Researchers Report Early Clinical Promise for Macrophage Checkpoint Blockade

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If 5F9 shows survival benefits and low toxicities in randomized phase 3 trials, it might usher in an era of macrophage checkpoint inhibition in hematological malignancies.
If 5F9 shows survival benefits and low toxicities in randomized phase 3 trials, it might usher in an era of macrophage checkpoint inhibition in hematological malignancies.

Immune checkpoint inhibition therapy strips cancer cells of their ability to exploit molecular safeguards that evolved to prevent autoimmunity. The first such immunotherapies targeted programmed cell death protein 1 and programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to unleash immune T-cell attack on cancer cells.

But cancers exploit numerous other molecular checkpoint systems, as well — possibly helping to explain, in part, high rates of innate and acquired resistance to existing anti-PD-1/PD-L1 and CTLA-4 immunotherapies. One example of another mechanism of immune evasion is the “don't eat me” checkpoint protein CD47 that is overexpressed on some hematologic cancer cells, allowing these malignancies to evade detection and phagocytic attack by a patient's immune system.1

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Now, researchers are clinically testing combination immune macrophage checkpoint blockade regimens, targeting tumor cell CD20 protein with rituximab and CD47 with the investigational antibody Hu5F9-G4 (“5F9”) immunotherapy (ClinicalTrials.gov Identifier: NCT02953509). That combination appears to safely offer therapeutic synergy, inducing macrophage phagocytosis of B-cell cancer cells in human patients, they reported in the New England Journal of Medicine.2 5F9 is a macrophage immune checkpoint-inhibiting antibody that targets CD47 to trigger phagocytosis of tumor cells.

“In this phase 1b study, combination therapy with 5F9 plus rituximab was associated with mainly low-grade toxic effects and produced responses in half the patients with relapsed or refractory aggressive and indolent lymphomas,” reported Ranjana Advani, MD, Stanford University, California, and colleagues. “A total of 50% of the patients had an objective (complete or partial) response, with 36% having a complete response.”2

Of 22 patients enrolled in the study, 15 had diffuse large B-cell lymphoma (DLBCL) and 7 had follicular lymphoma (FL). They had been heavily pretreated, with a median of 2 to 10 previous treatments and almost all (95%) had rituximab-refractory disease.2

Patients with DLBCL saw a 33% complete response (CR) rate, compared with 43% among patients FL. Most (91%) of all responses were ongoing at the time of analysis, at a median follow-up of 6.2 months among DLBCL patients and 8.1 months among FL patients.2  

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