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

Mechanisms and therapeutic targeting of the neuronal NMDAR signaling pathway promoting breast cancerpathogenesis

The research will focus on elucidating pathogenic mechanisms and exploring innovative therapeutic targeting strategies for breast cancer. The focus will be on a neuronal signaling pathway – centered upon the NMDA receptor (NMDAR) – that the Hanahan lab discovered to be hijacked by cancer cells to enhance invasion and metastasis, the hallmarks of malignancy that cause cancer mortality. The NMDAR’s role in cancer pathogenesis was initially discovered and described in 2013 (Li & Hanahan, Cell), and further characterized in 2018 (Li, Zeng et al., Cancer Cell), principally in pancreas cancer. Then in 2019, the role of NMDAR signaling in the metastasis of breast cancer to the brain was established in a major article in Nature (Zeng et al.). Unpublished data from the Hanahan lab suggest that the NMDAR may also be hijacked in certain primary breast tumors and in metastasis to other sites. Simge Yücel will use mouse models of breast cancer in conjunction with analysis of human breast cancer biopsies to pursue the following lines of investigation:

These lines of investigation are likely to reveal new opportunities, which will be incorporated in the research.

References

• Li, L., & Hanahan, D. (2013). Hijacking the neuronal NMDAR signaling circuit to promote tumor growth and invasion. Cell. 153: 86-100.
• Li, L., Zeng, Q., Bhutkar, A., Galvan, J., Karamitopoulou, E., Noordermeer, D., Peng, M.W., Piersgilli, A., Perren, A., Zlobec, I., Robinson, H., Iruela-Arispe, M.L., & Hanahan D. (2018) GKAP acts as a genetic modulator of NMDAR signaling to govern invasive tumor growth. Cancer Cell, 33: 736-751.
• Zeng, Q., Michael, I.P., Zhang, P. Saghafini, S., Knott, G., Jiao, W., Brian D. McCabe, B.D., José A. Galván, J.A., Robinson, H.P.C., Zlobec, I., Ciriello, G., and Hanahan, D. (2019). Synaptic proximity enables NMDAR signaling to promote brain metastasis. Nature, 573: 526-531.

Transcriptomic and phenotypic profiling of the white blood cells in breast cancer

Despite considerable improvements in breast cancer management, approximately one in four patients still die due to metastases. In order to decrease this mortality, the disease needs to be diagnosed as early as possible, and metastases must be prevented or treated effectively. Studies we have conducted show that the presence of breast cancer alters quantifiable phenotypic and transcriptomic characteristics of white blood cells (leucocytes) circulating in the blood. These results suggest that it may be possible to exploit these changes in the leucocytes circulating in the blood to reveal the presence of primary breast cancer (screening) or a relapse (monitoring).

The aim of our project is to generate additional data supporting these observations. To this end, we will use novel approaches and technologies (single cell RNA sequencing and multi-parameter analysis of the cell surface). We plan to compare first-diagnosis female patients with healthy women, and patients at the time of the first relapse after therapy with patients not having suffered a relapse. We will investigate the three biological subtypes of breast cancer (ER⁺, HER2⁺, triple negative). This multicentric study, conducted in the Lake of Geneva area, will be coordinated at the CHUV in Lausanne.

A 20 ml blood sample will be taken for the following lab tests: i) leucocyte phenotyping by flow cytometry; ii) transcriptomic analysis and phenotyping by single cell RNA sequencing, followed by bioinformatic analyses. The lab tests will be conducted at the University of Fribourg, the sequencing at the Genomic Technologies Facility of the University of Lausanne (LGTF) and the bioinformatic analyses at the Swiss Institute of Bioinformatics (SIB).

We hope that these analyses will help us validate our preliminary observations more precisely and that we will be able to identify candidate biomarkers (cells, phenotypes, gene expression) and combinations associated with primary breast cancer or the first relapse.

This study is part of a long-term goal to develop a cancer screening blood test and a monitoring blood test for early detection of relapses. The practical implications of these tests are potentially significant: the tests could contribute to changing the way women are screened and patients monitored, thereby greatly improving the quality of life of women in general (screening) and of breast cancer patients (monitoring). From a clinical point of view, the monitoring test would be a valuable new tool that could help support therapeutic choices in the treatment of breast cancer.

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

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