Macrophage engulfing cancer cell, CD47-SIRPa interaction blocked.

Myeloid Checkpoint: The Future of Cancer Treatment?

Nico Varela in Health & Wellness September 2025 • 4 min read.

"A new study reveals how blocking the CD47-SIRPa interaction can boost the effectiveness of existing cancer therapies and pave the way for innovative treatments."

The field of immuno-oncology is rapidly evolving, with researchers constantly seeking new ways to harness the power of the immune system to fight cancer. Immune-checkpoint inhibitors, which activate adaptive immunity, have become a cornerstone of cancer therapy. Now, scientists are exploring the potential of targeting innate immune checkpoints to further enhance the immune response against malignancies.

One particularly promising avenue is the CD47-SIRPa innate immune checkpoint. This checkpoint is formed by the interaction between CD47, a protein found on the surface of tumor cells, and SIRPa, an inhibitory receptor expressed on myeloid cells such as macrophages and granulocytes. CD47 acts as a "don't eat me" signal, preventing these immune cells from attacking and destroying cancer cells.

A recent study by Advani et al. marks a significant milestone in this field, providing the first-in-human data on the effects of an agent targeting the CD47-SIRPa interaction. This article delves into the findings of this study and explores the potential of myeloid immune-checkpoint inhibition as a novel approach to cancer therapy.

Unlocking the Potential of CD47-SIRPa Inhibition

Macrophage engulfing cancer cell, CD47-SIRPa interaction blocked.

The study by Advani et al. investigated the safety and efficacy of an anti-CD47 antibody, Hu5F9-G4, in combination with rituximab, an anti-CD20 antibody, in patients with non-Hodgkin lymphoma (NHL). The results were encouraging, demonstrating clinical responses with manageable toxicity levels. This combination therapy showed particular promise in patients with relapsed or refractory CD20-positive B cell NHL who had previously undergone multiple lines of therapy.

The clinical trial enrolled 22 patients with relapsed and/or refractory NHL. The results showed:

A 36% complete response rate and a 14% partial response rate.
Objective responses in both diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) subtypes.
Responses observed in patients with various DLBCL subtypes, including those with aggressive double-hit lymphomas.
A 91% ongoing response rate among responders at the data cut-off point.

Importantly, the treatment was generally well-tolerated, with mostly mild adverse events such as chills, headache, and mild anemia. While some patients experienced more serious adverse events, the overall safety profile was considered favorable, especially when compared to other cancer therapies like T cell-recruiting therapies or immune-checkpoint inhibitors targeting CTLA-4, PD-1, or PD-L1.

The Future of Cancer Therapy: A New Frontier

The success of the Hu5F9-G4 and rituximab combination raises important questions about the mechanism of action and potential for further improvement. While Hu5F9-G4 is known to inhibit the CD47-SIRPa interaction, its human IgG4 backbone could also contribute to its effects. Future research will need to explore the specific roles of different antibody isotypes and Fc regions in promoting anti-tumor activity.

Another key question is whether targeting SIRPa directly with anti-SIRPa antibodies could offer advantages over anti-CD47 antibodies. SIRPa has a more restricted expression pattern, potentially leading to fewer off-target effects. Furthermore, anti-CD47 antibodies may disrupt the recognition of other CD47 ligands, contributing to toxicity.

Despite these remaining questions, the study by Advani et al. represents a major step forward in the field of immuno-oncology. It demonstrates that targeting the CD47-SIRPa innate immune checkpoint is a safe and effective strategy for treating lymphoma, opening the door for further research and the development of novel cancer therapies.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1038/s41571-018-0155-3, Alternate LINK

Title: Myeloid Immune-Checkpoint Inhibition Enters The Clinical Stage

Subject: Oncology

Journal: Nature Reviews Clinical Oncology

Publisher: Springer Science and Business Media LLC

Authors: Timo K. Van Den Berg, Thomas Valerius

Published: 2018-12-20

Everything You Need To Know

What exactly is the CD47-SIRPa interaction and why is it important in the context of cancer?

The CD47-SIRPa interaction is a critical innate immune checkpoint that cancer cells exploit to evade immune detection. CD47, a protein on the surface of tumor cells, sends a "don't eat me" signal that binds to SIRPa, an inhibitory receptor on myeloid cells, such as macrophages and granulocytes. This interaction prevents these immune cells from recognizing and destroying the cancer cells. Blocking this interaction, as demonstrated by the use of anti-CD47 antibodies, removes this protective mechanism, allowing the immune system to attack the cancer more effectively.

Why is the combination of anti-CD47 antibodies and rituximab so significant?

The study's combination therapy of Hu5F9-G4, an anti-CD47 antibody, with rituximab, an anti-CD20 antibody, is significant because it demonstrates the potential of targeting the CD47-SIRPa interaction in cancer treatment. The results of the study indicated promising outcomes in lymphoma patients. It also supports the idea of incorporating myeloid immune checkpoints in cancer treatment. This approach, particularly the combination of Hu5F9-G4 with rituximab, showed encouraging results with acceptable safety, which is a big step for immuno-oncology.

What are myeloid immune checkpoints, and what role do they play in cancer treatment?

Myeloid immune checkpoints are crucial in the innate immune response, which is the body's first line of defense against cancer. Unlike adaptive immunity, which relies on T cells and B cells, innate immunity uses cells like macrophages and granulocytes. The CD47-SIRPa interaction is a significant example of this, as it influences how myeloid cells recognize and eliminate cancer cells. Targeting these checkpoints can improve the effectiveness of existing cancer therapies.

What were the main outcomes and implications of the Advani et al. study?

The study by Advani et al. showed that the combination of Hu5F9-G4 and rituximab had positive effects. The study revealed a 36% complete response rate and a 14% partial response rate in non-Hodgkin lymphoma patients. Responses were observed in various subtypes of lymphoma, including diffuse large B cell lymphoma and follicular lymphoma. The treatment was generally well-tolerated, with mild adverse events, which is a good outcome when compared to other cancer therapies.

What does this research suggest about the future of cancer therapy?

The future of cancer treatment may include more targeted therapies. The success of Hu5F9-G4 and rituximab raises questions about the role of antibody isotypes and Fc regions in promoting anti-tumor activity. Further research is needed to fully understand the CD47-SIRPa interaction and explore other myeloid immune checkpoints. This knowledge will help improve cancer treatment by improving existing therapies and developing new ones based on harnessing the immune system's ability to fight cancer.