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Mechanisms of new immunotherapy candidate explored

The Journal of Clinical Investigation has published a scientific article describing ONC201’s ability to cause intratumoral accumulation and activation of natural killer (NK) and CD3 T cells in mouse models and patients.

The publication is from the laboratory of Wafik El-Deiry MD, PhD, FACP, Scientific Founder of Oncoceutics, and Deputy Cancer Center Director for Translational Research at Fox Chase Cancer Center.

ONC201, founding member of the imipridone class of small molecules that selectively target G-protein coupled receptors (GPCRs), antagonizes dopamine receptor D2 that is expressed on tumour cells and immune cells.

ONC201 stimulates the infiltration of activated NK cells into the tumour that further contributes to the overall anti-cancer efficacy along with direct tumour cell kill.

Immune activation by ONC201 is consistent with its ability to stimulate downstream TRAIL pathway signalling that is part of the body’s immune surveillance mechanism against cancer.

An increase in activated TRAIL-secreting NK cells was observed in the peripheral blood of patients after receiving ONC201 treatment.

These results highlight the potential utility for ONC201 in combination with immunotherapy agents such as anti-PD-1 therapy.

The article also provides a preclinical rationale for ONC201’s weekly dosing clinical regimen and evidence of an anti-metastatic effect.

“Immune cell activation in the tumour and inhibition of metastasis with an oral, infrequently administered and well tolerated small molecule provides an attractive treatment option for patients. Immune activation is recognized as an important requirement to achieve durable and complete remissions in conjunction with standard-of-care therapies,” said El-Deiry. “We discovered ONC201 through its ability to stimulate TRAIL pathway signalling that now provides a mechanistic explanation for immune cell activation.”   

“The ability to selectively activate NK and T cells through an alternative mechanism is particularly relevant in immune-suppressed tumours such as glioma and provides opportunities for rational combinations with immunotherapy and other treatment modalities such as radiotherapy,” said Varun Prabhu, PhD, Associate Director, Research and Development, at Oncoceutics. “Immune cell activation further explains the durable tumour shrinkage and clinical benefit of ONC201 that has extended beyond 2 years in some glioma patients.”

Source:  Fox Chase Cancer Centre



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