Macrophage Checkpoint Blockade: New Immunotherapy Strategy

Alexander M. Castellino, PhD

October 31, 2018

A new immunotherapy approach that targets the macrophage and innate (nonspecific) immunity has shown some success in patients with relapsed or refractory non-Hodgkin's lymphoma (non-HL), thereby paving the way for macrophage checkpoint blockade as a strategy in the treatment of other solid tumors.

The new therapeutic approach used the investigational monoclonal antibody Hu5F9-G4 (5F9), which targets CD47, in combination with rituximab (Rituxan, Genentech/Roche), which targets CD20.

5F9 is an anti-CD47 antibody that inhibits a key macrophage checkpoint and facilitates macrophage destruction of lymphoma cells, the researchers explain. They further elaborate that when the drug is administered with a tumor-targeting antibody, such as rituximab, a synergistic enhancement of "eat me" signals promotes tumor cell killing through phagocytosis. The combination achieved an overall response rate (ORR) of 50% and a complete response (CR) of 36% in patients with relapsed or refractory non-HL who had received a median of four previous treatments.

The study was published October 31 in the New England Journal of Medicine.

"Substantial antitumor activity was observed without the use of chemotherapy in heavily pretreated patients who had rituximab-refractory DLBCL [diffuse large B-cell lymphoma] or follicular lymphoma," say the study authors, led by Ranjana Advani, MD, the Saul Rosenberg Professor of Lymphoma at Stanford University, California.

"The results reported by Advani et al are remarkable not only for their own clinical merit...but also because they have broader implications for cancer immunotherapy," write Alberto Mantovani, MD, the Humanitas Clinical and Research Center and Humanitas University, Milan, Italy, and Dan L. Longo, MD, Brigham and Women's Hospital and the Dana Farber Cancer Institute, Boston, Massachusetts, in an accompanying editorial.

"If confirmed and extended, the results reported by Advani et al pave the way to macrophage checkpoint blockade as a new immunotherapy strategy," Mantovani and Longo conclude.

How Macrophage Checkpoint Blockade Works

CD47 — a marker of poor prognosis — is a "do not eat me" signal that is overexpressed on virtually all cancers, the researchers note. The overexpression of CD47 helps cancer cells evade phagocytosis by macrophages and other phagocytes.

The interaction between CD47 and its ligand, the signal regulatory protein α, which is expressed on macrophages, is associated with evasion of phagocytosis. By blocking this interaction, 5F9 selectively induces phagocytosis of tumor cells.

Current T cell–targeted checkpoint blockade is an adaptive immune response that works on the basis genomic instability. But macrophage checkpoint blockade does not depend on recognition of neoantigens on tumor cells, and the two approaches complement each other and could be used synergistically, the editorialists suggest.

The responses seen in the study cannot be attributed to rituximab alone, because response rates with rituximab monotherapy are marginal, at 10% to 15%, when used as salvage therapy. With 95% of patients in the study having rituximab-refractory disease, Advani and colleagues suggest that rituximab sensitivity is restored when it is used in combination with 5F9 through antibody-dependent cellular phagocytosis. With the combination of rituximab and 5F9, a synergy between the innate and adaptive immune response occurs, they comment.

Study Details

The phase 1b study enrolled 22 patients with non-HL (15 patients with DLBCL and seven patients with follicular lymphoma) and assigned them to three dose cohorts.

Patients received a priming dose of 5F9 of 1 mg/kg given intravenously followed by weekly maintenance doses of 10, 20, or 30 mg/kg. Rituximab was given intravenously at a weekly dose of 375 mg/m2 for two cycles followed by 4 monthly doses. The median duration of treatment was 22 weeks.

The median age of the patients was 59 years; four patients (18%) had undergone autologous stem cell transplant, and 21 patients (95%) had tumors that were refractory to previous rituximab treatment. Patients with DLBCL had diverse molecular phenotypes.

In patients with DLBCL, the combination yielded an ORR of 40% and a CR of 33%. Among patients with follicular lymphoma, corresponding responses were 71% and 43%.

Median time to response was 1.7 months. After a median follow-up of 6.2 months and 8.1 months for patients with DLBCL and follicular lymphoma, respectively, the median duration of response was not reached for either cohort of patients.

Most adverse events were of grade 1 or 2, the researchers report. Chills (41%), headache (41%), anemia (41%), and infusion-related reactions (36%) were the more common adverse events. The investigators report that most adverse events occurred early, and no long-term side effects were seen.

Three dose-limiting toxicities were reported across the three dose cohorts — grade 3 pulmonary embolism, grade 4 neutropenia, and grade 3 thrombocytopenia purpura.

The frequency of the dose-limiting toxicity was 15% — well below the 33% threshold required for a maximum tolerated dose.

With the maximum tolerated dose not reached, the maintenance dose of 5F9 that will be used in phase 2 studies is 30 mg/kg.

Anemia is an expected on-target pharmacodynamic effect of CD47 blockade. To mitigate this effect, 5F9 was first given at a priming dose of 1 mg/kg, which eliminated aging red cells (having prophagocytic signals) and spared younger cells (lacking prophagocytic signals).

Macrophage Checkpoint Blockade: From Lymphomas to Other Solid Tumors

"The safety profile, ease of administration, and brisk responses that were seen with 5F9 plus rituximab therapy set the stage for larger and longer studies that involve the treatment of patients who have rapidly progressive lymphoma and coexisting conditions," Advani and colleagues write.

The editorialists suggest that macrophage checkpoint blockade could make its way into treatment paradigms for other solid tumors. Mantovani and Longo point out that antibody-dependent cytotoxicity plays an important role in trastuzumab's activity in breast cancer. They also indicate that CD47 is highly overexpressed in the cancer–stem cell compartment of pancreatic ductal carcinomas and that CD47 strategies have been successful in murine models of solid tumors.

"Hence, the results of this study involving patients with B-cell lymphomas raise the more general issue of the role of macrophage checkpoint blockade therapy in solid tumors," they write.

Noting that tumor-associated macrophage infiltration has been reported to have adverse prognostic significance across many cancer types, "it will be of significance to assess whether the degree of macrophage infiltration serves as a predictor of response to macrophage checkpoint blockade," Mantovani and Longo write.

The study was supported by Forty Seven Inc and the Leukemia and Lymphoma Society. Dr Advani received grants from Forty Seven Inc during the conduct of the study and has received grants and personal fees from several pharmaceutical companies. Significant financial relationships of coauthors are listed in the original article. Dr Mantovani has received personal fees from several pharmaceutical companies. Dr Longo is deputy editor of the New England Journal of Medicine.

N Engl J Med. Published online October 31, 2018.

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