These included Baby Layla at Great Ormond Street and February’s front-page coverage of clinical trials in patients with untreatable acute lymphoblastic leukaemia. This month’s Focus On provides a brief rundown of the key concepts underpinning T-cell therapy, alongside an overview of Bloodwise-funded research in this important area.
Like many historical cancer innovations, blood cancer research has acted as a leading light in the development of current immunotherapeutic approaches. Unlike chemotherapy, in which powerful toxic drugs are given to patients to attack rapidly dividing cells – cancerous and healthy alike – immunotherapies harness the power and selectivity of our own immune system. This often involves laboratory modification of cells or antibodies removed from a patient, providing them with additional capability to recognise and attack a previously invisible cancer.
The original concept of immune-based therapies, like many historical scientific discoveries, arose almost by chance, as doctors noticed the spontaneous degeneration of tumours in rare cases of lymphoma. Careful observation of these cases showed that elimination of the cancer was carried out by the patients’ own immune systems and critically, proved them capable of killing advanced tumours under specific conditions.
Since this discovery, researchers have realised that these natural responses often go awry during the development of cancer, a process called tolerance, which can instead co-opt the immune system in favour of tumour growth. The fundamental principle of immunotherapy-based treatments is, therefore, based on re-programming or stimulating these dormant immune responses back to life.
T-cell therapy in research and patient treatment
At present there are several immunotherapeutic approaches under continuing development but, in this overview we are going to focus on methods that boost both the number and function of immune cells, the most advanced of which is T-cell therapy. T-cells are white blood cells of the immune system that are adaptable in establishing unique memories of a specific infection or disease.
To respond to the almost limitless army of infectious agents and unpleasant visitors that enter our bodies, T-cells possess many different proteins on their surface, called receptors. It is the job of these surface receptors to attach and bind all possible configurations of invasive objects that may end up circulating in the blood. Once attached, the T-cells can then begin their attack or recruit other cells specialised to do this job. Importantly, these receptors are modifiable as T-cells grow, resulting in the production of millions of uniquely-shaped versions capable of ensnaring even the most evasive pathogens.
T-cell therapy relies on giving patients high doses of T-cells with different receptors than their own, which can recognise their specific cancer, stimulating the immune response back to life. This can be achieved in either of two ways. Firstly, by transfusing T-cells directly from a matched donor, whose T-cells will express an alternative receptor repertoire. The other more complex approach requires the artificial insertion of cancer-specific receptors along the surface of a patient’s own T-cells, which are grown in the lab and returned to the patient to do battle with the tumour once more.
Successful outcomes of T-cell therapy arise because many cancers have unusual proteins on their surface and so engineering artificial receptors is a useful way of targeting these cancer-specific markers. The most well-known of these are called chimeric antigen receptors (CARs), in which surface receptors are modified into shapes specific to a particular cancer and inserted along the surface of cells, creating CAR T-cells.
The first tests using CAR T-cells were performed in HIV patients around the late nineties and were followed-up shortly after in a group with pancreatic cancer. Unfortunately the CAR T-cells failed to live up to their lofty expectations, although the administered T-cells were found to persist for more than a decade.
A wave of second-generation alternatives was then produced in response, possessing an additional set of proteins tethered to the synthetic receptors. Upon binding to the cancer, the new receptors triggered the genetic machinery of the cell to release signals for other immune cells to come and help. T-cell therapies began truly bearing fruit around 2011 when CAR T-cells began inducing powerful anti-cancer responses, including the ultimate marker of triumph, long-term remission.
Now into their third generation, one of the major hopes of T-cell therapy is that, unlike drug targeting, this innate anti-cancer response will persist in the body long after the end of treatment, due to the natural memory-forming ability of T-cells. This could provide long-term resistance to the re-emergence of the cancer, just like the immune memory produced by vaccines.
Bloodwise and T-cell therapy
Bloodwise currently funds a number of leading UK researchers in the field of T-cell therapy. One programme at King’s College London aims to deploy current immunotherapy techniques to prevent relapses that are common in acute myeloid leukaemia (AML), particularly in patients undergoing a stem cell transplant.
Although patients often respond well following a transplant, relapse is common in AML. The first step to prepare for a transplant is to deplete the immune system, but many types of T-cell fail to recover and persist in critically low numbers for months, particularly the naïve T-cells needed to form immune memories. The KCL team believes this contributes to the regular patterns of relapse in AML.
By providing swathes of extra T-cells from a matched donor, the researchers are looking to provide a critical boost to the immune system in its weakened state. The transfused T-cells should be able to recognise any leftover cancer cells, proliferate naturally and create an immune memory in preparation of the cancer re-emerging in future.
We also support a large clinical trial called COBALT, led by Dr Karl Peggs at UCL, testing the re-engineered T-cell approach in diffuse large B-cell lymphoma (DLBCL). The specific treatment, designated as a 'breakthrough' by the main US-based drug approval body, is called CAR19 T-cell therapy and has been pioneered by Dr Michel Sadelain.
During the COBALT trial, modified T-cells will be given to patients containing synthetic receptors that recognise the other major cell type of the adaptive immune system, B-cells. B-cells are often those affected in leukaemia, lymphoma, and myeloma, therefore, the CAR19 T-cells are engineered to engage a protein unique to the B-cell surface, called CD19. Ground-breaking studies with CAR19 by Dr Sadelain produced striking results in relapsed or treatment-resistant acute lymphoblastic leukaemia, with 88% of patients entering complete remission.
We've invested just over £420,000 into the ongoing COBALT trial, the first in the UK to provide second generation CAR19 T-cells to patients. The trial began towards the end of 2014 to establish firstly, if this technique is even possible in DLBCL, and if so, whether it can safely be used to manage the disease in the run up to stem cell transplantation.
Given the genuine excitement surrounding the potential of T-cell therapy, the next few years promise to represent the foundation of T-cell therapy’s transition from a novel research tool into mainstream clinical oncology.
As well as those projects mentioned, Bloodwise is supporting many others, including Hans Stauss and Emma Morris’ programme at UCL and projects from David Gilham in Manchester, Anastasios Karadimitris and Cristina Lo Celso, both based at Imperial College.
Dr Sadelain’s appearance at Grantholders’ Day in October will undoubtedly provide great insight into the future direction and promise of T-cell therapies, which are likely to remain at the forefront of global efforts to produce new blood cancer treatments.