Abstract
The anti-CD47 drug Hu5F9-G4, also known as 5F9, in combination with the anti-CD20 therapy rituximab, may be a promising treatment for some forms of non-Hodgkin lymphoma because it allows macrophages to recognize and attack cancer cells. In a phase Ib trial testing the combination, patients with relapsed/refractory diffuse large B-cell lymphoma or follicular lymphoma had an objective response rate of 50% and few side effects.
Patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma, two forms of non-Hodgkin lymphoma (NHL), who become resistant to or relapse after standard chemotherapy and antibody-based regimens have a poor prognosis.
Seeking a more effective treatment for NHLs, researchers developed a macrophage-activating monoclonal antibody dubbed Hu5F9-G4 (hereafter 5F9; Forty Seven). In a recently reported phase Ib trial, the drug induced a high rate of durable responses in patients with DLBCL and follicular lymphoma (N Engl J Med 2018;379:1711–21).
Forty Seven cofounders Ravi Majeti, MD, PhD, and Irv Weissman, MD, of Stanford University in California, and their colleagues previously established that some cancer cells express high levels of CD47, an antiphagocytic signal that allows them to evade macrophages (Cell 2009;138:286–99). “It drew our attention because CD47 is essentially a checkpoint inhibitor for the innate immune system, for macrophages,” Majeti says.
The researchers developed 5F9 to block CD47 and its ligand, SIRPα—and thus provoke macrophages to recognize and attack cancer cells. In preclinical studies, they showed that the drug is active in various forms of lymphoma (Cell 2010;142:699–713). Moreover, they demonstrated that the drug augmented the activity of rituximab (Rituxan; Genentech), an anti-CD20 therapy commonly used to treat B-cell lymphomas.
For the clinical trial—the first to test 5F9 in combination with rituximab—researchers enrolled 22 patients: 15 with DLBCL and seven with follicular lymphoma. Patients had received a median of four prior therapies, and 95% had disease that was resistant to rituximab.
Overall, 11 patients responded to the drug, with eight complete responses—five in DLBCL and three in follicular lymphoma. Additionally, at a median follow-up of 6.2 months in the DLBCL group and 8.1 months in follicular lymphoma group, 91% of patients continued to respond. The most common side effects were chills, headache, and anemia, and most were grade 1 or 2.
Hu5F9-G4 blocks CD47 and its ligand, SIRPα, thus provoking macrophages to recognize and attack cancer cells.
“It's really encouraging to have a novel target that shows efficacy and is extremely well tolerated,” says senior author Ranjana Advani, MD, also of Stanford. She acknowledges that the results need to be validated in a larger patient cohort, and a phase II trial of the drug duo is under way. Other trials are testing 5F9 alone and in combination with other therapies for various types of hematologic malignancies and solid tumors.
“It looks like a promising combination that warrants more study,” says Brad Kahl, MD, of Washington University School of Medicine in St. Louis, MO, who was not involved in the study. “It's very nice to see a clinical experience that validates what was seen in the laboratory.” He notes that because the combination has mild, manageable side effects, it may prove particularly beneficial in older patients with aggressive, relapsed lymphomas who cannot tolerate other treatments.
Stephen Ansell, MD, PhD, of Mayo Clinic in Rochester, MN, who was also not connected to the research, is impressed that the combination elicited responses in patients who were refractory to rituximab alone. He says that this may be because CD47 inhibition amplifies rituximab's ability to attract macrophages to cancer cells.
The study not only demonstrates the potential of 5F9 as a treatment for NHL, Ansell adds, but also may signal a broader shift in the field. “We've predominantly focused on T cells as the way in which the immune system is getting after the tumor. This now allows us to take cells like macrophages and get them to be part of the antitumor response as well,” he says. “I would hope that this will become something that's beneficial across many diseases and many malignancies.” –Catherine Caruso
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