Microscopic image of a section of a precancerous colorectal lesion, colored using multiplex immunofluorescence: cytokeratin, delineating intestinal epithelial cells, appears in cyan, cell nuclei appear in blue. Particularly active immune surveillance is visible at the center: several types of T lymphocytes stand out in green, red, purple, and white. © Morgand Erwan and Galon Jérôme/Inserm

The prevention of colorectal cancer relies on the early detection and removal of precancerous lesions, which can significantly reduce the risk of progression to invasive cancer. However, the immune mechanisms involved in these lesions remain poorly understood. A research team from Inserm, Sorbonne University, and Paris Cité University has identified an association between immune activity in the microenvironment[1] of precancerous lesions, the frequency of polyp development, and the risk of colorectal cancer. These findings, published in Science Translational Medicine, pave the way for the identification of new biomarkers that could lead to the development of innovative immunotherapies.

Colorectal cancer develops in the epithelial cells of the intestinal lining from lesions known as precancerous lesions. Those that protrude and are easily visible are called polyps. Initially benign, these can gradually progress to a cancerous state. Early detection and preventive removal can significantly reduce the risk of developing invasive cancer and the associated mortality. However, the frequency of polyp formation varies from one individual to another, sometimes without any identified risk factors, and follow-up recommendations after an initial diagnosis are not always tailored to each patient’s specific risk.

Gaining a better understanding of the mechanisms underlying carcinogenesis (i.e., how a normal cell in the intestinal lining becomes cancerous) and enabling earlier intervention are therefore essential to reducing mortality due to these cancers.

Previous findings have shown that the prognosis—whether in terms of survival or response to treatment—for patients with colorectal cancer is associated with the composition of immune cells and molecules in the tumor microenvironment. Since cancers are often detected at advanced stages, this aspect remains understudied in precancerous lesions. However, recent studies have shown that the immune system is also capable of recognizing and eliminating tumor cells as early as the precancerous stage.

A research team led by Jérôme Galon, Inserm research director at the Cordeliers Research Center (Inserm/Sorbonne University/ Université Paris Cité) compared the microenvironment of a total of 258 precancerous lesions in 69 patients—none showing any risk factors for accelerated polyp development—based on the frequency of polyp occurrence.

The researchers thus identified distinct microenvironments whose specific immune profiles were associated with the frequency of polyp development. In particular, lesions in patients with a low frequency of polyp development exhibited a microenvironment indicative of enhanced immune surveillance[2] compared to those in patients with a higher frequency.

This immune surveillance was reflected in particular by a strong presence of antitumor immune cells, as well as a greater number and more mature stage of tertiary lymphoid structures. These clusters of immune cells form within the lesion itself to enable a local immune response and are associated with a better prognosis in many cancers.

“Our in-depth analyses of changes in the microenvironment also show that this ‘enhanced’ immune profile can develop very early on, as soon as the first polyp appears, and could enable the immune surveillance of emerging cancers,” adds Jérôme Galon.

Another major finding: lesions in patients with a low incidence of polyps exhibited gene activity profiles characteristic of particularly active antitumor immune surveillance, notably including increased expression of non-coding RNAs[3].

Conversely, precancerous lesions in patients with higher rates of polyp formation contained few of these non-coding RNAs. Their gene activity profiles were also characteristic of advanced carcinogenesis, even though the lesions appeared benign.

The frequency of polyp development and the risk of colorectal cancer thus appeared to be strongly associated with the immune profile of the lesions, which was itself associated with the presence of non-coding RNA.

“These observations suggest that these non-coding RNAs play a dual role: both in maintaining gene regulatory mechanisms and in orchestrating early antitumor immune surveillance at the local level,” explains Jérôme Galon. “Our hypothesis—which still needs to be verified experimentally—is that these RNAs could facilitate the recognition and targeting of precancerous cells by the immune system, thereby helping to limit the development of polyps and their progression to invasive cancer.”

The results of this study represent a significant advance in our understanding of the mechanisms of carcinogenesis. They point to the need to explore the role of non-coding RNAs in gene regulation and immunity in colorectal lesions.

“Identifying new biological markers of the progression of these lesions could enable the development of new personalized prevention and monitoring strategies, such as targeted vaccine immunotherapies, and allow for very early intervention to counteract the carcinogenesis leading to colorectal cancer,” concludes Jérôme Galon.

