Tackling problems related to 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.

Identifying 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.

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.

Combination TKI and next-generation CAR-T cells for improved treatment of sarcoma

This investment is intended to help the team establish the preliminary data that will provide background information required to pursue the use of next-generation CAR-T immunotherapy in the treatment of sarcoma. This project is built on strongly balanced contributions of Dr. Irving as a basic scientist with expertise in the generation of CAR-T cells, and Dr. Digklia as a clinician working in the sarcoma unit of CHUV. The team has obtained promising results in early phase I/II trials, suggesting that an inhibitor of the tyrosine kinase VEGFR (pazopanib) plus the anti-PD-L1 immune checkpoint inhibitor durvalumab may have tumor-arresting activity in soft tissue sarcoma. The team wants to combine such tyrosine kinase inhibition (TKI) with innovative CAR-T cell therapy to treat sarcoma. This is a challenging goal, but it is reasonable to test CAR-T cells as well as immune checkpoint inhibitor therapies. The scientists hope to use the erythropoietin-producing hepatoma type-A receptor-2 (EphA2), a cell surface marker specifically overexpressed in sarcoma, as a target for novel CAR-T cells. It is important that they compare patient biopsies before and after tyrosine kinase inhibitor treatment to identify the most specific targets for CAR-T cell co-engineering. As most of the team’s preliminary data were produced using prostate cancer cells, the funding is also given so that they can accumulate data that confirms EphA2 expression in sarcoma before and after TKI treatment, thereby substantiating the idea to use this marker as a CAR-T cell target.

The role of natural killer cells in cutaneous T cell lymphoma: pathophysiological mechanisms and clinical implications

Cutaneous T cell lymphoma (CTCL) is a group of rare but potentially lethal non-Hodgkin’s lymphomas, originating from malignant CD4+ T cells. The patient’s immune system is deemed an important determining factor of disease progression, and immunomodulatory therapies reliably improve outcomes. Therefore, understanding the effect of CTCL on the immune system and its cells is imperative for improving therapeutic options.

CTCL immunomodulatory effects lead to immune cell exhaustion, explaining the so far disappointing results of T- and dendritic cell-dependent therapies when compared to other types of cancer. However, there is recent evidence that natural killer (NK) cells account for the response of immunomodulatory treatment in CTCL.

Given the immunomodulatory nature of CTCL, its profoundly immunosuppressive tumor microenvironment and the reduced anti-tumor activity of NK cells in CTCL patients, I formulate the following hypothesis: the tumor microenvironment-driven suppression of NK cell function is a crucial factor for tumor progression in CTCL, and the rescue of NK cell activity can be used as an effective treatment strategy in CTCL and cancer in general.

The overarching goal of this project is to reverse the CTCL-impaired NK cell activity by targeting the factors which negatively regulate NK cell function. The first step will be to phenotype the NK cells in the tissue microenvironment (TME) of CTCL through computational, single-cell sequencing analysis. I will examine this comprehensive dataset for factors and pathways that specifically alter NK cells in CTCL by comparing it with that of the NK cells in healthy skin, inflammatory skin diseases and solid skin tumors.

All discovered candidate molecules will then be individually validated by reverse transcription PCR (RT-PCR), fluorescence-activated cell sorting (FACS) and protein immunoblotting in NK cells from CTCL patients and individuals suffering from the aforementioned other diseases as controls. The number and state of activity of NK cells will be compared to the existing patient-specific clinical data to evaluate the impact of disease stage and progression. I will then test the reversibility of the suppressive effect of promising candidate molecules on NK cell activity in vitro and develop a combinatorial therapy plan to treat CTCL in a syngeneic T cell lymphoma model. In this way, I will test in vivo whether the target molecules discovered in steps 1 and 2 can be used to rescue the anti-tumor potential of NK cells and improve the outcome of CTCL.

If successful, this project will advance our understanding of the role of NK cells in CTCL pathology and treatment, as well as in inflammatory skin diseases and solid skin tumors. The factors and pathways initially identified through computational analysis, experimentally validated in vitro as reversible and found to be effective in vivo can be the basis for further studies to test their clinical applicability. 

Employing new visualization technologies will further the understanding of CAR-T cell therapy

The immune system plays a crucial role in inhibiting tumor growth. Adoptive cell therapy is a kind of immune therapy, where the cells of the patient’s own immune system are extracted, reprogrammed separately, and introduced back into the body to combat tumors in a very targeted manner.

More specifically, an adoptive cell therapy that uses chimeric antigen receptor T cells (CAR-T) has been transformative for people suffering from selected hematological malignancies (cancers that begin in the blood forming tissue) that are prone to relapse or are refractory. CAR-T therapies are being expanded to treat solid tumors as well. Unfortunately, there are significant toxicities associated with CAR-T cell therapy, especially since preclinical tools to evaluate CAR efficiency and safety can be inaccurate, time-consuming, and expensive.

