Diagnostics of a rare lymphoma through integrative AI
Transforming the Diagnostics of Nodal Marginal Zone Lymphomas by Integrating Digital Pathology, Molecular Biology, and Artificial Intelligence
Nodal marginal zone lymphoma (NMZL) is a rare and difficult to identify B-cell malignancy that is often wrongly diagnosed. The applicants propose a digital pathology approach that they hope surpasses expert pathologists in correctly diagnosing NMZL. They will use deep learning to integrate imaging, clinical and molecular data, generating a classifier that will allow clinicians to upload all their slide scans and get a correct NMZL diagnosis. Based on 900 cases, samples and data obtained across Europe, they hope to provide a clinically applicable, yet technically sophisticated way to identify a rare lymphoma subtype.
Spatial biology for risk stratification of colorectal cancer
Stratifying colon cancer risk through imaging and transcription profiles
In order to identify prognostic biomarkers for stage II colorectal cancers (CRC), the investigators will use computational approaches to combine advanced molecular ‘omics data with histological images from 1800 past CRC patients. The goal will be to identify prognostic markers in networks, and to validate these in new patient cohorts. This is an advanced digital pathology project.
Does tissue fibrosis trigger brain cancer recurrence?
Spatial analysis and functional interrogation of fibrotic scarring niches in glioblastoma recurrence
Zones of fibrotic scarring are associated with tumor relapse in aggressive brain tumors. This study will use cutting-edge spatial multi-omics technologies and digital pathology analyses to explore the mechanisms that generate fibrosis in glioblastoma patients. Ultimately, the scientists hope to uncover novel therapeutic targets that disrupt the tumor-protective fibrotic niche and thereby prevent disease recurrence.
Distinguishing primary tumors from metastases in the lung using AI
Multiple lung tumor nodules: Establishing cost-effective molecular and digital pathology methods to separate multiple primary lung cancers from intrapulmonary metastases
Analyzing stained tumor biopsies by microscopy is the pathologist’s craft. Now, it can be enhanced and augmented by computer-based analysis and integration with other information.
Using a large data base of tissue sections from primary lung adenocarcinoma, the team will compare these with metastatic nodules in the lung derived from other primary tumors. The goal is to optimize a new digital pathology tool (DPLAS) that will stratify lung cancers and allow patient triaging. A strong feature of the project is that the technology is based on routinely available H&E slides, which enables broad usage of the tool.
Optimized predictions of patient-donor immune compatibility for hematopoietic stem cell transplantation
The primary goal of the project is to optimize the prediction of recipient-donor genetic compatibility for hematopoietic stem cell transplantation (HSCT) in hematological malignancies. Recipient-donor compatibility is one of the best predictors of the success of HSCT. By improving prediction accuracy, the project seeks to reduce the incidence of graft-versus-host disease and other immune-related complications. This advance could potentially increase the survival rates and quality of life for patients undergoing this common and key practice in the clinic.
Prof. Gfeller and Prof. Villard will capitalize on a combination of state-of-the-art immunopeptidomics data, machine learning algorithms and clinical data to develop their predictor of recipient-donor genetic compatibility. This model is designed to learn from past transplantation outcomes, thereby continuously improving its predictive capability. The team plans to integrate their results with current medical knowledge to develop a robust tool that can be used directly in clinical settings to assist in making more informed donor selection decisions.
Wounding as a driver of cancer progression in basal cell carcinoma
This project takes a systems biology approach to see if wounding during surgical removal is a driver of basal cell carcinoma progression, and will explore its impact on novel therapeutic interventions.
Basal cell carcinoma (BCC) is the most frequent human cancer. While most BCCs can be resected surgically, a fraction of tumors progresses to an advanced invasive stage for which effective therapies are needed. We hypothesize that wounding is a key factor promoting BCC invasive progression and that understanding this mechanism will lead to improved therapies. Here we propose to i) characterize the mechanisms by which wounding drives BCC progression in terms of cancer cell plasticity, tumor microenvironment remodeling, and cell-cell interaction circuits; and ii) identify actionable molecular targets to reverse wounding-induced BCC progression and overcome therapy resistance. To this end, the multi-disciplinary research team will combine single-cell spatial transcriptomics profiling and ex vivo culture of patient-derived tumor fragments with computational methods development.
The project has the potential to reveal fundamental mechanisms linking wounding and cancer progression with relevance in cancer types beyond BCC and to improve the outcome of patients with advanced BCC where standard-of-care therapies currently fail.
Improving treatment for colorectal cancer to prevent metastasis
Colorectal cancer (CRC) is one of the world-leading causes of cancer-related mortality, and chemotherapy still is the mainstream treatment used for stage II and stage III CRC. The problem with chemotherapy is that in addition to killing cancer cells, it also attacks healthy tissues such as the gut and the liver. It is not yet known how chemotherapy alters the physiology and the susceptibility of these tissues. Recent research has shown that upon introduction of chemotherapy, there is a release of gut-derived bacterial metabolites. These metabolites have the ability to prevent liver metastasis by halting metastatic growth and reprogramming the immune vascular niche of the liver.
With this TANDEM project, Prof. Petrova and Dr. Koessler will collaborate to investigate the therapeutic and diagnostic potential of these findings in colorectal cancer patients. They aim to do this by analyzing the metabolites that get released in response to chemotherapy, by identifying the liver metastasis niche, and by examining the effect of the metabolites on patient-derived organoids (miniature versions of liver cultivated in vitro).
More specifically, they will:
- Profile the metabolites that are released in response to chemotherapy in CRC patients and relevant animal models.
- Characterize alterations in the liver metastasis niche in response to chemotherapy and gut microbiota components.
- Analyze how the released factors act on the growth of patient-derived organoids and metastasis formation in vivo.