[1] The tumour microenvironment comprises all the cells or biological components (blood vessels, immune cells, fibroblasts, signalling molecules, extracellular matrix) located around cancer cells and which interact closely with them.

[2] Immune surveillance refers to the immune system’s ability to detect and eliminate, early and effectively, cells which, by accumulating mutations, have the potential to become cancerous.

[3] When DNA is transcribed into RNA, part of the resulting RNA—coding RNA—is translated to produce proteins. The other part, non-coding RNA, has regulatory functions that control gene expression (which genes are expressed and to what extent). In certain circumstances, non-coding RNA can also be translated into small protein fragments, known as peptides, which may be specific to tumour tissue. These peptides act as antigens, facilitating the detection of tumour cells by the immune system.

© Gustave Roussy/ Bérengère Denfert

Published in the journal Nature, the NIVIPIT study, led by Gustave Roussy and conducted by researchers from Inserm and the University of Paris-Saclay, demonstrates the benefit — in terms of both efficacy and safety — of administering an immunotherapy treatment intratumorally that is typically given intravenously. This approach, carried out via interventional radiology — a field in which Gustave Roussy is a leading actor — involves injecting the treatment directly into the patient’s tumour to increase its effectiveness while limiting side effects.

Immunotherapy treatments have revolutionized cancer management over the last decade. The immunomodulatory antibodies ipilimumab (anti-CTLA4) and nivolumab (anti-PD1) belong to the class of T-lymphocyte checkpoint blockers. They aim to train the patient’s immune system to attack their cancer more effectively. In the case of metastatic melanoma, a form of skin cancer that previously had a poor prognosis, advances in research have now made it possible to achieve a ten-year survival rate of 52%.

However, intravenous administration of these two immunotherapies is associated with severe adverse effects in approximately 60% of patients. Some of these effects may be irreversible or even lead to death in rare cases, which limits the use of this combination to around one in two patients in routine practice, despite its benefits in terms of efficacy.

The rationale for intratumoral injection

It was to address this issue — and thereby enable a greater number of patients to benefit from immunotherapy — that the NIVIPIT phase 1b randomized trial was developed, with results now published in Nature. This multicentre study was led by the dermatology team of Prof. Caroline Robert at Gustave Roussy, in collaboration with the teams of Prof. Stéphane Dalle at the Hospices Civils de Lyon, Prof. Céleste Lebbé at AP-HP (Paris), and Prof. Nicolas Meyer at the CHU de Toulouse. It was conducted at Gustave Roussy within the BIOTHERIS Clinical Investigation Centre (CIC), a structure funded by the DGOS and Inserm dedicated to intratumoral immunotherapy. This innovative treatment, based on the technical expertise of interventional radiology, consists of injecting the treatment directly into the core of the tumour rather than administering it intravenously throughout the body. Intratumoral immunotherapy allows the use of lower doses while powerfully stimulating the immune system precisely where the cancer is present, thereby reducing adverse effects for patients.

In total, 61 patients with metastatic melanoma who had never previously received immunotherapy were enrolled in the trial between 2016 and 2019. They were then randomly assigned to one of two groups: the first received the standard treatment for this indication combining two intravenous immunotherapies, an anti-PD-1 (nivolumab) and an anti-CTLA-4 (ipilimumab), while the other group received an innovative approach combining intravenous nivolumab with ipilimumab — the more toxic of the two immunotherapies — injected directly into the tumour at high concentration but at a total dose ten times lower than the dose typically administered intravenously. The objective of NIVIPIT was to evaluate the safety, tolerability and efficacy of this strategy by analysing tumour response and adverse effects over the first six months, as well as patients’ overall survival.

A safer approach

The results indicate that the primary endpoint of the study was achieved. Severe autoimmune side effects (colitis, skin rashes, hepatitis, etc.) were far less frequent in patients who received the direct intratumoral injection (22.6%) than in those treated intravenously with both molecules (57.1%), representing a reduction of more than half in severe toxicity. The safety profile observed with the intratumoral approach is comparable to that of anti-PD1 monotherapy alone. Achieving such a level of safety for a treatment combining two molecules demonstrates the value of intratumoral immunotherapy in limiting side effects.

Regarding the efficacy of the approach, the results are again very encouraging: 65.7% of tumours treated with intratumoral immunotherapy regressed, and 50% of “distant” lesions (those not injected) also regressed.

