Shots:
- Pheast Therapeutics is redefining innate immunity in oncology with PHST001, an anti-CD24 macrophage checkpoint inhibitor engineered to overcome the limitations of earlier macrophage-targeted therapies and unleash a powerful anti-tumor immune response.
- At AACR 2026, PHST001 delivered encouraging early clinical signals with favorable tolerability, clear immune activation, and promising anti-tumor responses across heavily pretreated solid tumor patients, reinforcing the potential of CD24 as a breakthrough macrophage checkpoint target.
- PharmaShots welcomes Roy Maute, Co-Founder and CEO, Pheast Therapeutics, to share insights into the future of macrophage checkpoint inhibition, the strategic advancement of PHST001, and how Pheast is building a next-generation immuno-oncology pipeline powered by innate immunity and innovative ADC combinations.
Saurabh: To begin, could you share the strategic vision behind advancing PHST001 as an anti-CD24 macrophage checkpoint inhibitor, and what differentiates it within the evolving immuno-oncology landscape?
Roy: PHST001 targets CD24, which is a crucial regulator of macrophages. We see a strong opportunity to harness these cells for an anti-cancer effect given their abundance in the tumor microenvironment, but true success requires having the right target and the right drug design. CD24 enables us to redirect macrophages toward anti-tumor activity in a way that’s biologically distinct from existing immunotherapies. Importantly, this approach is complementary to current treatments, and clinicians consistently highlight the need for new options in this space. We believe PHST001 has strong potential to fill that unmet need.
Saurabh: PHST001 targets the CD24–Siglec-10 axis, a relatively novel macrophage checkpoint pathway. How does this mechanism address limitations seen with earlier innate immune therapies?
Roy: Macrophages absorb a lot of information from the tumor microenvironment, but there are several key regulators that control their behavior. Most of the previous work on macrophage checkpoints has focused on broadly expressed regulatory signals, which ultimately were limited by their tox profile in the clinic. In contrast, the CD24–Siglec-10 axis is a safer target, with narrower expression on normal tissues. However, it acts as a dominant “don’t eat me” signal specifically in the environment of many tumors, where cancer cells overexpress CD24 and macrophages upregulate Siglec-10, thereby suppressing immune attack. By blocking this interaction, PHST001 reactivates macrophages in a more tumor-specific way than earlier innate immune approaches. CD24 signaling also has broader immunosuppressive effects, which makes it particularly compelling as a target. Another advantage is that CD24 expression is tremendously high in some tumors but not expressed in others, allowing us to identify where the drug is most likely to be effective and guide development accordingly.
Saurabh: Given CD24’s role as a “don’t eat me” signal, how do you see macrophage-directed therapies reshaping the tumor microenvironment compared to T-cell–focused approaches?
Roy: Most immuno-oncology therapies have focused on activating T-cells to attack cancers. While this has historically been a successful approach, we’ve seen diminishing returns with many next-generation targets. Our approach centers on macrophages and innate immunity, which represent a complementary yet so far largely untapped opportunity. These cells respond to different signals and are often the dominant immune regulators in tumors where T-cell therapies fall short. By activating macrophages already present in the tumor, we can potentially address cancers that haven’t benefited as much from T-cell–focused approaches, expanding the reach of immunotherapy into new indications.
Saurabh: The Phase 1a data presented at AACR 2026 demonstrated favorable tolerability. How do these findings inform the therapeutic window and dosing strategy moving forward?
Roy: A key challenge in macrophage-targeted therapies has been achieving a balance between efficacy and safety to find the right therapeutic window. Earlier approaches prior to Pheast’s work often triggered toxicities like anemia and thrombocytopenia due to the broad expression of those first-generation targets, and the sensitivity cells in the peripheral blood to macrophage attack. With PHST001, we’re seeing a more favorable profile, with transient neutropenia as the primary safety signal—something oncologists are quite familiar with and have the proper tools to manage. This limited tox suggests a wider therapeutic window, likely due to more selective CD24 expression, and opens up many opportunities for combination therapy. These findings give us confidence as we continue dose escalation and support the idea that we can achieve meaningful biological activity without the safety limitations seen in prior therapies.
Saurabh: Could you elaborate on the significance of observed CD24 receptor occupancy and its correlation with pharmacodynamic markers of innate immune activation?
Roy: In early clinical development, our focus is on confirming safety, achieving appropriate drug exposure, and demonstrating biological activity—and we’re seeing all three with PHST001. The drug shows a clean, dose-linear PK profile, meaning exposure increases predictably with dosing. We also see clear CD24 receptor engagement on peripheral cells, which helps guide dose selection. We’re also observing robust pharmacodynamic signals of immune activation, as demonstrated by major increases in peripheral cytokines associated with macrophage activation, across multiple monotherapy dose levels. Together, these data indicate we’re operating in an active dose range and moving toward identifying the optimal balance of safety and efficacy.
Saurabh: Early signals of clinical activity were reported! What key efficacy trends are you most encouraged by at this stage, particularly in heavily pretreated solid tumor populations?
