NHS Research Time Award

Since commencing my consultant post in January 2022, I have been active in establishing links with regional and national haematology/oncology centres, to develop research opportunities and a clinical service for patients developing neurotoxicity in the context of novel cancer immunotherapy (immune checkpoint inhibitors (ICPI) and Chimeric Antigen Receptor T cells (CAR-T cells)). Since Cardiff is the only place in Wales (Cardiff & Vale NHS Trust, Velindre University NHS Trust) to offer all of these highly specialist treatments, there is a unique opportunity for much-needed development in this burgeoning area of oncology/neurology.

Rationale

1. Immune checkpoint inhibitor therapy

Immunotherapy with monoclonal antibody ICPIs has had a profound effect on cancer treatment and survival with an exponential increase in their use since 2014, with per patient costs of tens of thousands of pounds. ICPIs allow T-cell destruction of cancer cells but despite their clinical effectiveness, toxicity is common and potentially life changing/threatening. Neurotoxicity occurs in up to 6% of patients and can affect both the central and peripheral nervous systems including myositis, myasthenia, Guillain-Barré-like syndromes, autoimmune encephalitis and aseptic meningitis. Currently there is a limited evidence base for management, but current approaches involve ICPI cessation and treatment with steroids, which adds additional treatment-specific risks and the potential to affect cancer-related outcomes. Several areas regarding neurotoxicity urgently need addressing:

1. Identification of predisposing risk factors/biomarkers
2. Understanding the underlying mechanisms
3. Identifying optimal management strategies
4. Indications for recommencement of immunotherapy after cessation
5. Effects of different treatment strategies on cancer outcomes
6. Economic impact of failed treatment

2. Chimeric Antigen Receptor T cell therapy

CAR-T cells have been used in the UK since 2019 and are currently licensed for use in a limited number of haematological malignancies. CAR-T cell therapy can eliminate disease where previous chemotherapy has failed, representing a significant breakthrough in treatment. The cost of individual treatment is approximately £250,000 and again, despite the clinical effectiveness, there are significant considerations around neurotoxicity. In particular, Immune effector cell-associated neurotoxicity syndrome (ICANS) can occur in up to 70% of patients, presenting as a continuum from tremor to cerebral oedema, and death in a minority of cases. Similar to ICPI therapy, several research questions urgently need addressing. Although the number of CAR-T treated patients is currently relatively small, this is expected to significantly increase as its use expands to other haematological malignancies and indications.

Aims and objectives of the research time award

1. Develop and submit one or more application(s) for competitive grant funding as a lead/co-applicant. Current applications in development include:

a) Neurocognitive outcomes in patients receiving CAR-T therapy. Aim to understand the mechanisms underlying acquired cognitive impairment in this population by introducing routine cognitive screening via an existing, NIHR-funded, validated web-based platform. Collaborators: Dr Keith Wilson, Dr Emma Tallantyre (Cardiff), Prof Roshan das Nair (SINTEF, Norway)

b) The bone marrow microenvironment as a driver of neurotoxicity associated with CAR-T cell therapies. Combine neurocognitive outcomes with biomimetic models of the bone marrow microenvironment and leucocyte migration, along with cytokine biomarkers, to investigate the pathophysiology of ICANS. Collaborators: Dr Claire Rice (Bristol), Dr Joanna Zabkiewicz, Dr Emma Tallantyre (Cardiff)

2. Develop a neurotoxicity arm within a planned (currently unfunded) clinical trial with Cardiff as the lead centre.

a) PORTRAIT: PlatfORm TRiAl of Immunotherapy Toxicity

Evaluate strategies to optimally manage neurotoxicities. Including routine collection of clinical data and patient samples to establish a disease registry and biobank to develop local, national, and

international collaborations. Collaborator: Prof Richard Adams (Cardiff)

3. Produce a national case-series and systematic review of ICPI-related neurotoxicity.

4. Develop a specialist Welsh national clinical service to manage patients with immunotherapy-related neurotoxicity.