Células CAR-NK de Duplo Alvo para Glioblastoma Recorrente/Progressivo e Glioma de Alto Grau
Um Estudo de Fase 1, Primeiro em Humanos, Guiado por Biomarcadores, de Escalonamento de Dose e Expansão de Células CAR-NK de Direcionamento Duplo Locorregional Dirigidas Contra IL13Rα2, EGFR/EGFRvIII, e/ou B7-H3 (CD276) em Adultos com Glioblastoma Recorrente ou Progressivo ou Glioma de Alto Grau
This is a first-in-human Phase 1/2 study evaluating locoregional administration of dual-targeting chimeric antigen receptor natural killer (CAR-NK) cells in adults with recurrent or progressive glioblastoma (GBM) or other high-grade glioma (HGG). Participants will undergo tumor antigen profiling for IL13Rα2, EGFR/EGFRvIII, and B7-H3 (CD276). Based on this assessment, each participant will receive the most suitable dual-target CAR construct to reduce antigen-escape risk.
Visão geral do estudo
Status
Condições
Descrição detalhada
GBM/HGG is molecularly heterogeneous and may evade single-antigen immunotherapy via antigen loss or heterogeneous antigen expression. This study evaluates a dual-target CAR-NK strategy that can recognize two tumor-associated antigens selected from IL13Rα2, EGFR/EGFRvIII, and B7-H3 (CD276).
Target assessment and cohort assignment: At screening, archived and/or fresh tumor tissue (from clinically indicated resection or biopsy) will be evaluated by immunohistochemistry (IHC) for IL13Rα2, EGFR, and B7-H3, and by molecular testing (e.g., RT-PCR or NGS) for EGFRvIII when applicable. Participants will be assigned to one of three biomarker-defined cohorts based on the two highest-priority antigens detected above protocol-defined thresholds. An internal review committee may recommend prioritizing one construct for later expansion based on emerging safety/feasibility/activity signals.
Investigational product: The investigational products are off-the-shelf allogeneic CAR-NK cells manufactured from a standardized NK-cell source (e.g., iPSC-derived NK cells or a qualified NK master cell bank) and genetically modified to express a tandem (dual-target) CAR. The constructs include a built-in safety switch and may include an NK-support cytokine module (e.g., IL-15) to enhance persistence. The exact dual-target construct used for each participant depends on the screening antigen profile.
Route of administration: CAR-NK cells will be delivered locoregionally to the surgical cavity wall and/or into the ventricular system via a neurosurgically placed catheter/reservoir, to maximize exposure at the tumor site while limiting systemic exposure.
Dose escalation and expansion: Each biomarker-defined cohort follows a modified 3+3 dose-escalation schema with up to three dose levels (e.g., 1×10^7, 3×10^7, and 1×10^8 CAR-NK cells per infusion). Dose-limiting toxicities (DLTs) will be assessed during the first 28 days after the first infusion. After an RP2D is identified within a cohort, an expansion stage will further characterize safety and preliminary activity and may allow repeat infusions at the RP2D.
Follow-up: Participants will be monitored closely for adverse events including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
Tumor response will be assessed with MRI using RANO criteria at regular intervals.
Long-term follow-up for gene-modified cell therapy safety will be conducted per applicable guidance.
Tipo de estudo
Inscrição (Estimado)
Estágio
- Fase 1
Contactos e Locais
Contato de estudo
- Nome: shan S Lu, Phd
- Número de telefone: +86 13076790030
- E-mail: Seni-Lu@beijing-biotech.com
Locais de estudo
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Guangdong
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Shenzhen, Guangdong, China, 518036
- Recrutamento
- Peking University Shenzhen Hospital
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Contato:
- Zhen J Peng, Phd
- Número de telefone: +86 13076790039
- E-mail: Zhen-Peng@beijing-biotech.com
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
Inclusion Criteria:
- Age 18 to 75 years at the time of consent.
- Histologically confirmed glioblastoma (WHO grade 4) or diffuse high-grade glioma (WHO grade 3 or 4) that is recurrent or progressive after standard therapy.
- Planned clinically indicated tumor resection or stereotactic biopsy (or availability of adequate archived tumor tissue) to support antigen testing and locoregional catheter placement.