Discovery of predictive markers

Beyond the clinical results, the NIVIPIT trial researchers succeeded in decoding the mechanism underlying the anti-tumour immune response. By precisely analysing the tumour microenvironment, they discovered a counter-intuitive phenomenon: for the treatment to work, the tumour must present a specific immune balance between cancer-fighting cells (lymphocytes) and cells known to prevent the immune system from recognising and attacking tumour cells (macrophages and regulatory T cells).

This immune trio, detected before the start of treatment, makes it possible to predict which patients will benefit from a durable response. The study shows that once the treatment is administered, the cells previously considered to be allies of the cancer disappear from within the tumours, giving way to a significant increase in cancer-killing molecules (granzymes). These biological findings were made possible by technical and logistical innovations enabling immediate analysis of fresh tumour biopsies, whereas the current diagnostic routine relies on fixed or frozen tissue.

This cutting-edge expertise in therapeutics and tumour biology confirms that the intratumoral approach is not only less toxic but represents a strategy for the future — one that can strike cancer with surgical precision from the earliest stages of the disease.

“By using interventional radiology to directly target the core of the tumour, we have shown that it is possible to trigger a powerful immune response while halving toxicity for the patient. This is a paradigm shift: the precision of the local procedure makes it possible to overcome the side effects of conventional intravenous treatments, thus opening the way to an earlier and safer use of these therapeutic combinations,” comments Prof. Lambros Tselikas, Deputy Head of the Department of Anaesthesia, Surgery and Interventional Medicine at Gustave Roussy, Professor of Interventional Radiology at the University of Paris-Saclay, and Director of CIC BIOTHERIS.

“Beyond clinical innovation, our in-depth biological analyses have revealed a crucial mechanism: the local injection does not merely destroy the targeted tumour — it reprogrammes the patient’s immunity. We observed that the initial presence of certain regulatory cells, which were thought to be associated with a poor prognosis, is in fact a favourable context for this treatment to effectively awaken the body’s natural defences. These results now allow us to better understand the tumour ecosystem to identify, from the point of diagnosis, the patients who will benefit most from this strategy,” explains Prof. Aurélien Marabelle, medical oncologist, Professor of Clinical Immunology at the University of Paris-Saclay, Director of the Translational Research Laboratory in Immunotherapy at Gustave Roussy, and Scientific Director of CIC BIOTHERIS.

“This is the first time that the benefit of injecting this type of immunotherapy directly into the tumour has been demonstrated, and this first study conducted in patients with metastatic melanoma has proven it, particularly in terms of toxicity. We have already initiated a new clinical study for localised melanomas in which the combination of both immunotherapies is administered intratumorally before surgery (NCT07230613), to reduce relapses while protecting patients from potential treatment-related toxicities,” concludes Prof. Caroline Robert, Head of the Dermatology Department within the Department of Oncological Medicine at Gustave Roussy, Professor of Dermatology at the University of Paris-Saclay, and Principal Investigator of the NIVIPIT study.

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BIOMEDE 1.0, sponsored and coordinated by Gustave Roussy, is the largest clinical trial ever conducted in diffuse intrinsic pontine glioma, an aggressive paediatric cancer in which survival rarely exceeds one year. The findings, published in the journal Nature Medicine, chart a new biological map of the disease, identify patient response biomarkers, and document the prolonged survival of four children — opening concrete avenues for the therapies of tomorrow. This study was led principally by a team of researchers from Inserm, the Université Evry Paris-Saclay, the Université Paris-Saclay, and Gustave Roussy.

Diffuse intrinsic pontine glioma (DIPG) remains a paediatric tumour carrying a grave prognosis. Its deep location within the brain and its highly infiltrating nature, in proximity to areas governing vital functions, rule out surgery as a therapeutic option.

Radiotherapy remains to this day the only treatment to have demonstrated a transient benefit, without offering a cure. The median survival of patients is under one year — a prognosis that has not improved in 50 years. The development of new therapies, therefore, remains a pressing priority, with approximately 40 to 50 children and young adults diagnosed with DIPG each year in France.

The advances of precision medicine

Some fifteen years ago, knowledge of this tumour remained severely limited. No biological tools existed to characterise the disease, and research was hampered by the fragmentation of clinical trials — typically small-scale and yielding little in the way of meaningful scientific insight.

