Does Targeting Macrophages Hold The Key For Treating Cancer?
A conversation with Roy Maute, Ph.D., cofounder and CEO, Pheast Therapeutics
What is the role of macrophages, macrophage checkpoint inhibitors, and targeting immune receptor CD24 in treating cancer? What’s needed for clinical success in this space? We caught up with Roy Maute, Ph.D., cofounder and CEO of Pheast Therapeutics, to discuss his insights and experiences.
1. What is the potential role of targeting macrophages in treating cancer? How might new macrophage checkpoint inhibitors have better success than other drug modalities?
MAUTE: The vanguard of the innate immune system, macrophages detect and “eat” pathogens or diseased cells through a process known as phagocytosis. Cancer cells can be the target of phagocytosis, but some tumors are able to avoid macrophage attack by expressing “don’t eat me” signals, which block the anti-cancer effects of macrophages. To counter this response, Pheast Therapeutics is developing macrophage checkpoint inhibitors that block “don’t eat me” signals, analogous to the T-cell checkpoint inhibitors (e.g., anti-PD-L1) that have become a major success story in cancer therapy.
Although the science behind macrophage checkpoint inhibitors is promising, the field has not yet seen major clinical success with this class of drug. Macrophage checkpoint inhibitors will be most effective in patients where the “don’t eat me” signal is highly expressed. In the case of CD24, this list includes most patients with high unmet need cancers such as ovarian cancer, triple negative breast cancer, and cholangiocarcinoma, as well as subsets of patients with other cancers such as pancreatic and colorectal. Immunotherapies have not yet lived up to their early promise in these indications, and so patients and clinicians have struggled with few new therapeutic approaches.
2. Why target CD24?
MAUTE: Pheast’s lead program PHST001 is a monoclonal antibody targeting CD24, an immune receptor that was discovered by several of the Pheast cofounders to be a potent “don’t eat me” signal in cancer.
Pheast has focused on CD24 because of the wealth of biological evidence, including human and cancer genetics, that highlights its important role in immune suppression in the tumor microenvironment. It is highly expressed in multiple cancer indications where other macrophage inhibitors have yet to demonstrate a clinical impact. In some cancer types, CD24 is also a strong indicator of prognosis, as patients with tumors that highly express CD24 have significantly lower survival rates than those with tumors expressing little CD24.
As described by two of Pheast’s cofounders in a paper published in Nature in 2019, CD24 on cancer cells interacts with the Siglec10 receptor, which is expressed on immunosuppressive macrophages. By blocking this interaction with PHST001, we can induce phagocytosis by the subtype of immunosuppressive macrophages that are most common in the tumor microenvironment. This activity contributes to potent, durable activity in preclinical models, which in side-by-side comparison is significantly better than the efficacy achieved by other macrophage checkpoint approaches.
One of the historical challenges of targeting CD24 is the structure of the protein itself. CD24 is a small unstructured peptide and is heavily glycosylated (modified with sugars). The patterns of these modifications can be quite complex and variable. This makes it very difficult to develop antibodies that can effectively bind to all relevant forms of CD24.
We engineered PHST001, however, to interact as broadly as possible with all the glycosylation variants of CD24, giving it very potent activity to block the suppressive activity of CD24. When macrophages are exposed to cancer cells expressing CD24 that is bound by PHST001, they start eating cancer cells, and this phagocytosis shrinks or de-bulks the tumor. This may then make the tumor more accessible to other immune cells, further improving the anti-cancer response of treatment.
3. What is the biggest hurdle in getting a macrophage checkpoint inhibitor from the lab to IND approval, and what is Pheast Therapeutics doing with its candidate to tackle that hurdle?
MAUTE: Clinical success for CD24, or any cancer target, will come by finding the right balance between safety and efficacy. On both fronts, CD24 presents advantages over some previously tested macrophage checkpoint targets. In particular, CD24 is not expressed on some sensitive hematopoietic cell types, such as red blood cells and platelets, which have posed safety challenges for other macrophage checkpoint targets. The key for clinical success in this scenario is to be less toxic than other clinical-stage anti-CD24 drugs.
With promising preclinical data and an eye to moving our testing into the clinic in the first half of 2025, we are actively working toward filing an IND application for PHST001. Given its novelty as a therapeutic target, there is little previous clinical data for CD24, so it will be important to make sure PHST001 is not only effective but also safe. Thus, our initial focus moving forward will be on understandingPHST001’s safety profile as a monotherapy. From there, we will be ready to rapidly move into testing therapeutic combination strategies in CD24-expressing cancers with high unmet needs (e.g., breast and ovarian). As we move into the clinic, we are also pursuing a broad preclinical effort to help define indications and patient subsets most likely to respond to PHST001, as well as biomarker approaches that can facilitate identifying these patients in the clinic.
4. Can you tell us about your proprietary discovery platform and how you use it for drug lead generation?
MAUTE: CD24 is just one of a multitude of “don’t eat me” signals, and our experiments make it clear that some cancers are protected by multiple barriers to macrophage activation. We are expanding the same genetic technologies and molecular methods that were used to identify CD24 to now identify other novel checkpoint targets. We’ve identified quite a few novel macrophage regulators that we think will form the basis of our future pipeline. In selecting our next development programs, our priority is to build upon our knowledge of macrophage biology to access additional indications and patient populations beyond those that are the focus of our lead program, PHST001. This will include oncology, as well as approaches tailored toward immunology and inflammation indications.
About The Expert:
Roy Maute, Ph.D., is a scientist and biotechnology entrepreneur and is a cofounder of Pheast Therapeutics. He serves as the company’s CEO and leads Pheast’s research and development teams. Prior to Pheast, he led the biomarker and translational science for the clinical anti-CD47 and anti-SIRPA programs at Forty Seven Inc. and Gilead Sciences. Maute also cofounded Ab Initio Biotherapeutics, an antibody discovery company acquired by Ligand Pharmaceuticals in 2019. He trained as a postdoctoral fellow in the laboratory of Irving Weissman, M.D., at Stanford University School of Medicine and received his Ph.D. in genetics from Columbia University and a B.A. in molecular and cell biology from UC Berkeley.