POSTED BY
John Swift
CAR-T therapy has been hailed as a breakthrough in cancer therapy. But just how ‘miraculous’ is it, how does it work, and who is leading the way?
Immuno-oncology is booming. The potential to engage our own immune system to fight cancer has created big expectations and attracted billions in investment.
CAR-T therapies have emerged in recent years as an effective way to treat blood cancers such as leukaemia.
There are five CAR-T therapies already on the market, and over 500 CAR-T clinical trials currently running worldwide.
CAR-T therapy consists of the infusion of engineered T cells that carry a chimeric antigen receptor (CAR) on the cell membrane. The external domain of this receptor is designed to recognise a specific molecule on a tumour cell. This activates the internal signalling domain of the molecule, stimulating the T cell to attack the cancer cell.
The most common type of CAR-T cell therapy begins with the extraction of T cells from the patient being treated, a process called leukapheresis. The T cells are then genetically modified to express a CAR molecule and expanded. Finally, they are injected back into the patient, ready to fight the tumour.
Immunotherapies based on checkpoint inhibitors have been quite successful in certain groups of cancer patients. Checkpoint inhibitors block a mechanism that tumour cells use to hide from immune cells. Immunotherapies based on CAR-T cells go one step further, engineering the T cells themselves to enhance the natural immune response against a specific tumour antigen.
However, CAR-T cells have been linked to some severe side effects like neurotoxicity and cytokine release syndrome. Some late-stage clinical trials testing CAR-T therapies against the CD19 antigen found in immune B cells – the most common target for CAR-T therapies - have even resulted in deaths.
Despite this CAR-T clinical trials have shown remission rates of up to 93% in some severe forms of blood cancer.
The innovators
Novartis was first to launch a CAR-T therapy – Kymriah - in 2017. This was a one-time treatment for B-cell acute lymphoblastic leukemia (ALL). It showed an 83% remission rate after three months in patients who were not responding to standard treatments.
Gilead’s CAR-T cell therapy called Yescarta induced remission in 72% of patients with aggressive B-cell non-Hodgkin lymphoma.
However, the toxic effects on the immune system, like cytokine release syndrome and nervous system disorders, remain a worry for both Kymriah and Yescarta. According to one study, the death rate for both therapies was 5.4%.
In February 2021, the FDA approved a third CAR-T cell therapy - Breyanzi developed by Juno Therapeutics - for certain types of non-Hodgkin lymphoma.
Just a month after that, the FDA approved the very first CAR-T cell therapy that does not target CD19. Abecma was developed by Bluebird Bio and Bristol-Myers Squibb. It targets B-cell maturation antigen (BCMA) and is the first CAR-T cell therapy for multiple myeloma.
The final CAR-T therapy to be approved was Kite Pharma’s Tecartus in early October 2021. This was developed for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL). It showed a remission rate of 52% after three months of treatment with no severe adverse effects reported. However, 92% of patients did suffer from some form of cytokine release syndrome and neurologic toxicities occurred in 87% of patients.
New developments
Developers are already developing next-generation, safer CAR T-therapies.
Cellectis has developed a CAR-T technology - now licensed to Servier and Allogene - that includes a switch control system that only activates the engineered T cells when the patient is given a specific drug.
Bellicum Pharmaceuticals in the US is developing a similar technology called GoCAR-T. This uses the drug rimiducid to activate the CAR T-cells. Unlike other CAR-T cell therapies, Bellicum’s approach targets solid tumours.
The company’s lead GoCAR-T candidate is currently in a phase I/II trial for patients with a specific type of pancreatic cancer.
What about solid tumours
Targeting solid tumours is one of the big challenges in the field of immuno-oncology because the amount of T cells that infiltrate naturally is low. Solid tumour cells tend to create an immunosuppressive environment that dampens the immune response. A major focus of translational research is to improve specificity, efficacy, and safety of CAR-T cells to be used in cancers beyond leukaemia.
Celyad Oncology is a clinical-stage biotechnology company. They are targeting solid tumours with a type of CAR-T that makes T cells carry the receptor of another type of immune cell called natural killer cells.
Another strategy is to combine CAR T-cells with other types of cancer immunotherapy by infusing them along with checkpoint inhibitors that block cancer’s defence mechanisms against T cells.
Combining T cell therapies with immunomodulatory agents such as checkpoint inhibitors and cytokines, and small-molecular antagonists that block biochemical pathways crucial for tumour growth, also provides some exciting opportunities.
Although this means the effectiveness of CAR-T cells could be improved and the dose lowered, it could drive up costs.
And cost is a real issue. In Germany, Novartis’ Kymriah is priced at €320,000 and Gilead’s Yescarta at €327,000. After hospitalisation and other medications, the total could exceed €1M per patient.
The reason for this is that many pilot processes for CAR T cell generation were originally developed in academic centres and only required small numbers of T cell products. Because many of these processes are based on manual and open-handling steps in safety cabinets, they are not always suited for upscaling to commercial manufacturing.
Off-the-shelf CAR T-cells
Cellectis and Celyad are working on off-the-shelf CAR-T therapies that would save time for patients, who currently wait two weeks for their cells to be sent to the manufacturing facilities, engineered, and returned. An off-the-shelf therapy still face some challenges.
Conclusion
As scientists try to understand how to overcome technical issues, cost and reduce side-effects, there is also a challenge in terms of regulation - CAR-T cells currently fall between regulatory frameworks.
Despite this, the CAR-T therapies already on the market offer unprecedented optimism for some otherwise hard to treat cancers, and may hold the key to new therapies in combination with other treatments. CAR-T has opened the door to many more and better immuno-oncology therapies in the next few years.
