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Published on: February 16, 2015
Trial in progress: phase I study of non-viral gene-modified CAR-T cell therapy for malignant solid tumors expressing
Chikako Funasaka1,2, Yoichi Naito1,2,3, Hitomi Kubota4
1Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Background:
Ephrin type-B receptor 4 (EPHB4) is overexpressed on the surface of various tumor cells, including cells from malignant bone and soft-tissue tumors. AP8901 CAR-T cell therapy can specifically recognize and kill EPHB4 receptor-expressing malignant tumor cells by modifying the natural EPHB4 receptor ligand, ephrin B2. AP8901 is being developed via genetic manipulation involving the "piggyBac transposon" and "genetically modified feeder cell" methods, which enables the stable expression of CAR proteins in T cells and prevents T cell exhaustion. AP8901 has demonstrated therapeutic efficacy and tolerability in mice transplanted with rhabdomyosarcoma cells. We planned a phase I study to evaluate the safety and efficacy of AP8901 for metastatic solid tumors.
Methods:
This is a single-center, single-arm, dose-escalation, phase I study to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary anti-tumor activity of a single intravenous dose of AP8901 in patients with Ewing sarcoma or solid tumors expressing the EPHB4 receptor. Key inclusion criteria include the following: subjects with histologically diagnosed Ewing sarcoma or solid tumor with confirmed metastasis or recurrence/no standard treatment for metastasis or recurrence, or refractory or intolerant to standard treatment; measurable or evaluable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; recent biopsy or surgical resection specimens with prescreening immunohistochemistry positive for EPHB4 in ≥1% of tumor cells; ECOG performance status 0 or 1; and subjects expected to survive ≥3 months from the date of enrollment. This study is being conducted at the National Cancer Center Hospital East, Japan.
Discussion:
The advantage of AP8901 is that it is expected to prevent T cell exhaustion and maintain its anti-tumor effect. This phase 1 study of AP8901 will provide new evidence for the application of this novel CAR-T cell therapy in patients with solid tumors, including Ewing sarcoma.
Insights
AP8901 CAR-T cell therapy targets EPHB4-expressing solid tumors. This Phase I study evaluates its safety and efficacy in patients with Ewing sarcoma or other metastatic solid tumors, aiming to prevent T cell exhaustion.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Ephrin type-B receptor 4 (EPHB4) is overexpressed in various malignant tumors, including bone and soft-tissue sarcomas.
- AP8901 CAR-T cell therapy is designed to target EPHB4-expressing tumor cells by leveraging a modified ephrin B2 ligand.
- Development utilizes piggyBac transposon and genetically modified feeder cells for stable CAR expression and prevention of T cell exhaustion.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary anti-tumor activity of AP8901.
- To assess AP8901 in patients with Ewing sarcoma or other solid tumors expressing EPHB4.
- To provide evidence for the clinical application of this novel CAR-T cell therapy in solid tumors.
Main Methods:
- Single-center, single-arm, dose-escalation Phase I clinical trial.
- Intravenous administration of a single dose of AP8901.
- Inclusion criteria: histologically diagnosed Ewing sarcoma or solid tumor with metastasis/recurrence, EPHB4 expression (≥1%), ECOG 0-1, and survival ≥3 months.
Main Results:
- AP8901 demonstrated therapeutic efficacy and tolerability in preclinical models (mice with rhabdomyosarcoma).
- The study aims to provide preliminary safety and efficacy data in human subjects.
- Pharmacokinetic/pharmacodynamic data will be collected to understand AP8901's behavior in vivo.
Conclusions:
- AP8901 CAR-T cell therapy shows promise for treating EPHB4-positive solid tumors.
- The therapy's design aims to overcome T cell exhaustion, potentially leading to sustained anti-tumor effects.
- This Phase I study is crucial for establishing the safety profile and potential clinical utility of AP8901.
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