The aim of this TANDEM project is to increase the precision and safety of engineered T cells by implementing new microscopy technologies to dissect and examine the interaction between the CAR-T cell and the tumor cell.  They aim to make these technologies easy to implement so that they can routinely be used in a clinical setting. They will in turn provide insight on whether the therapy will be effective or generate toxicity. If successful, this new imaging tool will be used to improve both the patient’s prognosis and the patient’s overall quality of life during CAR-T treatment of hematological malignancies.

Development of AI systems to assist in staging and treatment of bladder cancer patients

Bladder cancers (BLCA) are usually characterized as either superficial or invasive. As with all cancers, the tumor has to be staged in order to make a proper prognosis and decide on an appropriate course of treatment. Currently, bladder tumor staging depends on how deeply nested the tumor is into the bladder wall. However, recent research has shown that this may not reflect the most biologically relevant features of different forms of the disease. The aim of this collaboration is to better understand the biological behavior of bladder cancer on a molecular and cellular level in order to optimize the decision-making process for an effective course of treatment. This decision-making process is time-sensitive, as treatment must start by two weeks after the biopsy is taken.

There is a crucial need to optimize the staging process itself, as accuracy at this point will have a considerable impact on the choice of therapy and the patient’s quality of life. Both the over- and under-treatment of cancers can elicit serious problems.

The overarching goal of this TANDEM project is to explore the biological nature of BLCA through a range of advanced high-throughput molecular techniques (genomics, transcriptomics, epigenetics) combined with the monitoring of functional responses to different therapies. From this, an atlas of tumor cell types and sensitivities will be created, which will allow the researchers to generate an AI framework that should better guide BLCA patient care decisions. The collaborators bring different types of analysis together to shed light on both the tumor and its surrounding tissues (tumor microenvironment) and study the response of the BLCA to chemical inhibitors in vitro. The aim is to offer a more accurate platform for diagnosis and staging of BLCA, enabling clinicians to match patients with the most effective treatment.

Development of new therapy for patients with resistant colorectal cancer

Colorectal cancer (CRC) is the second most common cancer and is responsible for cancer-related deaths affecting men and women on a global scale. Even though therapeutic options have improved, including the promising introduction of immunotherapies, only a fraction of patients benefit or even respond to current treatments. For instance, checkpoint inhibitor therapy benefits only 5% of CRC patients so far. This collaboration aims to develop much needed novel therapeutic options, particularly ones adapted to the individual patient, in order to ensure higher efficacy and safety.  Their goal is a better the quality of life and prognosis for CRC patients.

It has been shown that patients affected with CRC have an altered intestinal microbiota composition that may contribute to cancer pathogenesis, treatment resistance, and increased toxicity of currently used cancer treatments. Promising data now show that specific bacteria are able to modulate antitumor immune responses and may, therefore, serve as potential therapeutic agents or adjuvants for new therapies. Further new studies have established a link between higher levels of intratumoral eosinophils (a type of white blood cell with specialized immune function) and a favorable prognosis. The eosinophil levels correlate with enhanced survival of CRC patients. 

The strategic aim of this project is to further the understanding of the patient’s microbiome and its interaction with the eosinophils to explore their potential roles as molecular biomarkers that could predict disease course and therapy response. Ultimately, this could lead to personalized microbiota-based precision medicine for CRC patients.

TCR-engineered CD4 T cell transfer for optimized cancer immunotherapy in adult and pediatric patients

This is a highly translational project aiming at harnessing the tumoricidal activities of CD4+ T cells to optimize cancer immunotherapies. The project includes preclinical validation of TCR-engineered CD4 T cells and the setup of a Phase 1 clinical trial for relapsed and refractory solid tumors in both adult and childhood cohorts.

Survey on cancer patient-reported healthcare experiences in Switzerland

Collecting patients’ opinions and their healthcare experiences is essential when assessing the quality of healthcare services and evaluating how well the healthcare system meets patients’ needs. This is particularly important in cancer care, as these patients have needs on multiple levels that very often are not covered by the existing healthcare system. Beyond the numerous health issues related to the disease and its treatment, cancer can indeed have significant psychosocial consequences for patients and their loved ones, including financial repercussions.

In 2018, we conducted the SCAPE-1 (Swiss Cancer Patient Experiences) study, a first survey of patients treated for one of the six most frequent cancer types in one of four hospitals in the French-speaking part of Switzerland. This survey addressed their experiences related to oncological care. In 2021, we repeated the survey. This SCAPE-2 study was extended to include patients with any type of cancer and treated in the same four French-speaking hospitals as well as in four medical centers in the German-speaking part of the country. Amongst other topics, the survey contained questions regarding emotional support, information and communication, treatment decision making, as well as inpatient and outpatient care. A section on the impact of the COVID-19 pandemic on cancer care and the patients themselves was also added.

The results of this study will provide insight into the way patients experience cancer care, and will help determine whether these experiences vary from one cancer center to another and depending on the language spoken. Furthermore, this study will help guide the development and the implementation of local and national interventions aimed at improving cancer care by identifying aspects less well perceived by patients.

The SCAPE-2 study was initially financed by the Swiss Cancer Research foundation. The additional support granted by the ISREC Foundation will make it possible to perform an in-depth analysis of the data collected within the study, and to enhance the value of this information through scientific publications as well as presentations at conferences and seminars.