By Dr Sheena Meredith
A new technology platform developed by researchers in Scotland could boost the number of tests that can be performed on a solid tumour sample by up to 50 times. The technique could enable large-scale testing of immunotherapies, and accelerate the development of novel cancer treatments, its developers said.
The team, from the universities of Strathclyde and Glasgow, the Technology and Innovation Centre in Glasgow, and the Cancer Research UK Beatson Institute in Glasgow, explained that while chimeric antigen receptor-T (CAR-T) cell immunotherapies have been “remarkably successful” in the treatment of haematological malignancies, using cellular immunotherapy to treat solid tumours has been more challenging.
Widespread application of CAR-T therapy has been hampered because of high manufacturing costs of CAR-T cell production, which requires an autologous acquisition process from patients. In addition, off-target toxicity can trigger serious or even life-threatening therapy responses.
A Window Into The Solid Tumour Microenvironment
Attempts to use CAR-T cell technology on solid tumours have been further hindered because the immunosuppressive tumour microenvironment comprises various cell types that release an assortment of cytokines, chemokines, growth factors and immune checkpoint molecules that aid tumour growth, all of which impede CAR-T cell infiltration into the tumour and lessen the effectiveness of CAR-T therapy. As an example, cancer associated fibroblasts are known to inhibit T- cell access to tumour cells and, while largely neglected in in vitro CAR-T models, are implicated in the outcomes of many therapies.
Research leader Dr Michele Zagnoni, a reader in Strathclyde’s Department of Electronic and Electrical Engineering, explained: “There are particular challenges with evaluating solid tumours, not just cancerous cells but those surrounding them.”
To enhance the anti-cancer effect of CAR-T therapy, several trials have investigated combining chemotherapy and immune checkpoint blockade to create a more hospitable immune microenvironment for CAR-T cells, and thus facilitate CAR-T tumour infiltration. Many combination treatments and CAR-T designs could be tested in vitro; however, the existing means to evaluate potential anti-cancer treatments for solid tumours to rely either on traditional 2D in vitro models, which fail to reproduce the complexity of the tumour microenvironment, or in vivo models, such as patient-derived xenografts, which are costly and labour intensive.
New Miniaturised Screening Platform Developed
To overcome these challenges and facilitate large scale testing, the team developed a miniaturised platform for screening 3D tumour models, which are significantly better than 2D models at reproducing what happens in the tumour microenvironment and in evaluating the toxicity of CAR-T therapy towards cancer cells. They used a triple-negative breast cancer (TNBC) model, as this tumour is highly aggressive with currently few successful therapeutic options.
In their study, published in the IEEE Open Journal of Engineering in Medicine and Biology, they reported that the platform, a novel proof-of-concept microfluidic immunoassay, enabled visualisation and quantification of how CAR-T cells rapidly targeted, broke up and killed cancer cells without causing significant harm to other cells.
Dr Zagnoni said: “We are developing a technology platform that could accelerate the development of therapies and provide models that are much more representative of what happens in the body than what is currently available.
“We are providing a platform for labs to conduct tests before proceeding to clinical trials, which uses fewer resources and can scale up cost-effectively.
“CAR-T cell development is expensive and patient-derived tissue is a limited resource. Our aim is to enable 20 to 50 times more experiments to be performed in these conditions.”
In addition, their model for the first time assessed treatments that mimic clinical TNBC regimens, consisting of various combinations of carboplatin chemotherapy and anti-programmed cell death ligand 1 (anti PD-L1) therapy, since combination therapy is more efficacious in TNBC than individual monotherapies in terms of progression-free and overall survival. They showed that combination treatment also influenced CAR-T cell-mediated cytotoxicity in the 3D microfluidic models and that, compared with monotherapies, CAR-T killing and targeting of cancer cells was enhanced in the combination studies.
‘A Huge Opportunity for Cancer Medicine’
“Combination therapies represent a huge opportunity for cancer medicine, and this technology will aid pharma companies’ efforts to look for new treatments,” the team said.
“This proof-of-concept work offers evidence of how the microfluidic platform and protocols can provide powerful, cost-effective and miniaturised in vitro assays to preclinically assess CAR-T cell therapies.”
Cancer Research UK research information manager, Dr Claire Bromley, told Medscape UK: “Understanding how well certain immunotherapies might work for people with cancer and how to improve their effectiveness is crucial. Though this research is at an early stage, this new tool could give scientists a far greater testing capacity, allowing them not only to see when therapies are likely to work, but also to test new combinations so that people with cancer receive the treatment that is most likely to be successful. This will help scientists refine the drug discovery process and get treatments from bench to bedside faster.”
The research received funding from AMS Biotechnology Europe Ltd (AMSBIO). The technology will now be commercialised by ScreenIn3D, a pre-spinout company co-founded in 2018 by Dr Zagnoni and established with the support of Strathclyde University’s IP & Commercialisation team.