Translational research project on the deconstruction of the spatial architecture of early-stage melanoma response to neoadjuvant PD-1 immunotherapy

This “allocated fund”, made possible by a generous contribution of the ORFEO Foundation, was granted to Dr. Krisztian Homicsko (CHUV),
Prof. Raphael Gottardo (UNIL) and Dr. Pierre Moulin (CHUV) in December 2024 for one year.

The landscape of immunotherapies is evolving rapidly, progressing from metastatic to adjuvant and, more recently, to the neoadjuvant setting. In melanoma, neoadjuvant immunotherapies have demonstrated excellent responses and promising long-term outcomes. Both monotherapy and combination immunotherapies have shown efficacy, yet it remains unclear which patients benefit more from one approach over the other. To date, no single biomarker reliably distinguishes patients who will experience clinical benefit, or determines the most appropriate treatment strategy. 

Given the complexity of the tumor microenvironment, we aim to investigate the spatial architecture of melanoma tumors before and after neoadjuvant immunotherapy, leveraging digital pathology and single-cell spatial transcriptomics. Our approach integrates multiple modalities, combining lower-complexity assays such as H&E staining and multiplex immunohistochemistry with high-resolution spatial transcriptomics. This strategy not only enhances our understanding of the tumor microenvironment, but also facilitates the identification of potential biomarkers. 

Moreover, we aim to translate biomarkers discovered through spatial transcriptomics into conventional pathology imaging methods, ultimately validating our findings in a more widely accessible clinical setting.

Enhancing CAR-T Cell Therapy for Refractory Multiple Myeloma

In December 2024, this “allocated fund”, amounting to CHF 100’000, was granted to Prof. Carsten Riether and Dr. Marc Wehrli for one year.

Chimeric antigen receptor (CAR) T cells represent a significant advancement in cancer immunotherapy, especially for blood cancers. This treatment involves genetically modifying a patient’s T cells to express engineered receptors that more effectively eliminate cancer cells. Recent advances focus on enhancing the effectiveness of CAR-T cell therapy for patients with relapsed or refractory multiple myeloma (MM).

MM is a type of blood cancer that originates from malignant plasma cells in the bone marrow. Despite recent advancements in treatments, MM remains a challenging disease due to its recurrent nature. B-cell maturation antigen (BCMA) targeting CAR-T cell therapy has demonstrated effectiveness, but its benefits are often short-lived.

This research seeks to identify specific surface proteins that could enhance the performance of BCMA CAR T cells. We will be conducting an analysis of blood samples from 20 patients. This group includes 10 patients who are either experiencing progressive or stable disease following CAR-T therapy and 10 patients who have achieved a complete response. Blood samples will be collected at various intervals. Our aim is to isolate anti-BCMA CAR-T cells from these samples to perform a CRISPR screening. This screening will target surface proteins that have been identified through advanced techniques in single-cell RNA sequencing. Ultimately, this study aims to identify surface proteins that enhance the persistence of CAR-T cells in multiple myeloma. This identification will lay the foundation for the next generation of BCMA CAR-T cell therapies, which could significantly improve patient outcomes.

Tackling problems of early diagnosis and prognostic stratification of mycosis fungoides using a systems medicine approach

Prof. Emmanuella Guenova (CHUV) was granted this “allocated fund” in January 2024 for 18 months.

Key strategies in the fight against cancer mortality are early detection and precise diagnosis. Especially in its early stage, mycosis fungoides (MF), the most common cutaneous T cell lymphoma, exhibits striking morphological similarities to benign inflammatory skin conditions. This results in two major problems: diagnostic delay and prognostic uncertainty. Here, we propose a large interdisciplinary effort, combining bioinformatics, biological research, and medicine to tackle the problems of early diagnosing and prognostic stratification of tumors such as MF. In the context of the Indo-Swiss research initiative, we profit from the unique opportunity to perform analysis of classical versus hypopigmented MF, a rare, distinct variant, prognostically clearly different from the classical disease. We postulate a key role of type 2-skewed immunity in MF cancer progression. We also see the naturally occurring hypopigmented MF variant with good prognosis and strong type 1 immunity as an ideal comparator to the classical MF phenotype that can help us understand disease complexity, identify negative immune regulators and define parameters for better MF patient classification and stratification.

Unravelling the rules by which T cells recognize cancer-specific epitopes

T cells play a crucial role in cancer immunotherapy by targeting and attacking cancer cells. They do so by recognizing specific molecules, called epitopes, displayed on cancer cells but not on normal cells. To maximize the chances of detecting the wide variety of epitopes found across cancer patients, different T cells are endowed with different receptors. T cell receptors recognizing cancer epitopes are promising for therapeutic applications, since T cells can be engineered to express these receptors and infused into patients.

Today, it is increasingly possible to identify the various T cell receptors and the epitopes present in a tumor. However, figuring out which T cell recognizes which epitope is still very challenging. 

