With Gideon D. Matthews PhD, Commercial VP, Alpha Tau Medical
Introduction
There are moments in science when a paper lands and you sense, before the data has been widely read, that a new frontier may perhaps be opened in the field of cancer research. The study published this week in Scientific Reports is one of those moments. Quietly titled “Effect of Intratumoral Alpha Radiation on Tumor Growth Delay and Tumor Microenvironment in an Orthotopic Colorectal Liver Metastasis Murine Model,” it is the kind of work that looks methodical on the surface and carries significant implications underneath. The paper, now available in Nature, is the product of a close collaboration between the Cancer Research Program at the McGill University Health Centre in Montreal and Alpha Tau Medical Ltd. in Jerusalem. Here is why it matters. Colorectal cancer kills more than 900,000 people globally every year. Its most dangerous habit is spreading to the liver. When it does, most patients cannot be treated with curative surgery, and the remaining options each carry real limitations. In addition, the presence of metastases in the liver is actually known to make the immune system tolerant to the tumor. This new paper proposes something different: a tiny implantable radioactive source placed directly inside a liver tumor, designed to release highly energetic alpha particles that destroy cancer cells with remarkable precision while leaving the surrounding liver tissue intact. And crucially, doing so while breaking down the liver immune tolerance which defends the tumor from the body immune system. I sat down with three of the paper’s authors, each bringing a distinct perspective.
Oran Zlotnik is a hepatobiliary surgeon in Rabin Medical Center, Israel and was a research fellow in the Cancer Research Program at the Research Institute of the McGill University Health Centre in Montreal, Canada, where he worked within the hepato-pancreato-biliary surgical team led by Professor Peter Metrakos. He is trained as both a physician and a researcher (MD/PhD), and has authored 15 peer-reviewed publications, with a research focus on the immune microenvironment of colorectal liver metastases and how locoregional therapies interact with it. His published work includes studies on immunotherapy strategies for microsatellite stable colorectal cancer (Cancers, 2023) and he co-authored papers regarding debulking hepatectomy survival benefit (Cancers, 2024) and circulating tumor DNA for detecting minimal residual disease after liver resection (Frontiers in Oncology, 2024). He is a first co- author – sharing equal first authorship with Anastasia Tsatoumas.
Dr. Oran Zlotnik MD
Vered Domankevich is VP of Scientific Affairs at Alpha Tau Medical Ltd. She completed doctoral studies at the University of Haifa, focusing on DNA repair mechanisms underlying cancer resistance and longevity and did her postdoctoral research at Tel Aviv University under the supervision of Prof. Yona Keisari, focusing on the immunology of Alpha DaRT technology in combination with cytoplasmatic delivery of viral RNA. After joining Alpha Tau Medical, she established the company’s advanced preclinical research facility and led a research team that characterized the immune-activating pathways induced by intratumoral alpha particle therapy, both as a standalone treatment and in combination with immune checkpoint inhibitors. Dr. Domankevich leads Alpha Tau Medical’s scientific collaborations with leading cancer research laboratories worldwide, including the collaboration with the lab of Prof. Metrakos at McGill university. Her publication record includes landmark papers showing that Alpha DaRT generates tumor-specific long-term immune memory (Cancer Immunol Immunother, 2019), synergizes with checkpoint inhibitor immunotherapy (Int J Radiation Oncology, 2023), and activates systemic antitumor responses in pancreatic and triple-negative breast cancer models (Frontiers in Oncology, 2020).
Dr. Vered Domankevich PhD
Ronen Segal is the Chief Technology Officer of Alpha Tau Medical Ltd., the Jerusalem-based clinical stage oncology company that developed Alpha DaRT, the Diffusing Alpha-emitters Therapy platform at the heart of this research. With more than20 years of executive and technological leadership across multiple fields, including earlier roles as CTO and Head of Business Development at the neurostimulation company Brainsway, and significant work within Israel’s defense research and development division, Segal brings the mindset of an engineer who thinks in systems. He is a coauthor on this paper and a key architect of the Alpha DaRT development program.
