Overcoming resistance to programmed cell death protein 1 (PD-1) blockade with allogeneic invariant natural killer
Matthew J Hadfield1, Howard Safran1, Marco A Purbhoo2
1Legorreta Cancer Center at Brown University, Lifespan Cancer Institute, Providence, RI, USA.
Abstract:
Gastric cancer is the 5th most common malignancy worldwide with only 36% of patients with metastatic disease surviving beyond 5 years. Despite therapeutic improvements with the advent of immune checkpoint inhibitors, most patients with gastric cancer develop disease progression related to tumor resistance. Novel immunotherapeutic approaches, including invariant natural killer (iNKT) cells, are in clinical development and represent potential therapeutic options to overcome resistance. AgenT-797 is an allogeneic human unmodified iNKT derived from healthy donors. Activation of iNKT cells by tumor lipid antigens can trigger direct cytotoxicity and promote indirect anti-tumor immune responses such as recruitment and activation of T cells, NK cells, and dendritic cells through secretion of cytokines and IFNγ. We describe immune modulation leading to durable tumor response in a patient with microsatellite instability-high (MSI-H) advanced gastric adenocarcinoma treated with agent-797 after progression on standard chemotherapy and anti-PD-1 therapy.
Insights
Invariant natural killer (iNKT) cell therapy, AgenT-797, shows promise for gastric cancer. This novel immunotherapy activated anti-tumor responses, leading to a durable tumor response in a patient with advanced disease.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Research
Background:
- Gastric cancer is a leading cause of cancer death globally.
- Metastatic gastric cancer has a poor prognosis, with limited survival rates.
- Tumor resistance to current therapies, including immune checkpoint inhibitors, remains a significant challenge.
Purpose of the Study:
- To investigate the potential of invariant natural killer (iNKT) cells as a novel immunotherapy for gastric cancer.
- To evaluate the efficacy and immune modulation of AgenT-797, an allogeneic iNKT cell therapy, in a patient with advanced gastric cancer.
Main Methods:
- Treatment of a patient with microsatellite instability-high (MSI-H) advanced gastric adenocarcinoma with AgenT-797.
- Monitoring of immune responses and tumor status following therapy.
Main Results:
- AgenT-797 activated iNKT cells, leading to direct cytotoxicity and indirect anti-tumor immune responses.
- The patient experienced durable tumor response after progression on standard chemotherapy and anti-PD-1 therapy.
- Immune modulation was observed, indicating a potential mechanism of action.
Conclusions:
- AgenT-797 demonstrates potential as a therapeutic option for gastric cancer, particularly in patients resistant to standard treatments.
- iNKT cell therapy can overcome tumor resistance and induce significant anti-tumor immunity.
- Further clinical development of AgenT-797 is warranted for gastric cancer treatment.
