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A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
Preclinical characterization and phase 1 results of ADG106 in patients with advanced solid tumors and non-Hodgkin's
Yuxiang Ma1, Fan Luo2, Yang Zhang1
1Department of Clinical Research, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
Abstract:
ADG106, a ligand-blocking agonistic antibody targeting CD137 (4-1BB), exhibits promising results in preclinical studies, demonstrating tumor suppression in various animal models and showing a balanced profile between safety and efficacy. This phase 1 study enrolls 62 patients with advanced malignancies, revealing favorable tolerability up to the 5.0 mg/kg dose level. Dose-limiting toxicity occurs in only one patient (6.3%) at 10.0 mg/kg, resulting in grade 4 neutropenia. The most frequent treatment-related adverse events include leukopenia (22.6%), neutropenia (22.6%), elevated alanine aminotransferase (22.6%), rash (21.0%), itching (17.7%), and elevated aspartate aminotransferase (17.7%). The overall disease control rates are 47.1% for advanced solid tumors and 54.5% for non-Hodgkin's lymphoma. Circulating biomarkers suggest target engagement by ADG106 and immune modulation of circulating T, B, and natural killer cells and cytokines interferon γ and interleukin-6, which may affect the probability of clinical efficacy. ADG106 has a manageable safety profile and preliminary anti-tumor efficacy in patients with advanced cancers (this study was registered at ClinicalTrials.gov: NCT03802955).
Insights
ADG106, an antibody targeting CD137 (4-1BB), shows promise in treating advanced cancers. This Phase 1 trial found it well-tolerated with preliminary anti-tumor activity and manageable side effects in patients.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- CD137 (4-1BB) is a target for cancer immunotherapy.
- Preclinical studies showed ADG106, a CD137 agonist antibody, has anti-tumor effects.
- A balanced safety and efficacy profile is crucial for novel cancer therapies.
Purpose of the Study:
- To evaluate the safety and tolerability of ADG106 in patients with advanced malignancies.
- To determine the preliminary efficacy of ADG106 in this patient population.
- To explore potential biomarkers of ADG106 activity.
Main Methods:
- Phase 1 clinical trial involving 62 patients with advanced cancers.
- Dose escalation to determine the maximum tolerated dose (MTD).
- Assessment of treatment-related adverse events (TRAEs), disease control rate (DCR), and biomarker analysis.
Main Results:
- ADG106 was well-tolerated up to 5.0 mg/kg; dose-limiting toxicity (Grade 4 neutropenia) occurred in one patient at 10.0 mg/kg.
- Common TRAEs included leukopenia, neutropenia, elevated liver enzymes, rash, and itching.
- Disease control rates were 47.1% in advanced solid tumors and 54.5% in non-Hodgkin's lymphoma.
- Biomarker analysis indicated target engagement and immune modulation of T, B, and NK cells, along with cytokine changes.
Conclusions:
- ADG106 demonstrates a manageable safety profile and preliminary anti-tumor efficacy in patients with advanced cancers.
- Biomarkers suggest that ADG106 engages the target and modulates the immune system, potentially influencing clinical outcomes.
- Further investigation in larger trials is warranted to confirm these findings.
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