Progress in precision medicine has transformed this outlook. First, by enabling the identification of the H3K27M mutation, present in the vast majority of DIPGs. Discovered in 2012, this genetic abnormality provided, for the first time, a diagnostic marker specific to these tumours. Subsequently, several mechanisms exploited by the tumour to grow and survive were brought to light. In DIPGs, certain cancerous cells exploit receptors on their surface — such as PDGFRA or EGFR — to receive growth signals. Others rely on an internal signaling pathway, the PI3K/AKT/mTOR pathway, to resist treatments such as radiotherapy.

Drugs capable of blocking each of these mechanisms were accordingly developed and evaluated in clinical trials, most often in combination with radiotherapy: dasatinib to target PDGFRA, erlotinib to block EGFR, and everolimus to inhibit the PI3K/AKT/mTOR pathway.

The advances of precision medicine

Drawing on these new insights, Gustave Roussy launched the BIOMEDE 1.0 phase II study in 2014 — the first randomised international clinical trial dedicated to children, adolescents, and young adults with DIPG. This innovative trial was built upon a comprehensive genetic analysis of each patient’s tumour, carried out via biopsy, which both confirmed the diagnosis (presence of the H3K27M mutation) and guided patients towards targeted treatments. Patients were subsequently allocated to one of the three treatment arms according to their tumour’s molecular profile, receiving either erlotinib, everolimus, or dasatinib. The allocation between the three treatments was thus guided by tumour biomarkers, making BIOMEDE — sponsored by Gustave Roussy — the first precision medicine trial of this scale in DIPG.

All three treatments were administered alongside radiotherapy, then continued for as long as the disease showed no progression, with the primary objective of improving survival. In parallel, the teams at Gustave Roussy conducted an extensive research programme, analysing the patients’ tumours in molecular detail. This work deepened understanding of the disease and identified potential avenues for tailoring treatments to each patient.

The trial, which randomised 233 patients between 2014 and 2019, brought together teams from France, the United Kingdom, Denmark, Sweden, Australia, Spain, and the Netherlands. France, as trial coordinator, enrolled most patients (72%). Each tumour underwent thorough molecular analysis, enabling the construction of the largest biological database ever assembled on this disease.

Major biological discoveries

The results of BIOMEDE 1.0, published in Nature Medicine, offer unprecedented biological insight into DIPGs. They identify the principal determinant of patient survival duration: mutation of the TP53 gene, which carries a poor prognosis. Patients whose tumours harboured this mutation sadly survived for shorter periods than others. This finding has now been incorporated to improve patient stratification in future trials and to adapt clinical management from the time of diagnosis.

As regards the three targeted therapies evaluated, none achieved a significant improvement in overall patient survival. In terms of tolerability, however, everolimus stood apart from the other two by virtue of a more favourable profile, with notably fewer adverse effects and a lower rate of treatment discontinuation due to toxicity (3%, compared with 14% for dasatinib and 20% for erlotinib). This outcome establishes it as the reference treatment for the next generation of trials.

Four long-term surviving patients

BIOMEDE 1.0 documented four so-called “long responder” patients — diagnosed with DIPG more than six years ago and still alive today. In a disease where median survival does not exceed eleven months, these cases represent far more than mere exceptions: they constitute an unprecedented scientific window onto the mechanisms that can, in rare circumstances, allow the body to achieve durable control over the tumour.

In-depth analysis of the tumours of these four survivors, along with approximately ten other patients who survived beyond two years, offers a preliminary explanation. Whilst they share no common genetic profile — thus ruling out the hypothesis of a simple pre-existing favourable biological anomaly — their tumours do exhibit a tumour microenvironment distinct from that of other patients, suggesting a more active local immune response. These observations place immunotherapy targeting the tumour microenvironment at the forefront of the next generation of trial development.

“BIOMEDE 1.0 is the culmination of ten years of collective effort to finally deliver a rigorous answer. The results have given us a solid foundation on which to build the next steps. We continue to investigate why these four children are in long-term remission,” said Dr Jacques Grill, paediatric oncologist, co-director of Inserm Research Unit U1360 and member of the Genomics and Oncogenesis of Paediatric Brain Tumours team at Gustave Roussy.

“Making biopsy a condition of entry into the trial was a bold undertaking in 2014. Yet it is precisely thanks to this approach that we now hold the largest biological database ever assembled on this disease. The TP53 mutation, the mTOR pathway, and the microenvironment of long survivors are all keys that BIOMEDE has enabled us to identify,” added Professor Marie-Anne Debily, Professor at the Université Evry Paris-Saclay and researcher within Inserm Unit U1360 (Université Paris-Saclay) at Gustave Roussy.

