Combinations of immunotherapies, like ipilimumab (Yervoy) with anti-PD-1 nivolumab (Opdivo), has shown a higher level of anti-melanoma activity than monotherapy with either nivolumab or ipilimumab, but is associated with increased toxicity. That is a problem that can be dealt with by using ImmunoPulse, while at the same time increasing IFN-y production by putting IL-12 in the mix, while at the same time helping the non-responders to the anti PD-1.
Bristol-Myers recently submitted a SBLA for the combination of Opdivo with Yervoy in advanced melanoma. The study application was granted priority review with a decision deadline of January 23, 2016. In the study, 945 patients with untreated unresectable or metastatic melanoma were randomized to receive nivolumab (n = 316), ipilimumab (n = 315), or nivolumab plus ipilimumab followed by nivolumab (n = 314). In this frontline study, approximately a third of patients were BRAF mutation-positive.
“You would give nivolumab first in the frontline setting followed by ipilimumab in nonresponders,” wrote Dr. Sznol, who sees potential for nivolumab to be used concurrently with ipilimumab. At the 2014 ASCO Annual Meeting he presented early-stage data demonstrating that the combination of nivolumab and ipilimumab nearly doubled median OS compared with either agent alone. “These data suggest that the concurrent administration of ipilimumab and nivolumab may be superior to sequential therapies.
“With recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” wrote Mario Sznol, MD, Yale Cancer Center, in an editorial published in a January edition of The New England Journal of Medicine. IL-12 has been researched long enough to know it will take part in that role. Once Oncosec proves that EP IL-12 can ‘safely’ increase IFN-y production and subsequently increase expression of genes related to antigen processing and presentation TILs, including the expression of PD-L1, Oncosec will have the upper hand in whatever decision they make. Their platform can become a standard of therapy for all combinations. Keeping in mind that Opdivo and Keytruda are both humanized IgG4 antibodies that block PD-1. They will behave the same when combined with IL-12., so if ImmunoPulse is approved for one, it will be for the other as well.
BMS last week announced that a phase ½ combination study was initiated testing Opdivo with Adcetris for patients with CD30-expressing relapsed or refractory B-cell and T-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma, peripheral T-cell lymphoma and cutaneous T-cell lymphoma. Recent preclinical data suggest that Adcetris causes immunogenic cell death of tumor cells, providing rationale for combination with Opdivo, a human antibody that targets and inhibits the programmed death receptor-1 (PD-1), resulting in T-cell activation. Sounds very familiar to what Oncosec is trying to achieve with the use of IL-12, which is known as a T cell-stimulating factor and can stimulate the growth and function of T cells. Basically it stimulates the production of interferon-gamma.
The collaboration was announced on January of 2015 and just now it began enrollment. Notice that it took them 11 months vs 9 months that it took for the UCSF Oncosec collaboration to commence in their Phase 2b.
