How can CAR-T therapy be improved?
CAR-T therapy is a new type of treatment and there are still a number of issues that need to be addressed to make it more effective. At Bloodwise we are funding ground breaking research to help overcome three main problems with current CAR-T treatment:
1) It's not always effective
Many people don't respond to CAR-T therapy and it can have fatal side effects. Patients can also relapse after initially going into remission.
2) Only a small number of patients can benefit
CAR-T therapies are currently only medically licensed to treat two types of blood cancer and many patients will be too frail to undergo the intensive treatment.
3) It's very expensive
Because CAR-T has to be made for each individual patient, it's extremely expensive, which limits its widespread use.
Professor Anastasios Karadimitris, Imperial College, London
Making CAR-T therapy more effective
Not all patients currently respond to CAR-T therapy and some will relapse. Professor Tassos Karadimitris from Imperial College London and his team are helping to develop the next generation of CAR-T therapies by genetically engineering a rarer but more powerful immune cell to recognise and kill cancer cells.
While T-cells are the basis of existing CAR treatments, the Imperial team are using a different type of immune cell called an ‘invariant natural killer T-cell (iNKT)’. Although these cells are much rarer in the body, they're potentially much more effective at eliminating cancer cells.
In research published in October 2018, Prof Karadimitris showed that 90 per cent of mice with lymphoma treated with CAR-iNKT cells survived in the long term, compared to 60 per cent of mice treated with CAR-T cells. Clinical trials are now being considered.
The COBALT clinical trial, run by Professor Karl Peggs at University College London (UCL) wants to help people achieve remission (become cancer free) before giving a life-saving stem cell transplant.
Dr Karl Peggs, University College London
People with a type of aggressive lymphoma called diffuse large B cell lymphoma (DLBCL) who relapse after standard treatment are currently treated with further intensive chemotherapy, followed by a stem cell transplant. If people don’t respond to the intensive chemotherapy before a stem cell transplant, they often relapse again, and treatment options begin to rapidly run out.
Bloodwise has invested over £420,000 into the ongoing COBALT trial, which is using CAR-T therapy to put these patients back into remission, enabling them to have a life-saving stem cell transplant. It’s the first attempt in the UK to use this approach.
Enabling more patients to benefit from CAR-T therapies
The majority of lymphomas and leukaemias originate from genetic faults in one of two types of white blood cell – T cells or B cells. CAR-T therapies are currently licensed to treat just two types of B cell blood cancer – DLBCL and childhood acute lymphoblastic lymphoma (ALL). Existing CAR-T therapies are effective at treating these cancers because they're designed to recognise a protein, called CD19, which is present in large numbers on the surface of these cancer cells.
While healthy T cells are used as the basis of CAR-T cell therapies, so far there have been none that work against blood cancers that arise from T cells. . This is because when T cells are 'armed' against other T cells, they tend to destroy each other.
Increasing the number of blood cancers that CAR-T therapies can be used to treat
A new project by Professor Waseem Qasim’s team at UCL is using the latest technology to edit T cell DNA to remove the 'flags' on their cell surface that encourage attacks from other T cells. This research could open up CAR-T therapy for use in blood cancers that arise from T-cells, such as certain lymphomas and leukaemias.
Dr Lydia Lee and Professor Kwee Yong’s team at UCL have been developing a new CAR-T cell therapy to treat myeloma. Previous experimental CAR-T therapies that targeted a common protein found on myeloma cells, called BCMA, were not very effective because BCMA only occurs on the surface of myeloma cells at a fraction of the level that the CD19 protein does on DLBCL and childhood ALL cells. Myeloma cells were also able to develop resistance to CAR-T therapy because they were able to stop producing the BCMA protein.
Dr Lee and Professor Yong’s team developed a CAR-T therapy that targets BCMA and TACI, another protein found on myeloma cells, at the same time. This is the first time that a CAR-T cell therapy for myeloma was developed to target more than one protein.
