When asked to define what a doctor means by a “drug”, most of us describe a chemical compound that has been extracted from a leaf or made from scratch in a laboratory. Recent research, particularly within the field of cancer, has shown that scientists are now able to engineer a patient’s own cells to make a “living drug”. This process involves artificial introduction of a known molecular entity, or chimeric antigen receptor (CAR), into immune cells using a viral-like case. The deactivated virus contains a sequence that allows the CAR to become present on the surface of the cell. The newly engineered cell is now able to specifically recognise, fight, and destroy the tumour, leaving healthy tissue unharmed.
Immune cells come in all shapes and sizes, from those that simply “gobble up” bacteria (such as macrophages) to those who are more specialised (such as T cells). T cells develop in the thymus and play a vital role in the second layer of immune defence, particularly against viral infection and cancer. In normal physiology, T cells circulate in the blood, scanning for infected or ‘stressed’ cells. However, in cancer, tumour cells may be hidden by excess ‘netting’ and/or lack of blood supply. As such, advances in immunotherapy have focused on improving T cell movement into tumours, preventing growth of “bad” T cell populations and engineering “good” T cells to enable them to recognise damaged cells.
Under normal conditions, T cells recognise a damaged or infected cell through its T cell receptor (TCR) (Fig. 1). On the surface of every cell in the body, there is a molecule known as MHC-I which enables T cells to bind to the cell. However, the T cell will only remove the damaged cell if an extra protein sequence (peptide) is present.
Peptides may be cancer-specific (containing mutations) or simply fragments of “normal” protein, which is abnormally abundant within a cancer cell. Either way, immature T cells must be trained to recognise unhealthy cells.
Interestingly, the body is great at creating mature T cells that fight viral infection but finds it more challenging to create those that fight cancer. This is because cancer is a disease of our own cells and therefore the danger signals, recognised by the T cells, are much subtle if at all distinguishable from normal, healthy cells. Hence, scientists have strived to genetically engineer the patient’s own T cells in order to artificially train the T cells to recognise the MHC-peptide molecules, specific to cancer cells. This is known as CAR-T therapy.
Figure 1 T cell interaction with a cancer cell T cells recognise cancer cells through their TCR which binds to major histocompatibility complex (MHC)-peptide complex. (Diagram made using Biorender.com)
By using a patient’s own immune cells, scientists minimise the risk of the body rejecting the new (and improved) immune cells despite the genetic changes that are carried out in the lab. CAR-T therapy relies on identification of one highly expressed target which is present on all cancer cells in a tumour. Blood cancer, such as that of B cells (another immune cell subtype), is known to express the molecule, CD19, on its surface and therefore this cancer type can be targeted with engineered T cells who’s TCR (or CAR) recognises CD19 (Fig.2). However, CAR-T therapies have shown limited clinical success in targeting solid tumours. This is because many cancers are composed of heterogenous populations of cells, meaning not all cells in the tumour have the same cocktail of molecules on their surface. This means that one type of T cell would be insufficient to target all of the cancer cells in a patient. Ineffective treatment like this would likely result in cancer relapse and disease progression and development of metastases (secondary tumours in other organs from the primary site).
Figure 2 Schematic of CAR-T therapy for B cell cancer patients CAR-T therapy involves genetically engineering a patient’s own immune cells to recognise a molecule, which is only present on the surface of the cancer cells. Removal of the patient’s own immune cells, or leukopheresis, is followed by genetic engineering using an inactivated virus to transfer genetic material into the T cells. This allows a CAR to be expressed on the surface of the T cells before they are re-infused into the patient. Chemotherapy is required to prevent subsequent destruction of the newly-synthesised T cells. CAR-T cells are able to divide in the patient and therefore continue to attack the cancer with minimal additional treatment, providing a long-lasting anti-cancer effect (Fernandez, C. R., 2019).
Recent research by scientists at Cardiff University (Crowther, M. D et al., 2020) has described another TCR, known as MR1, which has been shown to enable T cell-mediated attack on prostate, ovarian, breast, skin and lung cancer cells which have been grown in the lab dish (in vitro). This research also showed that engineered T cells remained viable in the blood for extended periods of time and were able to destroy implanted leukaemia cells in a mouse (in vivo). However, fellow researchers have stated, “this is very basic research and not close to actual medicines for patients.” Nevertheless, “there is no question that it’s a very exciting discovery, both for advancing our basic knowledge about the immune system and for the possibility of future new medicines.” (Daniel Davis, University of Manchester – as reported by the BBC). Theoretically, this work suggests that engineering MR1 into a patient’s T cells could promote recognition of several, distinct solid tumour types and hence improve cancer treatment options for a huge number of patients. However, future studies are required to understand what peptide(s) this TCR recognises and whether these T cells are capable of destroying solid cancer types in vivo.
References:
Callagher, J. (2020) Immune discovery ‘may treat all cancer’ BBC News (https://www.bbc.co.uk/news/health-51182451)
Crowther, M. D et al (2020) Genome-wide CRISPR–Cas9 screening reveals ubiquitous Tcell cancer targeting via the monomorphic MHC class I-related protein MR1 Nature Immunology 21:178–185 (doi: 10.1038/s41590-019-0578-8)
Fernandez, C. R. (2019) A Cure for Cancer? How CAR T-Cell Therapy is Revolutionizing Oncology (https://www.labiotech.eu/car-t/car-t-therapy-cancer-review/)
Featured image: The Scientist Magazine Online (Exploring Life, Inspiring Innovation)
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