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.

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.

Customizing treatment in cancer patients & uncovering cancer vulnerabilities

RAS proteins are among the most important members of the MAPK pathway, a signaling cascade relevant for cell growth and survival. Altered RAS genes (HRAS, KRAS and NRAS) represent the most frequently mutated gene family in human cancers, with KRAS being accountable for the development of roughly 35% of lung adenocarcinomas, up to 50% of colorectal cancers and even up to 95% of pancreatic cancers. Despite intensive research efforts, effective inhibition of mutated KRAS remains a major obstacle in the battle against cancer. The recent development of KRAS^G12C mutation-specific drugs has shed some light on this specific variant, but clinical success of these compounds is very limited, and first resistance mutations have already been reported. As these efforts in inhibiting KRAS have not been successful, the research focus has shifted towards the inhibition of MEK1/2, a regulator found downstream of the MAPK pathway. However, as resistance mechanisms are rapidly emerging, the notion that KRAS-mutated tumors remain unassailable persists. It is therefore of great importance to develop other strategies in the identification of cancer vulnerabilities.

In the era of precision medicine, strategies to confirm therapeutic efficacy and the identification of additional treatment options have become essential to both clinicians and patients. The functional tumor pathology group, led by Prof. Dr. med. Chantal Pauli and located in the Department of Pathology and Molecular Pathology at the University Hospital Zurich, has developed a platform incorporating the genetic features of individual patient tumors and the functional testing of patient-derived tumor organoids (PDTO). The overall goal is to identify effective therapeutic strategies for individual patients by performing a screen of cancer-relevant drugs. This approach has resulted in the identification of a novel synergistic drug combination involving a MEK inhibitor and a purine analogue. Interestingly, this synergy was not found in all tumor organoids, but was restricted to those with a mutation in the MAPK pathway.

This project will further examine the therapeutic potential of the identified drug combination in a larger cohort of PDTOs, and help to understand the genetic features responsible for this vulnerability seen in certain tumors. As resistance mechanisms against KRAS^G12C are arising, we plan to test if our combination is able to bypass the resistance mechanisms and affect the tumor’s viability. Ultimately, we seek to identify patients likely to benefit from this synergistic drug combination and elucidate mechanisms of patient-related drug sensitivities or resistances.

Project

Targeting novel molecular networks underlying bladder cancer recurrence and progression

Bladder cancer (BC) is a very significant world public health problem, in terms of prevalence, mortality, clinical management and cost. For most patients (around 70%), the disease is detected as a non-muscle invasive BC (NMIBC) at the surface of the bladder. For many years, it has been treated with BCG instillation and tumor resection within the bladder. This treatment is efficient, but most patients will undergo tumor recurrence and will necessitate several rounds of treatment over the years. The disease can also evolve into muscle invasive bladder cancer (MIBC, 30%). In these cases, the treatment consists in chemotherapy and bladder removal (cystectomy). Despite this radical treatment, the overall survival is low, with half of the patients not surviving beyond five years. Survival does not exceed 15 months when the disease is metastatic. In the last years, the tremendous success of immunotherapy has also led to some success in the treatment of MIBC. Immunotherapy, in this case, will restore the capacity of the immune system to fight the disease. 20 to 30% of the patients treated with antibodies blocking the PD-1/PD-L1 pathway showed a response to the treatment. But this rate of response is lower than in other cancer types and there is a clear need to understand why the patients do not respond to the treatment in order to improve and find new immunotherapeutic treatments.

In this optic, we plan to combine the expertise of our two research teams to decipher the molecular mechanisms driving BC recurrence/progression. We will carry out studies directly in patient samples and in a genetically engineered mouse model (GEMM) of BC that recapitulates the human BC tumor progression stages. Furthermore, we will dissect and validate novel therapeutic axes and biomarkers in this GEMM, in view of phase I/II clinical trials in BC patients to improve patient survival.

Preliminary genetic studies on primary and recurrent tumor tissues of a cohort of 12 BC patients led to the discovery of a gene signature associated with BC progression/recurrence. In our study, we will focus on two pathways found in this signature that can be targeted to improve tumor control/elimination. We validated that these two pathways were higher in recurrent versus non-recurrent tumors in a larger cohort of 36 patients. This same gene signature was also detected in the progressive stage of our BC GEMM, confirming the known clinical relevance of this model. Based on these findings, we hypothesize the existence of a therapeutically targetable crosstalk between immune and BC cells that involves the studied genes and their regulation.

Understanding how clonal hematopoiesis feeds lymphoma

Patients with lymphoma who do not respond to treatment have a bleak outcome. Annually, over 1100 patients die with leukemia and lymphoma in Switzerland. Lymphoma can arise when the DNA inside a lymphocyte changes in a way that prevents the lymphocyte from responding to signals that usually keep it under control. To outgrow and disseminate, lymphoma hijacks normal inflammatory cells to acquire protection and nurturing, while at the same time deceiving them by hiding from their attack. Inflammation may be age-related and can foster manifestations such as clonal hematopoiesis or can be sustained by chronic infections of the lymphoma cell itself.

