With new breakthroughs in cell therapies, Dr Diana Hernandez, Senior Research Scientist and Immunotherapy Group Leader at Anthony Nolan, explains the science behind these treatments, and how Anthony Nolan’s Cell & Gene Therapy Service is looking to support them.
Having worked in the stem cell field for many years, it is truly exciting to see the recent paradigm shift from medical treatments being solely based on chemical compounds, to alternatives based on cells which have been manipulated in vitro.
But cell therapies aren’t new
The use of cells as therapy is not necessarily new; hematopoietic stem cells have been used to restore the immune system of patients who have either suffered from a blood cancer or have been born with a blood disorder or immune deficiency. At Anthony Nolan, we have been facilitating such therapies for over 45 years now.
Such transplants from unrelated donors are carried out with minimum manipulation of the cells that are transplanted into the recipient. But the more recent breakthrough has been the manipulation of the cells, ex vivo (in a petri dish in the lab), to direct or enhance their activity for a specific therapeutic purpose.
One area where this is happening is CAR-T cells therapies. Nobody could have failed to see the press coverage around this, but what are these therapies and how do they work?
How do T-cells work?
To explain how these cells work, we have to understand a bit about our immune system. The human immune system is remarkable in that it has evolved mechanisms to defend us from both external (infection) and internal (cancer) attack. Our blood contains a variety of cells that patrol our bodies and mount responses to eliminate any threats. They do so in a variety of different ways: some cells (called macrophages) physically engulf or “eat” bacteria and other microorganisms, thus eliminating them from our systems. Others (B-cells) produce substances called antibodies, which neutralise pathogens rendering them inactive.
Others still, named T-cells (so called because they originate in the thymus) are very specific in that they interact with infected or malignant (cancer causing) cells using direct target recognition mechanisms.
A T-cell recognises an infected/malignant cell via specific proteins expressed by that cell (the antigen) in association with MHC (major histocompatibility complex (or HLA in humans)), using its own special surface protein called the T-cell Receptor (TCR). This recognition triggers cell activation, which allows that T-cell with that recognition signal to multiply, activate other cells of the immune system and induce cell death in the target cell.
All T-cells resulting from this multiplication will also recognise malignant or infected cells of the same type and kill them specifically, thus eliminating with pin point accuracy only those cells that are infected or are malignant, leaving all other healthy cells intact.
How do CAR-T cell therapies work?
Scientist have taken advantage of these properties of T-cells to genetically engineer them to recognise specific antigens and eliminate cells which express them. This is achieved by collecting a patient’s T-cells from their blood and adding a gene which expresses a chimeric antigen receptor (CAR). This works like the cells natural TCR, but it recognises only one molecule.
So far, most CAR-T cell therapies have been engineered to recognise the antigen CD19, which is only present on a type of blood cell called B-cell. Some blood cancers (including B-cell leukaemias and lymphomas [DLBCL, ALL]) are caused by the uncontrolled proliferation of B-cells or their precursors, and these can therefore be treated with CAR-T cells against CD19, as these cancer cells also express CD19.
This approach has shown remarkable results in most patients treated so far, where all other interventions had failed. However, extending this approach to other types of cancer has proven more difficult as most other types of cancer cells do not express unique antigens that can easily be targeted in this way. However, this has not stopped numerous groups around the world looking and trying other antigens that can be targeted using this type of approach.
Searching for other cell therapies
The search of other cells in the immune system that can be deployed to treat other diseases also hasn’t stopped there. Natural killer (NK) cells, as the name suggest, are very powerful cells in the immune system. They are good at detecting cells which are not quite right, and killing them. NK cells constantly patrol our bodies and go into battle mode when they find abnormal cells.
Unlike T-cells they mediate the recognition through not one, but a combination of so-called receptors (proteins on the outside of the cell). This gives them several advantages over T-cells, for certain cancer therapies, and these are being exploited to produce cancer killing NK cells derived from both adult blood cells, but also from cord blood making them more easily available and reducing some costs.
What the future holds
We are living in exciting times, not only are we discovering new treatments which are more targeted and may have fewer side effects, but also the time from discovery to clinical application has become shorter. This means that soon, more treatments will be available to patients quicker.
I feel indeed hopeful and very privileged to be working on the development of such therapies here at the Anthony Nolan Research Institute. Furthermore, through my involvement in the Anthony Nolan Cell & Gene Therapy Services we aim to support research like this at other institutions and companies to bring more novel therapies to patients.
If you’d like to find out more about Anthony Nolan’s Cell & Gene Therapy Service, please get in touch on CellAndGeneTherapies@anthonynolan.org