Macrophage checkpoint blockade shows promise in refractory lymphoma

A new approach of macrophage checkpoint blockade produces responses in half of patients with relapsed or refractory aggressive lymphoma, early research shows.

The combination of a novel anti-cancer antibody known as 5F9 (Hu5F9-G4) with rituximab, induced a positive response in 11 out of 22 people with relapsed/refractory non-Hodgkin’s lymphoma, according to results of a Phase 1b study published in the NEJM.

About 36% of the patients (8 out of 22) in the trial went into complete remission from their cancers, noted the study investigators from the University of Chicago.

They say the findings are promising given that the prognosis is poor for lymphomas that become refractory to standard antibody- or chemotherapy-based therapies including rituximab.

The results also point to a new pathway of immunotherapy based on macrophages, rather than T cells, they add.

The novel agent is a macrophage immune checkpoint inhibitor blocking CD47, which induces tumour-cell phagocytosis.

“5F9 synergises with rituximab to eliminate B-cell non-Hodgkin’s lymphoma cells by enhancing macrophage-mediated antibody-dependent cellular phagocytosis,” they write.

“This is one of the first successful anti-cancer drugs that can stimulate a macrophage to attack a cancer cell. It opens a whole new door,” says senior  Professor Sonali Smith, Director of the Lymphoma Program at the University of Chicago Medicine.

The cell surface marker CD47, displayed by many cancer cells, is a “don’t ‘eat me’ signal,” she explains.

“Macrophages don’t normally attack those cells. But there is a second “eat me” signal that is potentiated by the other antibody, rituximab. The combination of 5F9 and rituxamab “can overcome the signals that protect these cancer cells.”

“This is incredibly exciting,” she added. Checkpoint inhibitors “don’t work very well in non-Hodgkin’s lymphomas,” she explained. “Now we may have a way to manipulate the immune system for people with non-Hodgkin’s lymphomas that have relapsed and progressed after multiple prior therapies. And we can do it with limited side effects.”

The study involved 22 patients who had failed to respond to, or relapsed after, at least two and as many as 10 previous types of therapy. Fifteen patients had diffuse large B-cell lymphoma (DLBCL) and seven had follicular lymphoma.

All patients were treated with a combination of 5F9 at slowly increasing dosages and rituximab. Treatment, on average, lasted 22 weeks. Eleven patients showed a clinically significant reduction in their cancers. In eight of those patients, all signs of cancer were eliminated. The other three patients died due to disease progression.

Of the patients in the DLBCL subgroup, 40% achieved objective response and 33% reached a complete response. For the patients in the follicular lymphoma subgroup 71% had an objective response and 43% achieved complete response.

Most of the adverse events  – particularly anaemia were low grade and patients did not show the immune-related adverse side effects typically seen in T-cell checkpoint inhibitors.

However patients who had a prior CAR-T cell therapy did not respond to the treatment.

“There may be something about CAR-T that exhausts the T cells,” Professor Smith said. “This is not a T cell-mediated approach, but there appears to be some effects on the immune system that may make it less likely to work in this setting.” The researchers have agreed to exclude people who have a disease recurrence after CAR-T cell therapy.

An accompanying commentary in the NEJM notes that the trial results “build on solid preclinical evidence suggesting that antibody-dependent cellular phagocytosis unleashed by blocking the CD47–SIRPα checkpoint, can mediate antitumour activity and synergize with anti-CD20 in killing lymphoma cells.”

If confirmed and extended the results could “pave the way to macrophage checkpoint blockade as a new immunotherapy strategy,” it says.

However the authors say that challenges remain such as the prospective identification of patients who are more likely to have a response, since anaemia does not seem to be a promising biomarker.

“Tumour-associated macrophage infiltration has been reported to have adverse prognostic significance in a variety of cancer types. Therefore, the interplay of chemotherapeutic regimens with macrophage function will have to be considered in the design of integrated approaches.

“Moreover, it will be important to assess whether the degree of macrophage infiltration serves as a predictor of response to macrophage checkpoint blockade.

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