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.

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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:

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