The new avenues of lymphoma therapy rely on a combination of approaches that target both tumor cells and the supporting host environment, including: i) repairing the operative system inside lymphoma cells, which can be achieved by using small molecules that precisely identify and attack the factors that led to its failure; ii) reverting the stunned inflammatory cells from lymphoma feeders to lymphoma predators. The experiments will also allow us to understand how aging-related inflammation facilitates lymphoma development. We aim to understand how aging of the normal immune functions (designed to cause inflammation) modulate the tumor and the surrounding immune system. Single cell resolution now puts us in the unique position to track the aging of cells of the immune system (locally and globally) and to connect them to the behavior of cancer cells. We will use this knowledge to develop strategies to engage the healthy immune compartment in the fight against the tumor. This is of particular interest as the advent of multiple immunotherapy approaches puts increasing emphasis on the efficacy of drugs on immune responses or the fitness (exhaustion) of the anti-tumor response.

Project

Patient and healthcare provider experience in adoptive cell therapies: An experience-based co-design study

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) or chimeric antigen receptor T-cells (CAR-T) is a new and rapidly growing strategy in the field of cancer therapies. It aims to enhance a patient’s anti-cancer response by delivering specific anti-tumor immune cells. The fact that the procedure involves multiple professionals adds complexity to the care delivery, for both patients and healthcare providers (HCP). Patients’ experience and specific needs during these novel and particularly demanding therapies have not been examined so far.

Person-centered care (PCC) has been identified as one of the six main drivers of health care quality, in addition to safety, effectiveness, efficiency, as well as timely and equitable care. PCC approaches rely on building a provider-patient partnership relationship, improving communication techniques, and encouraging patients to actively participate in patient-provider interactions.

Experience-Based Co-Design (EBCD) is a multi-stage process that uses qualitative research methods to engage HCPs and patients in co-designing healthcare services. EBCD facilitates a high level of patient and HCP engagement, enables discussions about difficult topics in a supportive environment, leads to the identification of improvement priorities, and results in meaningful changes in how services are delivered with an impact on patient experience.

The overarching goal of this study is to investigate and improve the current delivery of care during TIL and CAR-T cell therapies by examining the experiences and perspectives of patients and HCPs across the treatment trajectory. Specifically, we aim to:

Exploring the role of neutrophils in brain metastasis

The development of metastases unfortunately remains the leading cause of death in cancer patients. Of all metastatic cancers, those invading the brain represent a particularly difficult challenge to treat. Brain metastases (BrM) frequently arise from melanoma, lung and breast cancers. Although considerable advances have been made in treating these cancers at the primary site, a steep increase in mortality is observed in patients who develop BrM. This is partly due to our limited knowledge about the BrM tumour microenvironment (TME), which directly translates into a lack of clinical treatment options.

While the importance of immune and stromal cells in the TME in shaping a favourable environment for tumour growth is well-established, much less is known about the complexity of these interactions during metastasis. This is particularly true for BrMs, where the unique properties of the brain create an environment that is very different to other organs. By comprehensively analysing the TME in diverse brain tumour patient samples, we recently identified neutrophils, the most numerous circulating white blood cell population in humans, as among the most abundant immune cells infiltrating BrM specifically.

The aim of this project led by Prof. Johanna Joyce (Department of oncology, UNIL,
Ludwig Institute for Cancer Research Lausanne), is to unravel how neutrophils may functionally contribute to the colonisation and metastatic outgrowth of cancer cells in the brain. It represents the first in-depth study of neutrophil phenotypes and functions in BrM patients and preclinical models.

The rigorous and integrated experimental strategy devised by the Joyce lab, including both mouse models and human tissue analyses, will provide the first comprehensive view of how neutrophils may regulate metastatic progression to the brain. Neutrophils have generally been associated with poor prognosis in cancer patients, but have also been found to serve opposing functions in other metastatic settings, specifically breast-to-lung metastasis, in a context-dependent manner. By contrast, the role of neutrophils in the context of BrM remains virtually unexplored. Thus, a rigorous analysis of their functions in BrM is urgently needed. The combination of functionally analysing neutrophils in human BrMs and utilising state-of-the-art murine BrM models represents a comprehensive strategy to explore neutrophil education by brain-colonising cancer cells. Critically, these data will reveal how neutrophils in the periphery and the brain TME evolve with, and contribute to, the progression of metastatic cancers. Regardless of whether we discover neutrophils to be tumour-supporting or tumour-suppressing in BrM, this is an essential question to answer, which we are uniquely capable to address.

This project will significantly enhance our understanding of neutrophil functions in metastasis and may have important implications for devising therapeutics to target the BrM TME in the future. The cancer immune-microenvironmental perspective of this project additionally addresses a topic of intense focus at present, as different immunotherapies are rapidly advancing to first-line treatments for many cancer types. However, patients presenting BrMs have been largely excluded from clinical trials, resulting in a critical lack of knowledge for how novel treatment modalities might specifically affect or benefit intracranial metastases. Thus, the advance in knowledge that we expect to achieve through this ISREC-funded project will provide the necessary bridge linking fundamental research on BrM tumour immunity to answering essential clinical questions.

Project