PS promise in cancer

Peregrine preclinical studies support a combo approach being studied in clinical trials

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TUSTIN, Calif.—Aimed at finding the right formula to fight cancer, West Coast biopharmaceutical Peregrine Pharmaceuticals Inc. has presented positive data from multiple new preclinical studies of the company’s phosphatidylserine (PS)-targeting antibodies in a poster to the Society for Immunotherapy of Cancer (SITC) in National Harbor, Md. The data highlight research showing PS-targeting antibodies, similar to bavituximab, synergize with checkpoint inhibitors and radiation to improve antitumor activity in various animal tumor models.
Initial results from Peregrine’s ongoing collaboration with Memorial Sloan Kettering Cancer Center (MSK) researchers were presented by Sadna Budhu at SITC. A team of MSK researchers headed by cancer immunotherapy leaders Taha Merghoub and Dr. Jedd D. Wolchok evaluated the effects of combining PS-targeting, anti-PD-1 and radiation therapies.
“Based on these study results, we believe that the targeting of PS is having meaningful activity within the tumor microenvironment in the B16 melanoma model,” Wolchok stated in a news release. “It appears that this activity creates a more immune-active environment in which other treatments, including radiation, are able to have a greater antitumor impact.”
Jeff T. Hutchins, Peregrine’s vice president of preclinical research, tells DDNews, “Peregrine’s clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments. This approach includes the recently announced grants awarded by the National Comprehensive Cancer Network to support three different clinical trials of bavituximab treatment combinations. These trials will evaluate novel bavituximab combinations in glioblastoma, head-and-neck cancer and hepatocellular carcinoma, including an immunotherapy combination.”
“While these trials are not direct follow-ups to the preclinical work presented at SITC, they do seek to build upon the scientific support that Peregrine is generating for combination cancer treatments featuring its PS-targeting antibodies,” he adds.
According to Hutchins, “A second study, conducted by Peregrine, evaluated the effects of combining PS-targeting, anti-PD-1 and anti-LAG3 therapies in the E0771 triple negative breast cancer model. Initial findings from this study were previously reported and demonstrated that eight of the 10 (80 percent) animals receiving the PS-targeting, anti-PD-1 and anti-LAG3 treatment combination experienced complete tumor regressions, whereas there were no animals in the anti-PD-1 and anti-LAG3 combination treatment arm that had a complete regression.”
The study was designed to include eight separate arms (control and treatment) with 15 subjects in each arm (10 in the main study and five for analysis of the tumor microenvironment), Hutchins explains. As such, this study evaluated a total of 120 mice. The data highlighted in this release compared the 15 mice in the triple combination arm, with the 15 mice in the anti-PD-1/anti-LAG3.
Peregrine’s next step is to “continue to conduct targeted preclinical research aimed at generating additional data to support the potential role of PS-targeting antibodies as part of anti-PD-1/PD-L1 combination cancer treatments,” says Hutchins.
The Peregrine study data showed that PS-targeting antibodies synergize with both anti-PD-1 and radiation therapy to reduce the size of the tumor. Median survival for the triple combination treatment still had not been reached at the end of the 80-day observation period with other arms in the study showing median survival that ranged from 24 to 70 days.
Researchers also evaluated the impact of the PS-targeting and radiation combination treatment on the level and type of immune activity, demonstrating that the combination led to a change in the tumor microenvironment in shifting it from immunosuppressive in which tumors are protected to immune active in which tumors are more susceptible to treatment.
Furthermore, an analysis of local immune responses in the tumors of the treated animals showed that the combination treatment increased the number of tumor-associated macrophages and shifted the macrophage polarization from the immunosuppressive M2 type to the immune active M1 type.
“We believe that these findings suggest the potential benefit of combining these agents to improve the outcomes of patients with cancer,” Taha Merghoub, co-director of the Ludwig Collaborative Laboratory at MSK, remarked. “With this in mind, we think this research may play an important role in designing future clinical trials of PS-targeting agents in melanoma and other cancers.”
Data from the analysis demonstrated that the triple combination induced a greater shift in the tumor microenvironment from immunosuppressive to immune active as compared to all other treatment groups. This was evidenced by greater increases in the activity of several critical immune activating pathways, including presentation and processing of antigens and signaling and activation of T cells for the triple combination as compared to all other treatments.
“It is very encouraging to see the consistent increase in antitumor activity triggered by triple combination treatments that combine PS-targeting agents and anti-PD-1 with other cancer treatments,” Hutchins says.
Upcoming trials will evaluate novel bavituximab combinations in glioblastoma, head-and-neck cancer and hepatocellular carcinoma, including an immunotherapy combination. Additionally, Peregrine continues to advance its preclinical collaboration with MSK with the goal of evaluating combinations of bavituximab with other checkpoint inhibitors and immune-stimulatory agents.

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