Ronen Segal, CTO
PART ONE – THE PROBLEM: WHAT HAPPENS WHEN COLORECTAL CANCER REACHES THE LIVER
Dr. Oran Zlotkin, let us start with the patients. You operate on people with colorectal liver metastases. Give us the human picture – who are these patients, how many of them are there, and what is their reality?
Oran Thank you for starting there. Colorectal cancer is the second leading cause of cancer death globally and the third most common cancer by incidence. Approximately 1.9 million people are newly diagnosed worldwide every year, accounting for roughly one in every ten new cancer diagnoses on the planet. In the United States alone, more than 152,000 people received a colorectalcancer diagnosis in 2024, and over 53,000 died from it. The liver is the disease’s first destination for spreading metastases. Roughly 25 percent of patients already carry liver metastases at the moment of their initial diagnosis and approximately 50 percent will eventually develop liver involvement. You are talking about an enormous number of people – tens of thousands in the United States every year – facing a scenario where a curative approach is no longer straightforward. The hard reality is that only about 20 to 25 percent of those patients are eligible for surgery, which remains the treatment offering the best chance of long-term survival. For everyone else, five-year survival rates sit between 5 and 10 percent. That is the gap we are trying to fill.
Ronen Those numbers are exactly why we built a dedicated research program around this indication at Alpha Tau. The surgical ineligibility rate is not a footnote – it is the majority. Our conviction, and this publication is a step toward validating it, is that a precisely delivered intratumoral approach can reach patients in that gap in a way that nothing currently available does.
Vered There is growing evidence that the response rates of metastatic colorectal cancer patients to immunotherapy are dependent on the tumor load in the liver. Since this organ induces strong immune tolerance, harnessing Alpha DaRT’s potential capabilities to eliminate lesions and to function as an in-situ vaccine that stimulate the immune system against specific cancer antigens, was the scientific motivation of the study. Oran, your own published research at McGill goes deep into why patients with liver metastases face such limited options. What are you seeing that drives the urgency?
Oran When you study these patients longitudinally – with real outcome data from hundreds of liver resections you see clearly where the current scientific knowledge fails them. Even when we achieve a successful resection, recurrence rates remain between 50 and 70 percent within two years. We also know that the way a metastasis grows into the liver at a microscopic level – what we call its histopathological growth pattern – fundamentally shapes how a patient responds to treatment and how long they survive. Colorectal liver metastasis is not one disease. It is a family of related phenomena, and meaningful advances have to be robust to that complexity. What draws me to Alpha DaRT is that it is not competing with surgery but rather complementary. It is offering a treatment for a patient whose tumors sit adjacent to major blood vessels or bile ducts where surgery or thermal ablation would be hard to achieve , or who has limited liver reserve where additional tissue loss could push them toward liver failure. The paper explicitly identifies these as the populations where this approach is potentially most advantageous.
Gideon Vered, before we get into the study itself – the liver is immunologically unusual. What makes it particularly challenging as a treatment site, and why does that matter for the immune strategy you pursue?
Vered The liver’s evolutionary function is to process everything absorbed from the gut without mounting an inflammatory response to every foreign molecule it encounters. It maintains a profoundly tolerogenic immune environment, dominated by Kupffer cells – the liver’s resident macrophages – that are tuned toward T cell suppression rather than activation. When colorectal cancer metastasizes into that environment, it exploits that tolerogenic bias. The tumor microenvironment becomes immunologically cold – little spontaneous T cell infiltration, and the immune cells that are present are largely working in service of the tumor rather than against it. A landmark 2021 paper in Nature Medicine showed that liver metastases actively restrain immunotherapy efficacy specifically through macrophage-mediated T cell elimination. This is why checkpoint inhibitors have largely failed in the subtype of colorectal cancer that makes up the vast majority of patients with liver metastases. Any strategy seeking to harness immune activation here has to actively dismantle the immunosuppressive architecture the tumor has constructed – not just spare the healthy tissue.
