CAR T-cell therapy is a revolutionary technology in which patients’ own immune cells are reprogrammed so they can recognise and destroy cancer cells. This has proven to be a powerful therapy for refractory blood cancers but has not yet been very effective for the treatment of solid cancers. At Leucid Bio we are developing a proprietary engine that builds upon Dr Maher’s novel CAR-T model which develops CAR-T molecules designed to be in a more natural biological configuration of cells. Our technology gives properties to the CAR-Ts that enable them to consistently outperform previous generations of CAR-T therapies in pre-clinical studies; enhancing T-cell potency and generating a persistent long-term response with reduced toxicity.
What is CAR T-cell therapy?
CAR T-cell therapy is a pioneering technology involving the reprogramming of patients’ own immune cells. As cancer cells have evolved from a patient’s own healthy cells they are able to hide from our immune system. Modifying immune cells with Chimeric Antigen Receptors (CARs) enables the immune cells to recognise and destroy the cancer cells.
CARs contain an antigen binding domain for recognition of tumour cell targets, and a signalling domain, which instructs the cells to attack. Expression of a CAR in a type of an immune cell, called a T cell, produces CAR T-cells which thereby acquire the ability to find and destroy cancer cells.
To produce a CAR T-cell product, a blood sample is collected. In the lab the immune cells are extracted and genetically engineered to express the CAR construct. The resulting CAR T-cells are now equipped to recognise and attack cancer cells. The CAR T-cells are expanded in the lab until there is a sufficient dose, before being infused back into the patient’s blood stream. The CAR T-cells travel around the blood until they meet tumour cells which they are now able to eliminate.
Treating solid tumours with CAR T-cells
CAR T-cell therapy has proven to be a powerful therapy for refractory blood cancers. However, the most common cause of cancer deaths worldwide are solid tumours, for which CAR T-cell therapy currently has little clinical benefit. Solid tumours represent 90% of cancers, and are fast becoming the leading cause of death in the Western world. Consequently, it is evident that there is a clear unmet need for more effective treatments for these cancers. Progress within the solid tumour field has been hampered due to the multiple defence mechanisms employed by the tumour cells, thus insulating them both from conventional treatments and from gene and cell therapies.
What are we doing?
At Leucid Bio we are developing improved CAR T-cell technologies that produce better and more durable responses than previous CAR-T generations. Our dedicated team of researchers use an integrated approach to overcome key challenges in CAR-T cell treatment of solid tumours, aiming to realise the full potential of this cutting-edge therapy for patients.
Leucid's integrated approach brings together a novel lateral CAR T platform and additional CAR T cell 'armour' to overcome key challenges in CAR T cell treatment of solid and blood tumours, including:
Lack of suitable targets: A suitable target must be chosen for CAR T-cells to recognise and attack tumour cells. Unfortunately, solid tumours share many surface proteins with healthy cells. We are working with a highly specific yet extensive set of targets which recognise 80% of cancers with minimal toxicity.
Tumour microenvironment: The hostile, immunosuppressive tumour microenvironment makes it difficult for immune cells to thrive and survive to successfully destroy tumours. Our parallel CAR technology overcomes this with improved potency and serial killing.
Poor trafficking and tumour infiltration: CAR T-cells must be able to find the tumour and must survive long enough to reach it and attack the cancer cells. Our lateral CAR technology improves CAR T-cell persistence so they can survive in the blood for longer periods of time. Additional ‘armour’ directs our CAR T-cells specifically to the tumour site.
Our improved, faster and scalable manufacturing platforms allow rapid translation of these technologies to the clinic.
Parallel CAR (pCAR) platform
Previous generations of CAR T-cell therapies built on the original concept of linear fusion:
First generation CAR-T therapies consist of an activating motif such as CD3ζ alone joined to a single targeting domain
Second generation CAR-T therapies consist of CD3ζ fused to one costimulatory domain and a single targeting domain
Third generation CAR-T therapies consist of CD3ζ fused with two costimulatory domains and a single targeting domain
The clinical success of CAR T-cell therapy against haematological cancers has largely resulted from the transition from the original first generation CARs to second generation CARs. However, despite the success of second generation CAR T-cells, only marginal improvement in T cell activity was seen with third generation CAR T-cells, highlighting the sub-optimal nature of the linear arrangement.
Leucid Bio’s lead asset is based on a novel CAR structure, dubbed ‘parallel CAR’ (pCAR), in which two costimulatory domains are integrated in parallel across the cell membrane. This formation replicates the natural side-by-side position of these molecules across the cell membrane that is seen in endogenous immune receptors. The resulting pCAR T-cells consistently outperform previous generations of CAR T-cells in pre-clinical studies, enabling better control over T cell activation, superior anti-tumour activity, and a favourable toxicity profile.
The increased efficacy of pCAR T-cells compared to previous CAR T-cell generations can be envisioned using an analogy of batteries within an electrical circuit: If two batteries (i.e. two costimulatory domains) are placed in a linear series arrangement, they fail to increase the capacity of an electrical circuit (the T cell), whereas placing two batteries in parallel increases the capacity of the batteries to impact the target component (the cancer cell).
NKG2D CAR T-cell therapy
Leucid’s LEU-011 programme is a NKG2D CAR T-cell therapy in pre-clinical development for the treatment of solid tumours and haematological malignancies. The NKG2D receptor is an activating immune receptor that triggers cell death upon recognition of human NKG2D ligands expressed on transformed, infected or damaged cells. LEU-011 has potential for the treatment of multiple cancer types as NKG2D ligands are expressed on more than 80% of human tumour cells.
T2, gd T-cells for off-the-shelf cell therapy
gd T-cells possess many traits that make them an attractive option for adoptive cell therapies. Unlike ⍺β T cells, their TCR is not HLA restricted permitting the development of allogeneic or off-the-shelf strategies. Additionally, gd T cells have an innate ability to detect the early stages of cellular transformation. Leucid has developed a patented technique to generate a distinct population of gd T-cells from the peripheral blood of a healthy donor. We call this platform T2. gd [T2] cells have enhanced potency and can be armoured to further boost the anti-tumour response.
Novel Manufacturing Platforms
Leucid Bio’s innovative IL-4 based selective CAR T-cell expansion approach which is being used in the T4 trial means CAR T-cell batches can be manufactured from a single blood draw instead of leukapheresis. This is less invasive for the patients, and allows for simplified and centralised manufacturing, reducing risks and costs. We are the only team able to produce effective CAR T-cells using this method, and we have not experienced any batch failures from the 18 patients treated to date, despite lymphopenia (low T cell counts) in most of the patients.
T4 is one of the first CARs that we developed and recognises 8 distinct molecular targets. These targets are homo- and heterodimers formed by the ErbB receptors. Aberrant expression and/ or function of the ErbB family is prevalent in a diverse range of solid tumours making it an ideal target for CAR T cells. T4 is polyspecific therefore it is difficult to conceive how a tumour could evade recognition by antigen down-modulation, which is one of the main causes of relapse after CAR T-cell therapy.
To date, we have treated 18 patients on the T4 trial, at doses of up to 1 billion CAR T-cells and have not yet experienced any dose-limiting toxicities. Patients suffering with untreatable head and neck cancer succumb to their disease within 30 weeks on average, while following T4 treatment 10 patients have achieved stable disease.