Many patients with haematological cancers including leukaemias, lymphomas and myeloma are cured by standard doses of chemotherapy, but a significant proportion of patients either fail to enter remission or relapse. One approach in this situation is to administer higher doses of drugs or total body irradiation, with the accompanying severe suppression of the bone marrow (resulting in dangerously low blood counts), being overcome by use of a stem cell transplant. The stem cells can be the patient’s own cells collected prior to the high dose therapy (autologous transplant) or can be from a donor, often a family member (allogeneic transplant). Allogeneic transplantation carries greater risks than an autologous transplant, but is more effective at eliminating blood cancers. This is because T lymphocytes derived from the donor attack and kill the cancer cells
Here, a T‐cell has recognized a cancer cell and is in the
process of killing it. The T‐cell will perforate the membrane lining the cancer cell and inject it with toxic proteins. Unlike usual cancer treatments, T‐cells are living cells.
T‐cells can reproduce themselves and one T‐cell can kill many cancer cells. T‐cells can migrate through different tissues looking for disease and may survive for years to form our immune system’s memory.
How engineered T‐cell therapy works in practise. T‐cells are plentiful in blood and we can easily harvest them from either a blood sample or with a blood cell harvesting procedure called a leukapheresis. In a specialized laboratory, the T‐cells are infected with an engineered virus. This virus permanently introduces a new gene which tells the T‐cell to make a receptor. The T‐cells are grown for a few days in the laboratory and then are given back to the patient in an i.v. drip.
The allogeneic transplant experience thus provides the proof that T lymphocytes can be a highly potent tool in the fight against cancer. The obvious next development is to devise means to use T cell therapy without the problems and risks of a stem cell transplant.
The normal role of T cells is to protect the body from infections particularly viral infections. Each T cell has a different receptor which allows it to recognise a specific virus or other invading organism, and if the body is infected with such an organism, the T cells that recognise it, expand in numbers to eliminate the threat. Many T cells also recognise foreign tissue. They are responsible for rejecting some transplants and launch the attack on tumours which makes allogeneic transplantation successful. The patient’s own T cells cannot do this because they do not recognise the tumour cells as “foreign.”
T‐cell receptors. The panel above shows why our immune system is typically blind to a tumour. The role of a T‐cell is to fight infection, so each T‐cell has a different receptor recognizing different foreign proteins which may come from viruses or bacteria. Most tumours come from normal cells in our bodies and are not infected by viruses. The T‐cells hence ignore them. The right panel shows the situation when we introduce a new receptor which recognizes the tumour cell into T-cells. Now the T‐cells no longer ignore the tumour and directly act, applying the considerable capacity of our immune system to reject the tumour.
This situation can now be modified thanks to advances in molecular biology and gene cloning. Receptors of various types that will recognise a tumour can be built in the laboratory and inserted into a virus (referred to as a vector) which can infect T cells [fig 2].
Once infected the gene for the new receptor is used to make the receptor which is then expressed on the surface of the T-cells. If a batch of T-cells is infected in the laboratory each T-cell will retain its own specificity for a particular antigen (e.g. viral protein), but all the infected T-cells will now recognise the tumour [fig 3].
The new receptors which are engineered into T cells can either be replicas of normal T cell receptors or they can be totally artificial constructs based on monoclonal antibodies against a particular tumour antigen. These artificial receptors have the antibody component on the outside to recognise the tumour and have various other motifs on the inside of the cell to enable cell division and amplification when the engineered T cells encounter their target. These artificial receptors are known as Chimeric Antigen Receptors or CAR T cells for short.
Chimeric Antigen Receptors. This cartoon shows the structure of an artificial T‐cell receptor called a chimeric antigen receptor. These receptors have two parts. One part is outside the cell and has been made from an antibody. This part recognizes a particular protein on the cancer cell’s surface. The second part of the receptor is inside the T‐cell. It sends the T-cell a signal to activate when the outside part of the receptor recognizes a cancer cell. Almost any cancer target can be recognized in this way, and the receptor can transmit very powerful signals to the T‐cell so it fully activates.
Initial clinical studies with CAR T cells began ten years ago and one of the key investigators at UCL, Dr. Martin Pule, was involved in one of these early studies. These early studies were of limited success, but provided important information to take back to the laboratory to improve the receptor constructs. A new generation of vectors is now available and the time is right to renew efforts into taking this modality of treatment into the clinic. A number of possible antigens could be targeted in both leukaemia and lymphoma, and there are several possible variations to the portion of the artificial receptors that makes the T cells grow. The only way to determine the best option is to carry out a series of clinical trials starting with relatively simple vectors and then modifying them according to the clinical results.
