid tumor

Summary

Patients with refractory and/or recurrent solid tumor have poor prognosis despite complex multimodel therapy and therefore, novel approaches are urgently needed. This study attempts 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 CD276 (B7-H3). The 4SCAR-CD276-modified T cells (4SCAR-276) can recognize and kill tumor cells through the recognition of CD276, a surface protein expressed at high levels on many types of tumors but at low levels on normal tissues. This study will evaluate the side effects and effective doses of 4SCAR-276 in treating refractory and/or recurrent tumors.

Description

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 CD276-specific chimeric antigen receptor (4SCAR-276). The CAR molecules enable the T cells to recognize and kill tumor cells through the recognition of the surface CD276, which is expressed at high levels on tumor cells including brain tumors, Ewing's sarcoma (PNET) and many other tumors 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-CD276 CAR T cells to target refractory and/or recurrent solid tumors.

Design

Participants will be screened through physical exam and medical history. Blood and tumor tissue samples will be collected. Imaging studies will be performed.
Peripheral blood mononuclear cells (PBMC) will be obtained by apheresis, and T cells will be activated and modified to express the 4SCAR-276 gene.
On Day -5 to -7, PBMC will be activated and enriched for T cells, which will be followed by 4SCAR-276 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.
The patients will receive ~10^6 CART cells/kg body weight per infusion, and may receive additional booster CART infusions if positive outcome is recorded.

Details

Condition	Solid Tumor
Age	1-75 years
Treatment	4SCAR-276
Clinical Study Identifier	NCT04432649
Sponsor	Shenzhen Geno-Immune Medical Institute
Last Modified on	19 February 2024

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Patients with tumors have received standard first-line therapy and have been judged to be non-resectable, metastatic, progressive or recurrent
	The CD276 antigen status of the tumor is determined for eligibility. Positive expression is defined by antibody staining results based on immunohistochemistry or flow cytometry analysis
	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: 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) 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 nonmyelosuppressive 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 to have hematologic toxicity
	For all patients enrolled in this study, themselves or 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, or grade 3 hematologic toxicity
	Untreated central nervous system (CNS) metastasis: Patients with CNS tumor involvement that has been treated and/or is stable for at least 6 weeks following completion of therapy are eligible
	Previous treatment with other genetically engineered CD276-CAR T cells or CD276 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

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Targeting CD276 (B7-H3) Positive Solid Tumors by 4SCAR-276