In our project, we will combine experimental and computational methods to characterize the recognition of cancer epitopes by T cell receptors. We then aim to develop AI models that can analyze large collections of T cell receptors from patients, in order to identify the most promising ones for clinical use. These results will complement ongoing research at the Department of Oncology and elsewhere, and help accelerate and streamline current pipelines to prioritize T cell receptor selection for T cell-based therapy.

Multisystem cancer biology: targeting the interplay between intra- and extracellular proteostasis

All human cells must assemble – and later break down – the right proteins at the right time and in the right quantities. To do this, they need to use and recycle building blocks such as amino acids, and provide energy for the molecular machines that make and break down proteins. The fine-tuned orchestration of these processes represents a considerable challenge that cells must continually master, as a correct cellular “proteome” (the entire set of proteins) is essential for the proper functioning of cells and for the health of the tissues and organs in which they reside.  As a result, a myriad of diseases often linked to age are linked to the inability of cells to keep the proteome in order.

Cancer cells usually grow and multiply faster than normal cells. They are therefore thought to be particularly dependent on the processes that regulate the proteome in order to keep up with high protein turnover. Disrupting these mechanisms is a promising therapeutic approach and has already led to new treatments for some cancers, such as multiple myeloma, a malignant disease of the bone marrow. Our team is working to better understand how different cancers try to keep their proteome in order, and to find ways to target these mechanisms with new drugs. One of the molecules we are interested in is called GCN2. It regulates how cells respond when their amino acid stores run low. We want to understand how to safely turn off GCN2 in cancer cells so that their proteome fails, killing them, while healthy tissue is largely spared. We know that this approach works well experimentally in some cancer cells, but not in others. One goal of our research is to identify the features that make cancer cells dependent on GCN2, which would help identify cancer patients (prior to therapy) that are likely to respond to treatments with drugs that target GCN2. To do this, we use a so-called systems biology or multi-omics approach, in which different technologies are used to study several cellular processes in parallel (e.g., to understand how cellular metabolism changes when certain genes are actively transcribed and translated into proteins). We and many others believe that such a holistic approach to molecular cancer research has great potential to identify previously unknown cancer cell vulnerabilities. To find and target these Achilles’ heels, we collaborate with academic colleagues and research partners from the biotechnology and pharmaceutical industry.

Mirror therapy for phantom breast syndrome

Breast cancer is the most frequently diagnosed cancer in women, with more than 6000 new cases diagnosed yearly in Switzerland; an incidence which is still increasing. Although still a leading cause of cancer-related death^1,2, mortality due to breast cancer has decreased considerably over the last decades^1,2, thanks to the implementation of mammography screening programs, surgery improvements, and more efficient medical treatments.

Approximately 40% of breast cancer patients must undergo a mastectomy to treat their disease³. Therefore, the management of long-term consequences of this surgical procedure is advocated, in order to limit the economic and societal impacts of its related morbidity and to improve the quality of life of cancer survivors.

Phantom breast syndrome (PBS), occurring after a mastectomy, is a condition characterized by a residual sensation associated with the removed breast tissue, accompanied by neuropathic pain (similar to phantom limb syndrome after amputation). Although of varying estimated incidence in the literature, its prevalence reaches up to 30% in patients having undergone this procedure³. Accordingly, 760 women are diagnosed with PBS in Switzerland every year. In addition to painful sensations described as shooting and burning, patients may also experience other discomforts, such as pins and needles, itching, tingling, pressure, and throbbing³. PBS severely affects the quality of life as a consequence of the physical disability and emotional distress it generates. Some studies demonstrated that depression, psychiatric morbidity, and fear of cancer recurrence are more important in women suffering from PBS³.

Parallels have been drawn between PBS and phantom limb syndrome, such as the timing of their installment after surgery. There are also clues that their development occurs on the same neurological basis. Research on PBS is still sparse and often inconclusive. However, it is increasingly clear that this condition has its own specificities. Therapeutic interventions for this type of pain include oral medications, such as opiates and antidepressants, in addition to topical agents. However, such medical treatments have limited efficacy once this type of chronic pain is installed. Similarly, preventive treatments aiming at reducing PBS incidence are currently not available. Patients are often isolated with their syndrome, as the awareness of the existence of PBS is limited outside of the specialized medical community, making the management of this syndrome a major unmet clinical need.

In this study, we aim to adapt “mirror therapy”, a common non-invasive treatment for phantom limb syndrome, for the care of PBS patients. This method, effective since the mid-1900s^4,5, relies on the usage of a mirror to hide the amputated limb and to replace its image with the reflection of the intact contralateral limb. By doing so, the patient’s brain is tricked by the visual perception of two functional limbs, which elicits cortical remodeling and subsequent neuropathic pain relief. After decades of research, the therapy has been improved and adapted using different combinations of physical mirrors and virtual reality.

This project aims at improving the quality of life and the performance status of women suffering from PBS thanks to non-invasive devices and accompanying physiotherapy sessions. The objective is to improve pain control and potentially reduce PBS-related disabilities and their economic and societal impacts. This project started a year ago, but requires substantial funding to achieve further improvements.

Chimeric antigen receptor T cell therapy for children and adults with relapsed acute myeloid leukemia

Press release