Dr Lydia Lee, University College London
Early results from the research, published in December 2017, showed that the treatment was highly effective at killing myeloma cells in the laboratory and in mice with myeloma, with limited side effects. The treatment – called AUTO2 – is now being tested in a new clinical trial underway at UCL. It's the only trial currently using CAR-T therapy to treat myeloma in the UK.
Reducing side effects
Dr David Gilham’ s team at the University of Manchester, looked at ways for patients to receive CAR-T therapy without the need to undergo additional intensive chemotherapy before starting treatment.
Currently patients have to receive toxic chemotherapy or radiotherapy to kill off their white blood cells before CAR-T therapy can be used, which not all people can endure. In research published in 2017, the Manchester team showed that CAR-T cells engineered to release a protein called ‘interleukin-12’ were able to kill lymphoma cells in mice that had not previously received chemotherapy. The researchers found that by releasing interleukin-12 , the new type of CAR-T cells not only killed lymphoma cells, but also ‘recruited’ other immune cells to join in attacks on cancer cells as well.
Helping to reduce the cost of treatment
CAR-T therapy is very expensive as it uses the patient’s own immune cells as the main building block for the treatment, meaning that it has to be personally manufactured for each individual patient. Reducing costs would make it more likely for CAR-T therapy to become widely available on the NHS.
As part of two Bloodwise research projects, researchers are also looking develop ‘off the shelf’ CAR treatments that can be manufactured for multiple patients, making them much cheaper.
Professor Waseem Qasim’s research at UCL, which is genetically editing T cells to treat blood cancers that arise from T cells , is aiming to create a universal CAR-T therapy. T cells from a donor will be reprogrammed in the lab and will be protected from attacks by other immune cells – allowing it to be grown and used in many different patients.
Professor Karadimitris’ team from Imperial College London, have used different immune cells as the basis for their treatment. This has the potential to be around 10 times cheaper than currently available CAR-T therapies, as it can be mass-produced to enable one batch to be used on many patients.
What does the future hold for CAR-T?
While CAR-T therapy is a game changer for blood cancer treatments, it is still a relatively new treatment.
It can cause some serious side effects, and is a major reason why this treatment is done only in hospitals that have an expert team to manage these. Researchers are designing CAR-T cells with’ off switches’ so their activity can be switched off when the patient starts experiencing side effects, preventing worsening of symptoms. But we still don’t know how effective this safety mechanism is. There’s also the challenge of delivering this therapy as multidisciplinary teams need to be in place with the expertise to help mitigate side effects and complications when they arise.
Although people receiving CAR-T therapy have gone into deep remissions, some patients will still relapse afterwards, and it is not yet clear how many will remain in long-term remission.
CAR-T therapy is also not suitable for all types of blood cancer, especially those that arise from T cells, like certain types of leukaemia and lymphoma. But researchers are looking at modifying other types of immune cells instead of T cells. Research to identify new targets on cancer cells, and to potentially develop new combinations of targets for CAR-T cells to hone in on are also underway. One further challenge will be to select better preclinical models to help predict efficacy of treatment.
CAR-T therapy is also very expensive, with costs estimated to be around £282,000 per patient, but developing universal treatments that do not have to be personalised for each individual patient will cut costs considerable. However, we still don’t know if using this approach will decrease the potency of CAR-T therapy.
We know from experience that the newest treatments are usually approved for people who have run out of existing treatments, and this is certainly the case for CAR-T therapy at the moment. But in the future we could see the treatment becoming available earlier in the treatment process. At the moment we don’t have enough information to tell us if this would benefit patients, but there are clinical trials happening at the moment collecting this data.
“It is likely that we are only beginning to see the benefits that CAR-T therapy can bring,” says Dr Alasdair Rankin, Director of Research and Patient Experience at Bloodwise. “Bloodwise research is part of the greater effort to push forward improvements in this incredibly exciting treatment. We look forward to seeing how CAR-T therapy will evolve over the next decade into a much safer, effective and widely used treatment."