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A compelling combination for TNBC
July 2016
by Kelsey Kaustinen  |  Email the author
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TUSTIN, Calif.—Biopharmaceutical company Peregrine Pharmaceuticals Inc. had good news to share at this year’s American Association for Cancer Research annual meeting, as it presented preclinical data supporting the combination of bavituximab and anti-PD-1 therapy in the treatment of breast cancer, specifically triple-negative breast cancer (TNBC).
 
Bavituximab is an investigational chimeric monoclonal antibody that aids the body’s immune system via targeting and modulating the activity of phosphatidylserine (PS), a highly immune-suppressive signaling molecule expressed broadly on the surface of cells in the tumor microenvironment. Signals from PS can inhibit immune cells’ ability to recognize and fight tumors, and bavituximab is thought to override PS-mediated immunosuppressive signaling by blocking the interaction of PS with its receptors and by sending an alternate immune activating signal. PS-targeting antibodies have been found to alter the functions of immune cells in tumors, leading to multiple signs of immune activation and antitumor immune responses. For the purposes of this study, Peregrine used ch1N11, the preclinical equivalent of bavituximab used in animal model studies as a guide for clinical development.
 
The research team compared ch1N11 and anti-PD-1 therapy vs. anti-PD-1 therapy alone in mouse models of TNBC, and found that the combination approach significantly improved overall survival and mediated complete tumor regression in more subjects than the anti-PD-1 therapy alone (60 percent vs. 20 percent). The animals in the combination treatment arm saw significant increases in tumor-associated indicators of immune system activation, including CD45+, CD8+ and CD3+ T cells, in addition to a lasting antitumor immune response—one that protected the animals that achieved complete tumor regression against a re- challenge with the same E0771 TNBC model tumor cells.
 
In addition, an examination of this combination—using the nCounter PanCancer Immune Profiling Panel from NanoString Technologies—backs up the effectiveness of this two-pronged approach, demonstrating that this combination caused a shift in the tumor microenvironment from immunosuppressive to immune active, as shown by a change in immune cell phenotypes, an increase in immune-activating cytokines and a decrease in immunosuppressive cytokines.
 
These results, according to Dr. Jeff T. Hutchins, vice president of preclinical research for Peregrine, were better than expected.
 
“When we look at [bavituximab] alone, there’s really just a modest decrease or slowing of tumor progression. And you can certainly get dramatic results with an anti-PD-1, but the problem is that you don’t get all the animals responding with anti-PD-1,” he explains. “What impressed us was that when you put a PS-targeting and an anti-PD-1 antibody together, you get really a complete retarding or lack of tumor progression once you have early established tumors, but what’s impressive is that all of the animals seem to be responding, rather than a fraction that respond to anti-PD-1. And then really the biggest piece that impressed us was that with anti-PD-1, you can get about 40 percent—maybe a little higher, 45 percent—of the animals to completely regress, with no further tumor growth at all or no rebound of tumor growth in a survival-type measurement. In the case with the combination, however, we’ve brought that up to about 85 percent.”
 
Peregrine has also looked at this combination approach in other types of cancer, says Hutchins, who notes that they started working with it in preclinical models of melanoma, the results of which were presented at the annual meeting of the Society for Immunotherapy of Cancer last year. These latest results in TNBC were much more dramatic, he explains, because “it's tough in B16F10 melanoma to get long-term survivors, it's really a lower percentage. But again the theme was pretty much the same, it's this combination that seems to bring tumor growth reduction down consistently in all of the animals, rather than a fraction or a subgroup of animals.”
 
Hutchins tells DDNews that they’re particularly excited because they expect a combination of bavituximab with durvalumab, nivolumab or pembrolizumab to have “a much lower toxicity profile than other checkpoint inhibitor combinations.” None of the animal models in the study saw any adverse effects or weight loss as a result of treatment.
 
“In all of our clinical studies with combinations to date, we don’t see any toxicities over the other standard of care, particularly any immune-related toxicities with bavituximab,” he adds. “So that’s why we think it’s also an ideal combination molecule going forward in the [immuno-oncology] space.”
 
Moving forward, Hutchins says the next step is definitely progressing to clinical work. In preclinical work, he says Peregrine wants to look at other immune checkpoint inhibitors as well, such as Tim-3, and potentially even a triple combination of anti-Lag-3, anti-PD-1 and anti-PS, especially in breast cancer.
 
Code: E071613

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