Two new clinical trials already underway

Armed with these new biological insights, the teams at Gustave Roussy have already launched BIOMEDE 2.0, the only international comparative clinical trial dedicated to malignant gliomas of the midline and brainstem — a family of malignant brain tumours that encompasses DIPGs but extends further, affecting other deep structures of the brain and spinal cord in both children and adults. Open across ten European countries, it is recruiting 368 patients over four years and comparing everolimus — now established as the new therapeutic standard through BIOMEDE 1.0 — with ONC201, the first representative of a new class of anticancer agents.

In parallel, Gustave Roussy is leading BIOMEDE IA, a pioneering research programme harnessing artificial intelligence to analyse the biological, genomic, and imaging data accumulated throughout the trial, to identify information beyond the reach of human analysis.

“BIOMEDE 2.0 and BIOMEDE IA embody the promise that the data from BIOMEDE 1.0 will serve the children who will be diagnosed tomorrow,” concluded Dr Grill.

This work was supported by a Hospital Clinical Research Programme from the INCa and by the associations Imagine For Margo, l’Étoile de Martin, les Amis d’Antoine, La Ligue contre le cancer du 74 et du 94, La marche de l’écureuil, the association Lisa Forever, and all donors to the “Guérir le cancer de l’enfant au 21e siècle” campaign of the Fondation Gustave Roussy. BIOMEDE 1.0, BIOMEDE 2.0, and BIOMEDE IA have all been made possible through the support of the association Imagine for Margo.

The presence of a compound present in cruciferous vegetables, indole-3-carbinol, is essential to make certain cancer treatments effective. © Photo by Monika Borys /Unsplash

It is a universally recognized truth that vegetables are good for your health. A study conducted by Institut Curie and Inserm reveals that the presence of a compound present in cruciferous vegetables, indole-3-carbinol, is essential to make certain cancer treatments effective. The researchers also highlight the biological mechanisms at play and explain how the absence of indole-3-carbinol induces dysfunction at the level of cytotoxic T lymphocytes and decreases the effectiveness of immunotherapy. Illustrating the importance of understanding the relationships between nutrition and immunity, these results are published in Nature Communications on December 2, 2025.

“We now know that the response to cancer treatments can be influenced by many environmental factors, such as nutrition. In particular, it has been shown that the composition of the intestinal microbiota, itself modulated by our diet, plays a role in the effectiveness of certain immunotherapy treatments (by anti-PD1 immune checkpoint inhibitor). And it is precisely this link between nutrition and anti-cancer treatments that we wanted to explore, ” explains Dr. Elodie Segura, Inserm Research Director at Institut Curie (Immunity and Cancer unit).

The role of indole-3-carbinol in the effectiveness of anti-PD1 treatments

In a study conducted at Institut Curie, the group of Dr. Elodie Segura, Inserm Research Director, was interested in one nutrient in particular: indole-3-carbinol, a molecule present in large quantities in cruciferous vegetables (cabbage, broccoli, cauliflower, watercress, turnips, arugula, radishes, etc.). In order to evaluate their role, the researchers compared the effectiveness of an immunotherapy in animals that had received two different diets: one containing indole-3-carbinol and the other one – without it. With indole-3-carbinol, the anticancer treatment has proven to be effective in 50 to 60% of animals. On the other hand, when indole-3-carbinol is eliminated, the effectiveness of the treatment decreases to 20%.

“These results show us that when we remove this compound present in cabbages, there is a drastic decrease in the effectiveness of anti-PD1 immunotherapy,“ summarizes Dr. Elodie Segura.

Cytotoxic T lymphocytes, pivot of the mechanism

It is known that cancer cells are capable of inactivating the cells of the immune system, thus preventing the cancer from being attacked by cytotoxic or “killer” cells. However, immunotherapy treatments, by anti-PD1 immune checkpoint inhibitor, counteract the inhibition by cancer of cytotoxic T cells and allows them to reactivate. Thanks to this treatment, the cytotoxic T lymphocytes that are reactivated become able to recognize the tumor cells and destroy them.

The researchers managed to identify the mechanisms of action of indole-3-carbinol at play in immunotherapy. They have thus demonstrated that indole-3-carbinol binds to a transcription factor called Aryl Hydrocarbon Receptor (AhR), in particular expressed in cytotoxic T lymphocytes[i].

In the absence of indole-3-carbinol, cytotoxic T lymphocytes are unable to respond to treatment.

