Attacking Cancer Through Activating “Big Eaters” of the Immune System

Macrophages are innate immune cells involved in the detection, phagocytosis and destruction of bacteria and other harmful organisms, including cancer cells. However, cancer cells can evade clearance by macrophages through the overexpression of anti-phagocytic surface proteins (e.g., CD24) called “don’t eat me" signals.

Drugs against these signals, known as macrophage checkpoint inhibitors, antagonize the interaction of “don’t eat me” signals with macrophage-expressed receptors and have demonstrated therapeutic potential in several cancers, becoming a major part of current cancer therapy.

Technology Networks spoke with co-founder and CEO of Pheast Therapeutics, Dr. Roy Maute, to find out more about macrophage checkpoint therapies and the potential they hold for cancer treatment.

Isabel Ely (IE): What are macrophage checkpoint therapies? How do they work and why are they an important approach to “defy” cancer?

Roy Maute (RM): Macrophages are the first responders of the innate immune system. They infiltrate most solid tumors and can detect cancer cells and “eat” them through the process of phagocytosis. However, cancer cells protect themselves from macrophages by expressing “don’t eat me” signals to avoid phagocytosis. Drugs against these “don’t eat me” signals are known as macrophage checkpoint inhibitors and are analogous to T-cell checkpoint inhibitors (e.g., PD-1 or PD-L1 inhibitors) that are a major part of current cancer therapy.

At Pheast Therapeutics, we are developing macrophage-focused immunotherapies and are building upon the discovery that certain cancers overexpress a distinct “don’t eat me” signal called CD24.  Two of our co-founders described this research in a 2019 publication in Nature. We have developed an antibody drug that binds and blocks the CD24 “don’t eat me" signal – allowing macrophages to destroy the cancer cells.

IE: You call CD24 a “don’t eat me” signal. Can you explain what this means regarding the body’s immune response to cancerous cells?

RM: As mentioned earlier, certain cancers overexpress CD24 to evade destruction by macrophages. CD24 interacts with the macrophage receptor Siglec-10, which causes it to send an inhibitory signal that suppresses phagocytosis by macrophages. Siglec-10 is expressed specifically by immunosuppressive, tumor-associated macrophages, and when these macrophages encounter a CD24-expressing cell, they are unable to phagocytose it.

Our lead program is PHST001, a novel antibody that binds CD24 on cancer cells with high affinity and specificity. PHST001 blocks the interaction between CD24 and Siglec-10. Due to the complex glycosylation patterns on CD24, not all antibodies against this target are created equal. We have engineered PHST001 to interact with all glyco-variants of CD24, which enables potent activity against a broad variety of CD24-expressing cancer cells. Once macrophages are activated by PHST001, they can directly de-bulk tumors by phagocytosing cancer cells, and this may also reshape signaling in the tumor microenvironment to improve an anti-cancer response by other immune cells.

IE: How is Pheast’s anti-CD24 antibody drug (PHST001) helping advance the development of cancer therapies?

RM: Although there is a lot of good science around macrophage checkpoint inhibitors, the clinical impact of this class of drugs has not yet been realized. We’re hopeful that PHST001 can be part of the first wave of successful macrophage checkpoint therapies and are excited about the data we’re seeing so far.

In May we unveiled our first preclinical data for PHST001 that demonstrated blockade of CD24 by PHST001 induced macrophage phagocytosis of multiple cancer subtypes in vitro and showed potent efficacy for PHST001 in vivo. In some preclinical models, PHST001 monotherapy was sufficient to shrink and fully eradicate tumors in all treated mice.

Our team is now making rapid progress in supporting the filing of an Investigational New Drug (IND) application with the goal of entering the clinic in the first half of next year.

IE: Can Pheast’s advancements be utilized as therapies across a wide range of cancers or for a specific few?

RM: One of the things that excite us most for PHST001 is that its target, CD24, is highly expressed in most patients in certain cancers with very high unmet need, including ovarian, triple-negative breast and cholangiocarcinoma, as well as in a subset of patients from many other cancers, including pancreatic and colorectal. These are indications where immunotherapies have not lived up to their early promise. Although no therapy will be universal across all cancers, we think PHST001 can have a major impact and are eager to work with patients and physicians to test it clinically.

Additionally, Pheast’s plans don’t stop at CD24. Macrophages simultaneously sense many signals in their environment, so we are applying our proprietary screening platform to find other “don’t eat me” signals. The same genetic techniques and biological insights that identified CD24 as an important macrophage regulator are now being used in our labs to identify additional novel macrophage checkpoint programs that will form the basis of an expanding pipeline of innate immune targets.

IE: What further research do you have planned? For example, clinical trials?

RM: As we complete the data package to support an IND application, we will be publicly presenting additional findings at an upcoming scientific meeting. Our major focus is preparing for our first clinical trial of PHST001. Given that CD24 is a new therapeutic target with relatively little clinical data, our initial focus is to understand the safety profile of PHST001 as a monotherapy.

Once that is established, we plan to quickly move to test indication-specific combination strategies in CD24-expressing cancers with high unmet needs, including breast and ovarian cancer. Our research team is leveraging preclinical models to help define and support these combination strategies.

IE: What do you see as the most exciting development area for therapeutic drugs for the future, in particular for the treatment of cancers?

RM: To start, I want to acknowledge the huge impact the cancer field has seen from the “first wave” of cancer immunotherapies – most notably, the T-cell checkpoint inhibitors and CAR-T approaches for heme indications.

After that incredible burst of early success, the field has been hard at work on next-generation targets, but many of the recent successes in cancer therapy have come from outside the immunotherapy field.

In my view, the most important thing now and over the next five years is to extend our immunotherapy toolbox to include more cell types in the immune system and to expand our understanding of how these drugs work in combination with other therapeutic modalities, for example with antibody-drug conjugates. This will require the development of drugs against novel targets, including ones that are focused on immune cell types like macrophages where initial efforts have yet to be successful. It will also require patience and the smart deployment of resources to understand how to use these drugs effectively.

I am pleased to say that Pheast is positioned to help lead this effort, through our focus on macrophage-mediated immunotherapy. The fight against cancer is personal to us and we are motivated every day by the life-changing impact that a new wave of immunotherapies could bring to people with cancer.

Dr. Roy Maute, co-founder & CEO of Pheast Therapeutics, was speaking to Isabel Ely, Science Writer for Technology Networks.

About the interviewee:

Dr. Roy Maute is a scientist and biotechnology entrepreneur and is a co-founder of Pheast Therapeutics. He serves as the company’s chief executive officer 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. Roy also co-founded Ab Initio Biotherapeutics, an antibody discovery company acquired by Ligand Pharmaceuticals in 2019. He trained as a postdoctoral fellow in the laboratory of Dr. Irving Weissman at Stanford University School of Medicine and received his PhD in genetics from Columbia University and a BA in molecular and cell biology from UC Berkeley.