Oran When we examine resected colorectal liver metastasis specimens under the microscope, the immune context at the tumor margin is one of the most powerful predictors of how long a patient survives after surgery. Tumors with high cytotoxic T cell infiltration do better. Tumors surrounded by immunosuppressive macrophage barriers do worse. Those are not abstract observations – they map to real survival differences in real people. A treatment that shifts that balance in a favorable direction is doing something biologically meaningful that could change outcomes.
PART TWO – WHAT THE STUDY DID AND WHAT IT FOUND
Gideon Dr. Oran Zlotnik, you are first author on this paper. What makes the experimental model used here different from what had been done before, and why does that difference matter?
Oran The key choice was using an orthotopic liver implantation model rather than a subcutaneous one, and alongside that, carefully preserving the immune system of the animals throughout. In most preclinical cancer research, tumors are inserted and observed under the skin. It is convenient, but it places the tumor in a completely foreign environment – the skin is not the liver, and the immune cells, the blood supply, the structural architecture are all different. An orthotopic model means we implanted colorectal metastatic tumor tissue directly into the livers of mice. We created a liver metastasis that more adequately mimics the way a human colorectal liver metastasis actually behaves, sitting within the hepatic parenchyma, surrounded by the liver’s unique immunological milieu. Crucially, we also designed the model to keep the spleen intact, because the spleen is central to systemic immune response and Alpha DaRT has been shown to activate that response. Moreover, the splenocytes of mice treated with Alpha DaRT and immunostimulators previously showed to mediate specific and systemic immune memory induced by Alpha DaRT and to protect naïve mice from tumor challenge. Using a model that required splenectomy – as some conventional liver metastasis models do – would have directly interfered with the immune biology we were trying to study and measure. That deliberate choice is what made the immune findings meaningful.
Ronen From the engineering perspective, the study also confirmed that source delivery is feasible inside the liver using a standard 21-gauge needle – the same gauge routinely used in clinical interventional procedures. No unexpected distress was observed in any of the animals following implantation. That simplicity matters enormously for clinical translation. No specialized infrastructure. No expensive dedicated equipment. The source is placed during a standard interventional procedure and does its work over approximately 15 days.
Vered The huge added value of the study is that it established a scientific platform for future investigation of Alpha DaRT in the liver environment alone or in combination with immunotherapy and other drugs. It developed for the first time a robust imaging method for the validation of Alpha DaRT positioning in the tumor and for the monitoring tumor progression in an internal organ, while overcoming technical artifacts.
Gideon What were the headline findings? What did each of you take away as the result that mattered most?
Oran The primary efficacy signal induced by a single Alpha DaRT source implanted in the tumor core was clear and statistically significant. Seven days after source implantation, tumors in the treated group were on average approximately three times smaller than in the inert control group. But the finding I would underline for any liver surgeon is the safety signal alongside it. Dr. Anthoula Lazaris, which has many years of experience of nvestigating hepatic tumors and is the leading researcher in Metrakos lab’s research group, has examined the hepatic parenchyma surrounding the treated tumor and found no histopathological changes compared to the control group. Portal triads, hepatocyte morphology, sinusoids and stroma – all preserved their tissue architecture. These findings were confirmed by both standard tissue staining and an independent apoptosis assay, with a pathologist consulted to verify the findings. That combination – potent anti-tumor effect alongside intact surrounding liver tissue – is the central promise of this technology in this organ, and this study demonstrates both simultaneously for the first time in an orthotopic setting.
Ronen For me, the combination of those two signals in the same study is what gives this paper its weight. We had demonstrated both in external tumors across multiple clinical and preclinical settings. Replicating them together in the liver, in a biologically faithful model, is a meaningful and distinct milestone.
Vered The finding that speaks most directly to my work is the immune result. And I want to give it the attention it deserves, because it tells a story that extends well beyond this single paper.
PART THREE – THE IMMUNE DISCOVERY
Gideon Vered, the paper found a significant reduction in immunosuppressive macrophages at the tumor boundary after treatment. For a general audience, what does that actually mean, and why does it matter where that reduction occurred?