Roy: We’re very encouraged by early signs of anti-tumor efficacy in this monotherapy setting, especially given this is a Phase 1a all-comer study in heavily pretreated cancer patients. Although the tumor biology has given us a sense of where PHST001 will be most relevant, in this initial study we’re testing widely to understand potential drug activity from a broad range of cancers. Many participants coming to these studies have already undergone numerous prior therapies, often with little to no success, so even disease stabilization is meaningful for these patients. We’ve seen several patients with slowed or halted disease progression, and in some cases tumor shrinkage. These responses are observed across multiple tumor types but are particularly notable in ovarian cancer, where we can also confirm shrinkage by biomarkers such as circulating tumor DNA, and CA-125 levels. We consider this monotherapy activity to be very promising, and a clear confirmation that CD24 is an active target, and PHST001 is an active drug. Still, our broader strategy is to advance quickly into combination studies, where we expect to see more significant clinical impact based on early safety and activity signals.
Saurabh: Are there specific tumor types or biomarker-defined populations where you believe PHST001 could demonstrate the greatest clinical impact?
Roy: CD24 expression is one straightforward parameter we have considered for selecting indications for treatment. In this analysis, we see that CD24 is broadly expressed across multiple high unmet-need cancers, often at much higher levels than in normal tissue, which helps guide our initial focus. We’re prioritizing ovarian, cholangiocarcinoma, and endometrial cancers for early combination studies. This is due to multiple factors, including high target expression and clear unmet need in the patient population, always an important factor for us. We also see strong potential in breast, colorectal, and lung cancers in our next wave of development. At this stage, we’re not selecting patients based on a CD24 expression biomarker, as we’re still learning how expression levels correlate with response in each disease. However, we do believe biomarker-driven approaches may become increasingly important in identifying the right population within some of our future indications.
Saurabh: Macrophage-targeted therapies are gaining momentum in oncology. How does PHST001 position itself against other approaches targeting innate immunity, including CD47 and beyond?
Roy: There are significant interest and momentum in macrophage-targeted therapies, because the fundamental biology is so compelling. However, earlier approaches, such as anti-CD47 drugs, have been constrained by safety challenges despite strong biological rationale. We view CD24 as an opportunity to maximize the benefits of macrophage activation, particularly in high unmet-need solid tumor indications, while improving tolerability. It is very rare in drug development that the first attempt at an entirely new modality is successful, and so we’re not deterred by the challenges that previous targets in this space have encountered. Instead, we’re focused on building on that hard-won clinical experience to pursue a target with a more favorable profile. Ultimately, we expect multiple approaches in innate immunity to succeed, but we believe PHST001 is positioned to be among the most clinically impactful options.
Saurabh: Looking ahead, what key milestones should stakeholders watch for as PHST001 progresses through clinical development and combination strategies?
Roy: We’re continuing to advance our Phase 1a dose-escalation study, with more mature monotherapy data expected as we treat patients in our highest dose cohorts, and enrolled patients throughout the dose escalation cohorts continue to remain on treatment. In parallel, we’ve already begun initial Phase 1b combination studies with standard of care chemotherapy in patients with ovarian, cholangiocarcinoma, or endometrial cancers. These studies are enrolling well, reflecting strong enthusiasm from our clinical investigators as well as the clear need for new therapies against these diseases. We will generate early safety and efficacy data from these combinations this year, which will be key to informing our strategy for a randomized controlled trial starting mid next year. We’re also exploring other combination modalities with antibody drug conjugates, or ADCs. These drugs are a natural fit for the PHST001 mechanism of action, show excellent synergy with PHST001 in preclinical models, and are very important in the treatment landscape of our current diseases of focus. Recently, we also disclosed our next pipeline program, a bispecific ADC we call PHST677. This is an exciting multifunctional drug that activates macrophages by blocking a novel target we discovered, completely distinct from CD24, is targeted to the tumor microenvironment, and brings the cytotoxic payload all together in a single drug. Altogether, we expect to present meaningful clinical data from multiple programs over the course of 2026.
Saurabh: As you reflect on the AACR 2026 presentation, what broader implications do these early findings hold for the future of macrophage checkpoint inhibition in cancer therapy?
Roy: AACR marked our first clinical data disclosure for PHST001, and it was an important milestone for our company, the program and the field. The initial data is exactly what we were aiming to demonstrate: acceptable safety, clear immune activation, and early anti-tumor activity. From this starting point, we’re feeling confident in the continued development path for this drug. For us, it validates the CD24 approach and highlights the potential of macrophage-targeted therapies to expand the impact of immuno-oncology. We think this is just the starting point for Pheast as we broaden our pipeline to include multiple targets and modalities.
About Roy Maute:
Dr. Maute is a scientist and biotechnology entrepreneur, and co-founder and CEO of Pheast Therapeutics. Previously, he led the Translational Science and Biomarker team at Forty Seven Inc., continuing as Biomarker lead on the magrolimab and anti-SIRPA programs following Gilead Sciences’ 2020 acquisition. He also co-founded Ab Initio Biotherapeutics, leading research as Head of Biology from founding in 2015 until its 2019 acquisition by Ligand Pharmaceuticals. He trained as a postdoctoral fellow with Dr. Irving Weissman at Stanford, holds a Ph.D. in genetics from Columbia University, and a B.A. in molecular and cell biology from UC Berkeley.
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