“Normally, during an anti-PD1 immunotherapy, the lymphocytes are stimulated and reactivated to detect tumor cells. However, in the absence of indole-3-carbinol in the diet, the lymphocytes are not able to recover their functions,” continues to explain Elodie Segura. “Our work makes it possible to better understand the role of nutrients in anti-tumor immune responses. For patients, these data could make it possible to optimize diets in order to ensure the effectiveness of treatments.”

While waiting for these results to be confirmed through dedicated clinical studies, cancer patients are encouraged to follow nutritional recommendations and their doctor’s advice.

[i] Cytotoxic T lymphocytes, also called CD8+ T lymphocytes, are a category of immune cells intended to kill target cells, such as cells infected by viruses, or tumor cells.

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In ICARUS-BREAST 01 study, more than half of the patients with metastatic breast cancer saw their disease reduce or disappear completely thanks to the treatment. In some cases, this response has now lasted for more than two years. Dr Barbara Pistilli, Head of the Breast Cancer Group at Gustave Roussy and Guillaume Montagnac, Inserm researcher, Head of Tumor Cell Dynamics unit, coordinated the study, the results of which have just been published in Nature Medicine. They highlight the efficacy of patritumab deruxtecan (HER3-DXd), an antibody HER3-directed-drug conjugate (ADC), in patients with hormone receptor-positive metastatic breast cancer who had already received multiple treatments, including hormone therapy, chemotherapy, and targeted therapies. The study also offers early insights into why some patients respond better to this targeted therapy than others. This research was conducted within the UNLOCK program at the IHU Prism, in collaboration with Daiichi Sankyo.

Breast cancer remains the most common malignant tumour among women, with 2.3 million new cases and 685,000 deaths worldwide in 2020[1]. These figures underline the urgent need to develop new treatments in this indication.

Antibody-drug conjugates (ADCs) are an emerging class of therapeutics that combine an antibody, designed to recognise and bind to cancer cells, with a cytotoxic agent, often a chemotherapy drug. The antibody delivers its toxic payload directly into the cancer cell while sparing as much healthy tissue as possible.

ADCs have already shown highly encouraging clinical results in a number of solid and haematological tumours. However, despite their promise, their efficacy remains variable across patients. To date, the biological mechanisms underlying this variability, especially the causes of resistance, are still poorly understood. Identifying predictive biomarkers of response is a key challenge in optimising the personalised use of these therapies.

Published in Nature Medicine, ICARUS-BREAST 01 is a phase II trial sponsored by Gustave Roussy. It evaluated the efficacy and safety of patritumab deruxtecan (HER3-DXd) in 99 patients with HR+/HER2- metastatic breast cancer whose disease had progressed following treatment with a CDK4/6 inhibitor and one line of chemotherapy. The trial also included an exploratory component aimed at identifying biomarkers predictive of response or resistance to this innovative therapy.

Promising Clinical Results

Patritumab deruxtecan is an ADC designed to target the HER3 protein, which is expressed in a high proportion of hormone receptor-positive breast cancer cells. This protein is known to play a role in resistance mechanisms to certain standard treatments, including hormone therapy and some targeted therapies.

From May 2021 to June 2023, ninety-nine women received patritumab deruxtecan by infusion every three weeks, until disease progression or the onset of a serious toxicity. The study met its primary endpoint: 53.5%of patients experienced a significant reduction in tumour size with patritumab deruxtecan, and around 63% of patients derived clinical benefit from the treatment (tumour shrinkage or disease stabilisation lasting at least six months). Notably, two patients experienced complete disappearance of visible signs of disease, a response that has now lasted more than two years.

The median follow-up period was 15.3 months. Median progression-free survival was 9.2 months, and the average duration of response was 9.3 months. The most common adverse events were fatigue (83%), nausea (75%) and diarrhoea (53%). The safety profile was consistent with that previously reported.

The Role of the UNLOCK Programme

The exploratory research component of ICARUS-BREAST 01 shed light on why some patients respond better than others do to patritumab deruxtecan, by identifying biomarkers linked to resistance mechanisms. This research, conducted within Gustave Roussy’s UNLOCK programme at the IHU Prism, was based on exploratory analysis of tumour samples taken before and after treatment, as well as imaging and genetic data.

These exploratory analyses suggest that the response to the drug may be linked to how HER3 is distributed within the tumour and to the absence of certain mutations, such as ESR1. Another finding indicates that disease control may last longer in patients whose tumours express higher levels of HER3.