Vered Let me start from scratch with what these cells are, because the finding only comes alive if you understand what they were doing there in the first place. When a tumor establishes itself in a tissue, it does not sit passively. It actively recruits immune cells and reprograms them to work on its behalf. Macrophages are among the most important cells it recruits. Generally, macrophages are powerful defenders – they patrol tissues, engulf pathogens, kill abnormal cells, and communicate threats to the immune system. But tumors convert macrophages into a suppressive phenotype that does the opposite: they protect the tumor, promote blood vessel growth that feeds it, and block the cancer-killing T cells from getting inside. In the mouse model, these immunosuppressive macrophages are identified by a marker called F4/80. Their location at the tumor’s boundary with normal liver tissue is the critical detail. That border zone is where the tumor is actively expanding and the blood vessels are still relatively normal and functional compared to those of the tumor core, potentially enabling T cells to infiltrate. These macrophages standing at that gate deny them entry. They are essentially the bouncers keeping the immune system out of the building. What the talented PhD student of Metrakos lab, Anastasia Tsatoumas, succeeded to show in this study is that those bouncers were significantly reduced following Alpha DaRT. Specifically at that boundary, where it matters most, together with an approximately twofold shift in the ratio of cancer-killing CD8+ T cells to immunosuppressive macrophages in favor of the T cells.
Oran And that spatial specificity is what makes this clinically meaningful rather than just mechanistically interesting. The immune context at the margin of colorectal liver metastases – the balance between immunosuppressive and antitumor immune effector cells at that exact zone – is one of the strongest predictors of patient prognosis we know. A treatment that remodels that margin is engaging something that is directly relevant to long-term outcomes of the patients.
Gideon Vered, you have spent years studying how intratumoral alpha particle therapy interacts with the immune system. Put this macrophage finding in the context of what you have built across your research career.
Vered The foundational insight, which came from research, is that when alpha particles destroy tumor cells they do not do it silently. We have previously shown that intratumoral treatment with Alpha DaRT leads to the induction of interferon signaling in the treated tumor and enhanced gene expression related to presentation of tumor antigens to the immune cells. The dying cells release molecular alarm signals – what scientists call damage-associated molecular patterns – that flag the destruction to the immune system and call it to respond. This process is called immunogenic cell death, and it is qualitatively different from the quiet forms of death tumors sometimes trigger to avoid immune detection.
In a 2019 paper in Cancer Immunology and Immunotherapy, we showed in a colorectal tumor model that combining Alpha DaRT with immunomodulators rejected the tumors in more than 50 percent of treated animals through a tumor-specific, long-term immune response and resistance to tumor rechallenge. The splenocytes of these mice protected naïve mice from tumor development of the same type. In 2020, we demonstrated in Frontiers in Oncology that pairing Alpha DaRT with an innate immune receptor activator led to rejection of pancreatic tumors and clearance of triple-negative breast metastases. And in 2023, a paper from our laboratory showed that Alpha DaRT promotes a proimmunogenic tumor microenvironment and synergizes with PD-1 checkpoint blockade – producing greater T cell infiltration and greater release of the cancer-killing molecule granzyme B than either therapy alone.
The new publication adds the liver dimension to that story. It demonstrates, for the first time in a biologically faithful liver model, that Alpha DaRT reduces the macrophage barrier at the tumor boundary in one of the most immunosuppressive tumor environments in oncology. That is not a small step. It connects directly to the known mechanism of immune failure in this specific disease – the one identified in that 2021 Nature Medicine paper – and it opens the door to combination strategies capable ofconverting a cold, resistant colorectal liver metastasis into a tumor the immune system can engage.
Gideon Ronen, how does this immune finding shape Alpha Tau’s strategy going forward, and where does the combination with immunotherapy fit in?