A trial has already been started using a CAR vector created at UCL for children with relapsed leukaemia and we now wish to initiate programmes in adult leukaemia and adult lymphoma. These clinical trials are initially very expensive because of the costs of producing vectors that are of sufficiently high purity to be approved for use in man, and because this strategy involves “gene therapy,” very rigorous regulatory oversight is required. To `kick start’ the adult studies in a timely manner, we estimate that £1,000,000 must be raised from charitable funds. Thereafter we believe the programme will attract sufficient funds form the Medical Research Fund and other funding agencies to be self‐sufficient. To take this ambitious programme forward requires a team of leukaemia and lymphoma experts, clinical trials specialists and molecular biologists with experience in gene therapy. This team is now in place at the Cancer Institute at UCL/UCLH and senior team members include:
Professor David Linch
Head of Haematology Department
Dr. Martin Pule
Lead Clinician/Scientist for
CAR T-cell programme
Professor Amit Nathwani
Head of Haemophilia Centre
Dr. Karl Peggs
Reader in Stem Cell transplantation
Dr. Sergio Quesada
Professor Asim Khwaja
Clinician Scientist specialising in acute leukaemia
Professor Kwee Yong
Clinician Scientist specialising in myeloma
Professor Adrian Thrasher
Clinical Immunologist and Head of
cellular manufacturing facility at UCL
Mr. Paul Smith
Clinical Trials Management
Many patients with haematological cancers including leukaemias, lymphomas and myeloma are cured by standard doses of chemotherapy, but a significant proportion of patients either fail to enter remission or relapse.
University Hospital Birmingham (UHB) are conducting a number of innovative trials that seek to enhance the treatments of haematological cancers, through the combination of stem cell transplants and new drugs, and they’re beginning to witness tremendously positive results.
How do current treatments work?
Stem cell transplants can be sourced from the patient prior to the high dose therapy (autologous transplant) or from a donor, which is ideally a family member (allogeneic transplant). Allogeneic transplant is the most effective transplant process, as the injection of fresh lymphocytes from the donor attack and kill the cancer cells, however it also brings greater risks. This is typically exhibited in Graft versus Host Disease (GvHD), whereby the cells a patient has received from their donor are recognised as “foreign” and a separate treatment regimen is required.
It’s evident that further research and development is required to produce more effective means of treatment and UHB are pioneering trials that could save thousands of lives.
How are UHB improving treatments?
Two studies that are heavily supported by SPF are Figaro and Viola:
To compare a new stem cell transplant treatment regimen (FLAMSA-BU) with one of three of the current UK transplant treatment regimens.
This study will seek to improve treatments for those who have been diagnosed with high risk Acute Myeloid Leukaemia (AML) or Myelodysplasia (MDS) and have been considered to undergo an allogeneic stem cell transplant.
Approximately 170 patients from the UK will be invited to take part and the trial is expected to run for over 3 years and then a further 2 years to complete follow up and data collection.
The patients will receive a randomised course of treatment on a 1.1 basis meaning patients have a 1 in 2 chance of receiving current treatments and a 1 in 2 chance of receiving the FLAMSA-BU regimen.
The transplant process will involve the use of drugs in order to supress the immune system and allow for the transplanted cells to form new blood and a new immune system for the patient.
'Early studies have shown that this transplant regimen may have a better outcome compared to the currently used regimens but requires further evaluation amongst a larger sample group.
There are a number of drug trials being conducted that will test the viability of alternative treatments for those who cannot withstand intensive chemotherapy.
To discover the maximum dose which is safe to give of two drugs; Azacitidine and Lenalidomide, when given to patients with Acute Myeloid Leukaemia (AML) or Myelodysplasia (MDS) whose disease has come back after undergoing an allogeneic stem cell transplant.
Azacitidine is a chemotherapy drug used to treat a group of disorders that affect the bone marrow and blood. This drug is used when treatment with a stem cell transplant is not suitable.
Lenalidomide is used to treat people with myeloma, a cancer that affects the plasma cells found inside bone marrow.
During this trial Azacitidine will be administered through an injection under the skin (subcutaneous injection). Azacitidine will aim to switch off a protein called DNA methyltransferase, which switches on genes that stop cancer cells developing and helps control cell growth.
Lenalidomide will be delivered as an oral capsule. Lenalidomide prevents tumours from making their own blood vessels. It is a type of biological therapy drug and affects how the immune system functions, which is referred to as an immunomodulatory agent.
Approximately 30 patients from the UK will be invited to take part across the UK and it’s expected that the trial will last around 3 years.
Azacitidine and Lenalidomide are delivered as cycles of treatment for 42 days or 6 weeks. If at the end of 6 cycles of therapy your disease has improved, you will be able to continue therapy with azacitidine and/or lenalidomide as long as it is medically advisable.
These potentially life changing trials require a team of medical professionals who develop scientific theorem, which creates the foundation of the study. Research analysts are then required to collate data in the correct manner so that it can be evaluated to ensure reliability of the results.
Research nurses play a critical role in the longevity of the study and therefore its validity as they are the team of people who care, advise and support the patient (and often their family) through the course of the study.
This is a very expensive processes that cannot be funded by the NHS, which is why SPF are assisting with funding this research; to improve the survival rates of patients – this is our Mission.
The team are prepared and active at UHB and senior members of the team include:
Professor Charles Craddock