This project will provide insight into how the response of organs to chemotherapy can directly influence patient outcome. The translational goal of this project is to address the current lack of biomarkers that could predict the sensitivity of chemotherapy in clinical practice. Ultimately, this could improve both diagnostic tools and therapeutic options.
Evaluation of the neoantigen-specific T cell response in pleural carcinosis managed by pressurized intrathoracic hyperthermic aerosol cisplatin chemotherapy (PITHAC)
Pleural cancer occurs outside the lungs, in the cavity between the lungs and the chest wall that contains a lubricating fluid, as well as along the pleural lining, a membrane surrounding the lungs and lining the chest cavity. Cancer in the pleural cavity has usually spread from somewhere else in the body, most commonly from lung cancer, but it can also come from the breast, ovary, pancreas, colon, or other locations. Given that pleural tumors are almost always metastatic and difficult to operate, prognosis is poor. One in four patients survives five years after diagnosis of pleural carcinoma. Fortunately, the incidence is low, affecting one in 2’000 cancer patients.
A novel therapeutic approach for pleural carcinoma combines localized, pressurized drug delivery with heat-induced immune stimulation, and goes by the name of PITHAC (pressurized intrapleural hyperthermic aerosol chemotherapy). It is thought that PITHAC triggers a tumor-specific immune response, yet its efficacy in pleural carcinosis remains poorly understood.
This novel project combines a clinician with expertise in the treatment of pleural carcinosis and a biochemical protein analysis expert. The aim is to determine if PITHAC induces novel antigens on the tumor cells, which in turn trigger a neoantigen-specific response in the immune system, notably in T-cells. By determining the antigenic landscape in the tumors of patients with pleural carcinosis, this study will determine if the mode of action of PITHAC includes the induction of a protective neoantigen-specific T-cell response. If so, it would then be reasonable to combine PITHAC with immunotherapies to make them more efficacious.
The researchers will apply this analysis to the patients enrolled in a Phase I clinical trial that started in 2023 at the CHUV. The trial will assess the feasibility and toxicity of PITHAC in pleural carcinosis patients, and during this trial blood and pleural fluid samples will be collected (after surgery and periodically for a month). The TANDEM grant will finance the analysis of these samples.
The novelty of this project is its longitudinal antigen discovery study, comparing patients before and after therapy, potentially facilitating the integration of PITHAC with immune checkpoint blockade inhibitors and enhancing the study’s translational impact.
Immunotherapy in malignant pleural mesothelioma
Primary pleural cancers such as the malignant pleural mesothelioma, a lung cancer related to asbestos exposure, are cancers that develop in the chest cavity. Mesothelioma is a devastating cancer of high unmet medical need, and its heterogeneous response to immune checkpoint blockade is the rate-limiting factor for improved treatment.
The project led by Profs. Peng and Ochsenbein and Dr. Schmid aims to discover novel immune targets and mechanisms of resistance to immunotherapy in mesothelioma patients. The work builds upon the present state of understanding of mesothelioma treatment, and by determining the variables that correlate with patient response, this study will pave the way for future innovative therapies.
Making use of a large cohort of 109 malignant pleural mesothelioma patients, they will identify the molecular and cellular determinants that correlate with a response to treatments that unblock the patient’s immune response against the tumor. They will use state-of-the-art molecular technologies that visualize the gene expression patterns in the cancer and in the surrounding tissues, cell by cell.
They hope to identify signatures that distinguish responsive from nonresponsive tumors. They will then compare the signature across sections of malignant pleural mesothelioma to determine the effects of the treatments on tumor cell behavior, examining not only the tumor but also the immune cell response to the treatment. To confirm what they will have learned from patient samples, they will then use mouse models of the disease, applying various inhibitors to the mice bearing human mesothelioma. Finally, they will combine immune checkpoint inhibitor therapies with effective inhibitors of growth, both in mouse models and eventually in patients.
The goal is to improve treatments against this devasting disease.
Improving the efficiency of immunotherapy for acute myeloid leukemia
Acute myeloid leukemia (AML) is a cancer that starts in the blood-forming cells of the blood marrow, and which results in the rapid death of the patient if left untreated. Formerly, treatment was based on chemotherapy followed by a hematopoietic stem cell transplantation. More recently, immunotherapy, which programs killer T-cells to attack the cancer cells, has been attempted. Unfortunately, even after intensive and aggressive treatments, a large portion of patients still relapse, and immunotherapy tends to attack healthy as well as leukemic cells. New, innovative treatments and approaches for AML are an urgent unmet clinical need.
To date, the search for AML-specific targets for targeting by cancer-killing CAR-T immune cells, has been unsuccessful. The scientists in this project are now trying a different approach by reversing the therapeutic concept. Their primary goal is now a complete eradication of the disease, including the leukemic stem cells (LSC), while protecting healthy hematopoietic stem cells from the immunotherapeutic attack. This should prevent relapse and overall improve patient outcome.
The TANDEM team, consisting of Prof. Jeker and Prof. Holbro, will investigate a potential “cloaking mechanism” that can be used to shield healthy hematopoietic stem cells from the agents that are used to kill the cancer cells. To do this, the scientists need a cell marker (cell surface protein) that is present on both the healthy and the cancer cells, and which they can modify genetically on the hematopoietic stem cells taken from the patient. The protected hematopoietic stem cells will then be re-introduced after AML therapy to regenerate the bone marrow, providing the altered protein does not prevent the cells from functioning normally. The AML-directed immunotherapy will be introduced into the patient and will only recognize the targeted marker on the cancer cells, since the healthy cells carry an altered or mutated marker. This could favor recovery, prevent relapse and improve efficacy of AML treatment.