Ronen The combination strategy sits at the center of our long-term scientific vision, and this publication strengthens its rationale in the setting where the need is greatest. Think about what Vered has described: Alpha DaRT seems to trigger immunogenic cell death that makes the tumor visible to the immune system as an enemy that needs to be eliminated, and it simultaneously reduces the macrophage suppression that was potentially preventing T cells from acting. Checkpoint inhibitors work by releasing the brakes on T cells that have been inhibited. If Alpha DaRT has already remodeled the environment – clearing the macrophage barrier and flooding the area with tumor antigens – then checkpoint blockade is acting in a setting where it has something meaningful to work with. You are not just releasing brakes on T cells that cannot reach the tumor. You are releasing them into a space that has been cleared and primed. What is particularly important for colorectal cancer specifically is that this mechanism does not depend on the tumor having a particular genetic profile. The immunogenic cell death induced by alpha particle energy is a physical and biological event. It does not require the tumor to already be immunologically visible. That is deeply significant for microsatellite stable colorectal cancer – the subtype that makes up the overwhelming majority of patients with liver metastases – which is the population that has failed checkpoint inhibitor therapy as a monotherapy. Exploring exactly these combination strategies is the subject of our current effort with our collaboration from McGill university and leading academic institutions in the United States.
Gideon A final question to each of you: what is the single most important message you want a patient, an oncologist, or a colleague reading this paper to take away?
Oran That the biology of colorectal liver metastasis is being challenged in a genuinely new way. Everything we have tried historically has been either systemic – hitting the whole body to reach the liver – or mechanically ablative, burning or freezing or cutting. Alpha DaRT is neither. It aims to destroy tumor cells with precision, spares the surrounding liver, and appears to simultaneously remodel the immune landscape in a favorable direction. For the patients I care for who have run out of good local options, that is not an incremental development. That is a meaningful reason for scientific hope, grounded in rigorously conducted research.
Vered I want the oncology and immunology communities to recognize what this paper demonstrates in the context of existing published biology. A 2021 paper in Nature Medicine showed specifically that liver metastases restrain immunotherapy efficacy through macrophage-mediated T cell elimination. That is the precise cellular mechanism this paper shows Alpha DaRT seeking to disrupt. The macrophage finding is not a side observation. It is a direct engagement with the known mechanism of immune failure in this disease. Add the evidence from prior work on immunogenic cell death and the synergy with checkpoint inhibitors, and what you have is a technology that may be able to convert a cold, resistant tumor into one the immune system can recognize, infiltrate, and destroy. The combination potential is what I find most exciting about where this leads. I encourage scientists and physicians to stay tuned for and remain updated on the upcoming results of our ongoing investigation into these proposed combinations in this immune “desert” liver tumor model.
Ronen Alpha Tau has moved through the translational pipeline in a disciplined, evidence- driven way: from subcutaneous proof of concept, to orthotopic liver model, to a Health Canada-authorized human trial. We have built academic collaborations with elite institutions that bring independent scientific scrutiny to our work. This paper is one step in a coherent story. The next chapter is being written in Montreal right now, and I am enormously proud of what this collaboration is building toward.
CLOSING
Listening to Oran, Vered, and Ronen talk through this work, what strikes me most is not any single finding but the way the pieces fit together. A treatment that could hit a tumor precisely, potentially leaving the surrounding liver untouched, and then appears to re-engage the body’s own immune system to join the fight. That is not a modest claim. And the fact that it is now backed by a carefully designed, peer-reviewed study in Scientific Reports – published by a team that clearly thought hard about every methodological choice – makes it worth paying serious attention to. But here is what excites me most as someone trying to make sense of this: this paper is one piece of a much bigger picture that is still coming into focus. Alpha DaRT has recently shown outstanding results in pancreatic cancer patients – one of the most feared and treatment-resistant diagnoses in oncology – and there is compelling data emerging in brain tumors as well. Now this new work in colorectal liver metastases adds another dimension entirely, because it is not just about destroying the tumor from the inside. It is about potentially shifting the immune tolerance in one of the coldest tumor microenviorments. Scientists have a phrase for this idea: the in situ vaccine effect. The notion that treating one tumor can teach the immune system to recognize and pursue cancer cells wherever they are in the body. Alpha DaRT may be doing exactly that, and if the human trial at McGill supports what these researchers saw in the laboratory, the implications might potentially reach well beyond the liver. There is a lot more of this story still to be written. I for one cannot wait to read the next chapter.
