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

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:

Project

Project

Development of a novel B cell-based vaccine for metastatic solid cancers

It is now well established that the immune system plays a very important role in controlling tumor growth; in fact, the remarkable results achieved in the past few years with the arrival of cancer immunotherapies and checkpoint inhibitors have clearly revolutionized the field of oncology and have dramatically changed the therapeutic scenario in many tumor types. Among the different cancer immunotherapies now available, cancer vaccines focus on the therapeutic use of a special type of immune cells called antigen-presenting cells (APCs). The main physiological role of these cells is to intercept and recognize pathogen-associated and foreign material (called antigens), and to subsequently initiate an immune response aimed at clearing the original antigen-containing threat from the host. Given the pivotal role played by APCs in orchestrating an immune response, it comes as no surprise that this type of cells has been employed since the infancy of modern cancer immunotherapy in the fight against cancer.

Canonical approaches have so far relied on the use of a special type of APCs called dendritic cells (DCs), which have long been considered the most potent type of APCs in the human body. However, despite proving generally safe and being associated with very mild collateral effects, DC-based therapeutic vaccines have so far demonstrated limited therapeutic efficacy. Mounting evidence now suggests that a second type of APCs called B cells present a valid alternative with several advantages. First of all, B cells can be obtained and expanded in large quantities from the human body, while cell availability often constitutes a limiting factor with DC-based vaccines. Contrary to DCs, B cells are also resistant to functional inhibition induced by tumor-produced factors, another aspect often limiting DC therapeutic efficacy. Several previous studies have also shown that B cells are indeed able to induce a potent and cancer-specific immune response.

Based on this collective evidence, our project focuses on developing a novel therapeutic vaccine against cancer, based on B cells. One of the first project goals is to manipulate and engineer B cells to express special receptors that increase their accumulation at the tumor site after infusion into the patient. This aspect is obviously crucial in improving their efficacy against their tumor targets and in limiting off-side and systemic effects. In a second phase, we will test our B cell vaccine formulation in combination with checkpoint blockade inhibitors, another promising immunotherapy with a different and complementary mode of action. Checkpoint blockade refers to specific pathways normally developed by tumors that inhibit T cell activities, exerting a sort of “break” on the function of the immune system and anti-cancer properties. Thus, combining these two therapies constitutes an interesting potential therapeutic option, in which B cells would activate the immune system (more specifically T cells) against tumor targets, whilst checkpoint blockade inhibition would remove inhibitory “breaks” on T cell function and unleash these cells’ true anti-cancer potential.

In the last part of this project and thanks to the infrastructure for translational studies available at the University Hospital of Lausanne and at the Ludwig Institute (Lausanne Branch), we will also develop protocols and tests for an efficient production of our B cell final formulation in a good manufacturing practices (GMP) context, so as to enable its future application in clinical studies and patient tests. The requirements for testing cellular therapies in patients (usually referred to as GMP conditions) are obviously very different and stricter than laboratory bench and animal research settings, and a great deal of work is usually needed to adapt therapy production in order to meet such requirements. Thus, the validation of the findings of this project in a GMP context will pave the way for future translational studies in cancer patients, and will potentially help advance both the therapeutic scenario and clinical outcomes.

Project Part 1

Project Part 2