Current treatments fail to cure many children with solid cancers. recent advances in adult cancers such as checkpoint blockade and targeted small molecules have made little impact in childhood cancer.
Engineered T-cell therapies can achieve durable responses in refractory lymphoid cancers without long-term toxicity. These are precisely the characteristics required for new treatments for pediatric solid cancers.
In contrast to blood cancers, solid cancers are challenging due to a lack of targets, tumour heterogenity, and hostile tumour microenvironment (TME). We propose that through advanced cellular engineering we can overcome these challenges.
To identify suitable targets for engineered T-cells to recognise.
As cancer vulnerabilities differ between childhood and adult tumours, novel targets for cell therapy in children are urgently needed.
We will use mass spectroscopy and chip cytometry to discover and explore surface antigens which can be used to selectively target pediatric solid cancers. As well as traditional surface proteins, we will also explore membrane abnormalities, peptide/major histocompatibility complex (MHC) and so called “dark antigens”.
This work will allow us to strategically select the optimal targets for several paediatric cancer types, which will facilitate subsequent receptor development in work package 3.
To understand the tumour microenvironment (TME) in childhood solid cancers.
The TME is a complex multicellular milieu that can enable tumours to resist treatment and is a major barrier to T-cell therapy.
By using a novel tissue chip cytometry approach, we will characterise the TME so we can engineer our therapeutic T-cells to survive and adapt to it to make tumours more vulnerable.
This work will guide us to intelligently engineer T-cells in work package 3 to resist and modulate the TME.
To develop receptors and other engineering components which target tumour cells and resist or adapt to the TME.
Most components of immune-cell engineering are designed for adult cancers, which have well-known antigens, mutations and immune-evasion strategies, and are fundamentally different from childhood cancers.
We will develop novel engineering components for targeting the antigens identified in Work Package 1, to increase cell therapies’ potency and to develop the ability to resist the TME. Protein engineering methods will be used.
The most promising engineering components will result in novel artificial receptors that will be co-expressed in T-cells and evaluated in preclinical tumour models in work package 4 and ultimately in the clinic in work package 5.
These engineering components will be available for incorporation into therapeutic T-cell strategies by the entire community.
To evaluate the function of engineered T-cells developed in Work Package 3.
Most existing models of paediatric cancer do not incorporate the immune environment, meaning testing cell therapies is often difficult and largely uninformative.
We will integrate multiple engineering components to generate advanced T-cells; we will test these T-cells in novel models mainly on intact tumour samples such as tumour-on-a-chip and immune patient-derived xenograft (PDX) models. In addition, we will explore use of mathematical models and machine learning to select the optimal design for clinical testing.
We will test and develop T-cells engineered in complex ways. The most promising engineering strategies will be fed into work package 5 for clinical translation.
The functional data obtained from this work will be available for incorporation into therapeutic T-cell strategies by the entire community.
To translate approaches from Work Package 4 and test them in clinical studies designed for maximal impact.
We will launch three innovative phase 1 clinical studies testing engineered immune cells with clinical studies designed in ways to accelerate development of complex cell therapies. Clinical product generation will involve autologous closed system semi-automated manufacturing.
Synergy between these initial clinical studies and work in work packages 1-4 will allow the development of a refined engineering strategy (building on the initial clinical strategy) that we expect to have break-through potential.
Clinical study data should lead to registration studies, improving cure rates and overcoming the issue of long-term toxicity in order to realise our vision.
To promote data sharing across all Work Packages.
This is an over-arching work package which integrates, analyses and exploits data generated from the entire programme. This will be achieved by using standard and custom databases and data sharing platforms. Tumour target and TME data from Work Package 1 and 2 will be uploaded to these databases.
This article entitled “Co-opting signaling molecules enables logic-gated control of CAR T cells” was published in March 2023.
NexTGen scientists and advocates feature in this article relating to the changing face of the landscape of the childhood cancer sector.
Professor Bertozzi is part of NexTGen work package one, which aims to discover targets for childhood solid tumours.