Samples collected during treatment revealed that the drug’s efficacy appears to depend on its ability to penetrate the tumour, and on the activation of a specific immune response marked by an interferon signature, proteins naturally produced by the body that play a key role in stimulating the immune system.

“In this study, HER3-DXd demonstrated promising efficacy and good tolerability in patients with advanced hormone receptor-positive breast cancer who had exhausted standard treatment options,” says Dr Pistilli. She adds, “ICARUS-BREAST 01 also highlights interesting biological insights that could ultimately help us better identify patients who are most likely to benefit from this approach. These initial results now need to be confirmed by larger trials, some of which are already under way internationally and will soon open in France. Another study, ICARUS-BREAST 02, is currently ongoing with HER3-DXd. It aims to evaluate the efficacy of this ADC in combination with Olaparib following progression on a previous ADC, trastuzumab deruxtecan (T-DXd).”

[1]Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA: A Cancer Journal for Clinicians 2024;74(1):12–49

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A new class of molecules capable of killing the cancer cells that are refractory to standard treatments and responsible for recurrence has just been developed by scientists at Institut Curie, the CNRS, and Inserm. This crucial advance in the fight against metastatic cancer is based on identifying the cellular site for ferroptosis initiation, a natural process, catalysed by iron, that sparks the oxidative degradation of cell membranes. These promising preclinical results will be published in the journal Nature on 7 May 2025.

Current anticancer treatments essentially target the primary tumour cells that proliferate quickly, but do not effectively eliminate specific cancer cells able to adapt to existing treatments and which exhibit high metastatic potential¹. Yet metastases are responsible for 70% of cancer deaths.

A French research team from Institut Curie, the CNRS and Inserm has just developed a new class of small molecules that bring about the destruction of cell membranes,and hence triggers cell death. Led by scientists at the Laboratory of Biomedicine (Institut Curie/CNRS/Inserm)², this study is based on the remarkable properties of what are known as drug-tolerant persister cancer cells, with high metastatic potential. The latter express a large quantity of the protein CD44 at their surface, allowing them to internalise more iron, making them more aggressive and able to adapt to standard treatments. These cells are consequently more sensitive to ferroptosis, a cell death process catalysed by iron, which causes oxidation and the degradation of membrane lipids.

Thanks to innovative chemistry developed by the team led by Raphaël Rodriguez, researchers showed that the cell death initiated by iron in lysosomes3 can alter the structure of intracellular membrane compartments. In the lysosomal compartment, iron can react with hydrogen peroxide, generating oxygen-centred radicals, highly-reactive chemical entities that damage cell membranes. This reaction then propagates in the cell forming lipid peroxides in the membranes of other cellular organelles, ultimately causing cell death. Ferroptosis thus results from the cell’s failure to repair the membrane damage.

Using these initial discoveries, the scientists successfully conceived and synthesised a new class of small molecules that can activate ferroptosis: phospholipid degraders. The molecules possess one fragment that allows them to target the cell membrane (plasma membrane)—and to then accumulate in lysosomes via endocytosis—as well as another part that binds to and increases the reactivity of iron, which is abundant in this compartment of pro-metastatic cancer cells, thereby triggering ferroptosis. The molecule fentomycin (Fento-1) was designed to be fluorescent, allowing scientists to visualise it in the cell using high-resolution microscopy, as well as to confirm its localisation in lysosomes.

After the administration of Fento-1, the researchers observed a significant reduction in tumor growth in pre-clinical models for metastatic breast cancer, in addition to a pronounced cytotoxic effect on biopsies of pancreatic cancer and sarcoma patients, thereby confirming the treatment’s effectiveness at the pre-clinical level⁴ for these cancers, for which the effectiveness of standard chemotherapy is limited.

Clinical tests are needed to show that this ability to induce ferroptosis could serve as a therapeutic avenue that complements current chemotherapy in the fight against cancer, especially by targeting cancer cells that are pro-metastatic and refractory to standard treatments.

Ferroptosis diagram. Iron is internalized in the cell via the protein CD44 present on its surface, allowing it to acquire metastatic properties and tolerance to standard treatments through epigenetic reprogramming, which plays a key role in cell adaptation. The activation of lysosomal iron by a phospholipid degrader causes the oxidation and rupture of cell membranes, leading to cell death.

