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Tumor macrophage target fuels $1.7-billion deal

On October 26, Bristol-Myers Squibb (BMS) and Five Prime Therapeutics signed a deal worth up to $1.05 billion over an antibody targeting CSF-1R (colony stimulating factor-1 receptor) in oncology indications. The New York–based pharma paid $350 million up front for an exclusive license to the biotech's FPA008 monoclonal antibody and $340 million in milestones for non-oncology indications. CSF-1R has become a popular target in oncology, with as many as nine agents, including antibodies and small molecules, in clinical development. Much expectation surrounds CSF-1R inhibitors' and their potential to synergize with immune checkpoint inhibitors to overcome the immunosuppressive microenvironment in tumors. Tumor-associated macrophages (TAMs), a distinct macrophage subtype, contribute to that milieu by secreting immunosuppressive cytokines like interleukin-10. TAMs also express high levels of CSF-1R, and tumors express high levels of the ligand, CSF-1. Blocking their interaction or interrupting CSF-1R signaling with drugs could thus further unleash T cells, making immune checkpoint blockade much more effective.Proof of principle for CSF-1R inhibitors has been achieved in pigmented villonodular synovitis (PVNS), a rare tumor of the synovial lining of joints. PVNS is usually caused by a translocation causing CSF-1 overexpression. Basel-based Roche and Plexxikon (fully owned by Japanese pharmaceutical Daiichi Sankyo) have reported a greater than 80% response rate in this population for their respective agents in phase 1 trials, with minimal toxicity. But in common tumors, CSF-1 inhibition has a much more modest outcome. In May at the ASCO annual meeting, Carlos Alberto Gomez-Roca of the University Cancer Institute of Toulouse reported phase 1 results for Basel-based Roche's RG7155 (emactuzumab) monotherapy in solid tumors. Of 80 patients treated, there were no objective responses by standard criteria. But “about half of patients experienced stable disease as best response, which is a tricky result in phase 1 trial patients,” Gomez-Roca said. A phase 1 combination trial with Roche's atezolizumab anti-programmed cell death ligand 1 (PD-L1) is underway. Similarly, whether S. San Francisco–based Five Prime and BMS will prosper from their October deal depends on FPA008's ability to make BMS's Opdivo (nivolumab) even more effective. The phase 1 combination trial began in June and will enroll 270 patients in several hard-to-treat tumors, including lung and pancreatic cancers.

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Garber, K. Tumor macrophage target fuels $1.7-billion deal. Nat Biotechnol 33, 1222 (2015). https://doi.org/10.1038/nbt1215-1222

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