- Tumor demonstrates expression of at least two of the following antigens above protocol-defined thresholds: IL13Rα2, EGFR (wild-type) and/or EGFRvIII, B7-H3 (CD276).
- Karnofsky Performance Status (KPS) ≥ 60.
- Adequate organ function (hematologic, renal, hepatic) as defined by protocol laboratory criteria.
- Ability to undergo brain MRI with contrast (unless contraindicated and alternative imaging is permitted).
- Negative pregnancy test for women of childbearing potential; agreement to use effective contraception during study participation and for a protocol-defined period after infusion.
- Ability to understand and willingness to sign informed consent.
Exclusion Criteria:
- Active, uncontrolled infection (including uncontrolled bacterial, viral, or fungal infection).
- Known HIV infection with uncontrolled viral load; active hepatitis B or hepatitis C with detectable viral load (unless permitted per protocol).
- Clinically significant autoimmune disease requiring systemic immunosuppression within the past 6 months.
- Requirement for high-dose systemic corticosteroids (e.g., >4 mg/day dexamethasone equivalent) within 7 days prior to lymphodepletion/infusion (physiologic replacement permitted).
- Prior gene-modified cellular therapy (e.g., prior CAR-T/CAR-NK) within 6 months, or prior therapy targeting IL13Rα2, EGFR/EGFRvIII, or B7-H3 where residual engineered cells could confound safety assessments.
- Diffuse leptomeningeal disease as the only site of disease, or anatomy that precludes safe catheter placement (unless specifically allowed by protocol).
- Uncontrolled seizures despite optimal medical therapy.
- Clinically significant cardiovascular disease (e.g., recent myocardial infarction, uncontrolled arrhythmia) that would increase risk with lymphodepletion or infusion procedures.
- Pregnant or breastfeeding.
- Any condition that, in the investigator's judgment, would make the participant unsuitable for the study or could interfere with protocol adherence.
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Não randomizado
- Modelo Intervencional: Atribuição sequencial
- Mascaramento: Nenhum (rótulo aberto)
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
|---|---|
|
Experimental: IL13Rα2 + EGFR/EGFRvIII Dual-Target CAR-NK
Participants whose tumors meet eligibility thresholds for IL13Rα2 and EGFR will receive a dual-target (tandem) CAR-NK product recognizing IL13Rα2 and EGFR/EGFRvIII |
Dual-target CAR-NK cells (IL13Rα2/EGFR/EGFRvIII construct): Allogeneic natural killer (NK) cells genetically engineered to express a chimeric antigen receptor (CAR) designed to recognize tumor-associated antigens including IL13Rα2, EGFR, and EGFRvIII. This multi-targeting strategy aims to enhance tumor recognition, reduce antigen escape, and improve cytotoxic activity against heterogeneous tumor cell populations. The engineered CAR-NK cells are administered via locoregional delivery (e.g., intracavitary or through an Ommaya reservoir) to achieve targeted anti-tumor effects while minimizing systemic toxicity. An alkylating chemotherapy agent used as part of lymphodepleting conditioning prior to CAR-NK cell infusion to enhance cell expansion, persistence, and anti-tumor activity. A device (e.g., Ommaya reservoir) implanted in the brain to enable direct, repeated administration of CAR-NK cells or other therapies into the tumor site or cerebrospinal fluid, improving local drug delivery and reducing systemic exposure. A purine analog chemotherapy used in lymphodepletion prior to CAR-NK cell therapy to enhance the expansion, persistence, and anti-tumor activity of the infused cells. |
|
Experimental: IL13Rα2 + B7-H3 (CD276) Dual-Target CAR-NK
Participants whose tumors meet eligibility thresholds for IL13Rα2 and B7-H3 (CD276) will receive a dual-target (tandem) CAR-NK product recognizing IL13Rα2 and B7-H3. |