1 – Tumour cells that detach from their site of origin and migrate toward other parts of the body, forming new tumours known as metastases. This ability to spread is a characteristic of advanced cancers.

2 – This research primarily involved scientists from the Laboratory of Biomedicine (Institut Curie/CNRS/Inserm/PSL Research University), the Cancer Research Center of Marseille (Aix-Marseille Université/CNRS/Inserm/Institut Paoli Calmette), the APHP (Hôpital Paul-Brousse), the Institute of Molecular Chemistry and Materials of Orsay (CNRS/Université Paris-Saclay), Harvard T.H. Chan School of Public Health, Helmholtz Zentrum München, Julius-Maximilians-Universität Würzburg,, Columbia University and the University of Ottawa.

3 – Lysosomes are the organelles responsible for the degradation of cell debris, biological macromolecules, foreign particles (bacteria, viruses, and parasites), and damaged intracellular organelles.

4 – Pre-clinical tests on animals showed a significant decrease in tumour volume after the lymphatic injection of Fento-1, with tolerance to treatment.

This research notably received support from the Ligue contre le cancer (3 Equipe Labellisées), the Horizon 2020 Research and Innovation Programme of the European Union (ERC), the Fondation pour la recherche médicale, the Fondation Charles Defforey–Institut de France, the Klaus Grohe Foundation, l’Institut national du cancer, the Ile-de-France Region, the ANR, the Fondation Bettencourt Schueller, the CNRS, Institut Curie, and Inserm.

Around 30% of cancers develop in the wake of chronic localised inflammation. This is particularly the case of certain colorectal cancers, or cancers of the small intestine, liver or pancreas. © Adobe Stock

Nearly one in three cancers develops following chronic inflammation, whose origin remains unclear. In a new study, researchers from Inserm, CNRS, Université Claude-Bernard Lyon 1 and the Léon Bérard Centre at the Cancer Research Center of Lyon[1]identified lymphocytes involved in the inflammatory processes and that are thought to be implicated in the generation of these cancers. This research opens up new avenues in terms of prevention and treatment, and its findings have been published in Nature Immunology.

Around 30% of cancers develop in the wake of chronic localised inflammation. This is particularly the case of certain colorectal cancers, or cancers of the small intestine, liver or pancreas. However, many questions remained unanswered regarding their development. Is one specific immune cell responsible for the inflammatory process that leads to cancers, or more than one? And if so, which?

Answering these questions is one of the objectives of Inserm Research Director Julien Marie[2] and his team at the Cancer Research Center of Lyon (Inserm/CNRS/Université Claude-Bernard Lyon 1/Léon Bérard Centre) in order to better understand how the disease is initiated.

The researchers were particularly interested in TH17 lymphocytes – a population of immune cells which are already known to be involved in many inflammatory diseases, such as multiple sclerosis and Crohn’s disease.

Cells that cause cancer

The hypothesis was that TH17 cells are not a homogeneous population, but can actually be divided into several subgroups. Using single-cell RNA sequencing approaches, the scientists demonstrated this heterogeneity of TH17 cells within the gut.

‘More specifically, this study shows for the first time that there are actually eight TH17 subtypes with distinct roles. One of them has a tumorigenic role, which means that when certain activation barriers are removed, it will contribute to the development of cancers. On contact with these TH17 cells, the previously healthy gut cells become cancerous’, explains Marie.

The scientists then showed this tumorigenic population to be increased in patients at high risk of cancer. Finally, they also identified that a protein – cytokine TGF–β – is capable of inhibiting the formation of tumorigenic TH17 cells.

‘This study may make clinicians stop and think about the long-term use of immunotherapies in cancer patients, whose aim is to stimulate lymphocytes’, emphasises Marie.

While these therapies have transformed cancer care, they are also known to cause chronic gut inflammation. Therefore it is important to consider, for a given patient, the risks of immunotherapy being accompanied by the emergence of tumorigenic TH17 lymphocytes, which could eventually lead to the development of another cancer. Furthermore, this study lays the foundations for the development of new cancer preventive therapies by blocking the appearance of the TH17 subtype implicated by the scientists in this research.

[1]Scientists from the Institute of Molecular Genetics of Montpellier (CNRS/Université de Montpellier) also participated in this research.

[2]Julien Marie is the winner of the Bettencourt Coups d’Élan Prize for French Research.
Created by the Bettencourt-Schueller Foundation in 2000, this prize had been awarded to 78 French laboratories and over 900 researchers until 2021.