The potential of CD24 in cancer immunotherapy

Pheast Therapeutics is developing macrophage-focused immunotherapies to treat cancer. The company’s lead programme is targeting CD24, an immune inhibitory signal that is hijacked by cancer to suppress immune attack. Pheast’s drug candidate, PHST001, blocks CD24, thereby allowing immune cells, including macrophages, to attack the cancer.

What is the significance of the interaction between CD24 and Siglec-10 in the context of cancer immunotherapy?

CD24 is an immunosuppressive ligand which is very highly expressed by a subset of cancers. In these cancers, CD24 is bound by the Siglec-10 receptor expressed on immune cells, including macrophages. This interaction inhibits inflammation and immune activation, and in particular prevents macrophages from phagocytosing and destroying cancer cells. By blocking CD24 with an antibody drug, our goal is to powerfully reactivate the anti-cancer immune response and drive therapeutic efficacy.

How does CD24 contribute to immune evasion in ovarian cancer and triple-negative breast cancer?

Ovarian cancer and triple negative breast cancer are both enriched for immunosuppressive macrophages in the tumour microenvironment, and a majority of patients in both indications express high levels of CD24. In preclinical models, we see that therapeutic blockade of CD24 leads to a potent anti-tumour immune activation. This immune response is led by macrophages, but multiple lines of evidence suggest that multiple parts of the immune system can also play an important role.

Can you explain the mechanism by which CD24 interacts with Siglec-10 and its downstream effects on immune responses?

Siglec-10 binds CD24 in a manner that is dependent on CD24 glycosylation, and in particular on its O-linked terminal sialylation. Once bound, Siglec-10 signals through intracellular inhibitory ITIM domains, which is a downstream pathway shared with other well-studied immune receptors, such as PD-1 and SIRPA. The exact consequences of this signalling are slightly different depending on the immune cell receiving the signals, but in macrophages, ITIM signalling blocks phagocytosis and reduces secretion of immune-activating signals such as cytokines.

What evidence supports the idea that CD24 is a potential target for cancer immunotherapy?

CD24 is highly expressed by a subset of cancers, in some cases many times greater than their normal tissue of origin. In some patients, this overexpression is driven by genetic amplification, a classical oncogene hallmark. In many CD24‑expressing cancers, patients with high CD24 have significantly worse survival rates than those with low CD24. This is consistent with the known function of CD24 in suppressing tumour‑infiltrating immune cells, including macrophages. When we block this signal, we induce potent immune activation and phagocytosis in vitro and significant anti-cancer efficacy in preclinical in vivo models.

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Are there other ‘don’t eat me’ signals that are known to play a role in cancer immune evasion?

Aside from CD24, there are several other ‘don’t eat me’ signals that have been characterised, and there are multiple programmes currently in clinical development that target these signals. At Pheast, we have built upon the biology of these known targets to develop a discovery platform focused on identifying new regulators of macrophages. We are building a pipeline of first-in-class and best-in-class drugs against these targets.

What is the significance of tailoring macrophage checkpoint inhibitors to the specific signals present in each tumour?

Macrophages simultaneously sense many signals in their environment. It is the balance of ‘eat me’ and ‘don’t eat me’ signals that determines whether a macrophage will phagocytose or ‘eat’ a cancer cell. Long term, we hope to build a tool box of drugs, including drugs against CD24, that can allow us to block all relevant ‘don’t eat me’ signals in an individual patient’s tumour in order to maximise efficacy. On the other side of the equation, we are also working to increase our understanding of which drugs can most potently provide ‘eat me’ signals in patients.

What is the impact of CD24 expression on patient outcomes in ovarian cancer and breast cancer?

In many CD24-expressing cancers, including breast and ovarian, patients with high CD24 expression have significantly worse outcomes than those with low CD24. Based on our knowledge of CD24 biology, this may be due to suppression of tumour‑infiltrating immune cells, which contributes to disease progression and blunts the efficacy of many anti-cancer drugs.

How does CD24 blockade compare to CD47 blockade in terms of enhancing phagocytosis of cancer cells?

We observe that in some cases, a single ‘don’t eat me’ signal dominates- – for example, some triple negative breast cancer models express very high levels of CD24, and blocking CD24 alone is sufficient to induce very strong phagocytosis, regardless of whether other ‘don’t eat me’ signals like CD47 are blocked. Anti‑CD47 has little effect on these types of models. In other models, maximum efficacy requires blocking multiple ‘don’t eat me’ signals at once – for example, simultaneous blockade of both CD24 and CD47.

How have the scientific discoveries related to these blockades influenced Pheast’s approach to developing cancer immunotherapies, and what potential impact do they foresee in treating difficult‑to‑treat and aggressive malignancies like ovarian and breast cancer?

A key focus for Pheast is to better understand factors that enhance or limit the efficacy of targeting macrophage checkpoints like CD24. That includes a better understanding of effective combination therapies, design of the drugs targeting these factors, dosing and indication or patient selection that can help us achieve success with our CD24 programme and additional macrophage checkpoint inhibitors in our development pipeline.