Dual-target CAR-NK cells (IL13Rα2/EGFR/EGFRvIII construct): Allogeneic natural killer (NK) cells genetically engineered to express a chimeric antigen receptor (CAR) designed to recognize tumor-associated antigens including IL13Rα2, EGFR, and EGFRvIII. This multi-targeting strategy aims to enhance tumor recognition, reduce antigen escape, and improve cytotoxic activity against heterogeneous tumor cell populations. The engineered CAR-NK cells are administered via locoregional delivery (e.g., intracavitary or through an Ommaya reservoir) to achieve targeted anti-tumor effects while minimizing systemic toxicity. An alkylating chemotherapy agent used as part of lymphodepleting conditioning prior to CAR-NK cell infusion to enhance cell expansion, persistence, and anti-tumor activity. A device (e.g., Ommaya reservoir) implanted in the brain to enable direct, repeated administration of CAR-NK cells or other therapies into the tumor site or cerebrospinal fluid, improving local drug delivery and reducing systemic exposure. A purine analog chemotherapy used in lymphodepletion prior to CAR-NK cell therapy to enhance the expansion, persistence, and anti-tumor activity of the infused cells. |
|
Experimental: EGFR/EGFRvIII + B7-H3 (CD276) Dual-Target CAR-NK
Participants whose tumors meet eligibility thresholds for EGFR (and/or EGFRvIII) and B7-H3 (CD276) will receive a dual-target (tandem) CAR-NK product recognizing EGFR/EGFRvIII and B7-H3. |
Dual-target CAR-NK cells (IL13Rα2/EGFR/EGFRvIII construct): Allogeneic natural killer (NK) cells genetically engineered to express a chimeric antigen receptor (CAR) designed to recognize tumor-associated antigens including IL13Rα2, EGFR, and EGFRvIII. This multi-targeting strategy aims to enhance tumor recognition, reduce antigen escape, and improve cytotoxic activity against heterogeneous tumor cell populations. The engineered CAR-NK cells are administered via locoregional delivery (e.g., intracavitary or through an Ommaya reservoir) to achieve targeted anti-tumor effects while minimizing systemic toxicity. An alkylating chemotherapy agent used as part of lymphodepleting conditioning prior to CAR-NK cell infusion to enhance cell expansion, persistence, and anti-tumor activity. A device (e.g., Ommaya reservoir) implanted in the brain to enable direct, repeated administration of CAR-NK cells or other therapies into the tumor site or cerebrospinal fluid, improving local drug delivery and reducing systemic exposure. A purine analog chemotherapy used in lymphodepletion prior to CAR-NK cell therapy to enhance the expansion, persistence, and anti-tumor activity of the infused cells. |
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Incidência de toxicidades limitantes de dose (DLTs) após infusão de CAR-NK (CTCAE v5.0; classificação de CRS e ICANS).
Prazo: 28 Dias
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28 Dias
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Determination of recommended phase 2 dose (RP2D)
Prazo: 12 months
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Determination of recommended phase 2 dose (RP2D) if the maximum tolerated dose (MTD) for each biomarker-defined cohort has been established |
12 months
|
Medidas de resultados secundários
Medida de resultado |
Prazo |
|---|---|
|
Taxa de resposta objetiva (ORR) pelos critérios RANO (RC+RP)
Prazo: 12 meses
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12 meses
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Taxa de controle da doença (DCR) pelos critérios RANO
Prazo: 6 meses
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6 meses
|
Colaboradores e Investigadores
Patrocinador
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo (Real)
Conclusão Primária (Estimado)
Conclusão do estudo (Estimado)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Real)
Atualizações de registro de estudo
Última Atualização Postada (Real)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Neoplasias
- Neoplasias por Tipo Histológico
- Neoplasias Glandulares e Epiteliais
- Astrocitoma
- Neoplasias Neuroepiteliais
- Tumores Neuroectodérmicos
- Neoplasias, Células Germinativas e Embrionárias
- Neoplasias, Tecido Nervoso
- Glioblastoma
- Glioma
- Produtos químicos orgânicos
- Hidrocarbonetos
- Mustarazas de fosforamida
- Compostos de mostarda de nitrogênio
- Compostos de mostarda
- Hidrocarbonetos, halogenados
- Fosforamidas
- Compostos organofosforos
- Ciclofosfamida
- fludarabina
Outros números de identificação do estudo
- EBNK-GBM-112
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