CAR T cell therapy is revolutionising cancer treatment, but at what cost?
CAR T cell therapy is one of the latest innovations in gene therapy. The process is primarily used to treat blood cancers, where a patient has their T cells extracted and modified into CAR T cells, which will precisely attack the cancer cells. While a revolutionary and life-saving technology, it is extremely expensive and is not guaranteed to work, meaning that American health insurers and European socialised healthcare systems are hesitant to widely cover the treatment in its current form. Conor Kavanagh will assess the benefits and drawbacks of CAR T cell therapy and what can be done to make it more economically viable as a cancer treatment.
T cells are a type of immune cells that have their own receptor proteins, which attach to foreign antigens and trigger the immune system to destroy foreign substances. Cancer cells also have antigens, but if your immune cells don’t have the right receptors, they cannot attach to the antigens and help destroy the cancer cells.
CAR T cell therapy works by first removing a patient’s blood through one IV line. The white blood cells, including T cells, are then removed before the blood is put back in the patient through another IV line. After the removal, the T cells are separated and sent to a lab, where they are genetically altered by adding the specific chimeric antigen receptor (CAR). It usually takes a few weeks to finish making the large number of T cells needed for the therapy.
Once enough is made, they are given back to the patient to launch a precise attack against the cancer cells. Sometimes the patient may be treated with chemotherapy before the procedure to lower the number of immune cells and give the CAR T cells a better chance to fight the cancer. Once the CAR T cells bind with the cancer cells, they start to increase in number and are able to kill even more cancer cells. This treatment is currently approved for certain types of lymphoma and leukaemia patients.
The downside of this therapy is that it can have severe side effects. When the CAR T cells multiply, they create massive amounts of cytokines, which prompt chemical messages to be released into the blood that can stimulate very high fevers and dangerously low blood pressure, as well as neurotoxicity or changes in the brain that cause swelling, confusion, seizures and severe headaches.
The history of CAR T cell therapy
The research that led to the development of CAR T cell therapy began in 1961, when immunologist Jacques Miller identified the thymus gland as the place where T cells developed while studying for his PhD at the University of London. This helped inform the initial development of treatments that would become the basis of CAR T therapy. In 1986, Steven Rosenberg and his team at the Surgery Branch of the National Cancer Institute treated patients with tumour-infiltrating lymphocytes by removing these cells from a tumour, expanding them in a lab and giving them back to the patient. This cured some patients, proving a human’s own immune cells can fight cancer. This is a broadly similar method to how CAR T therapy is conducted today.
In terms of the T cells themselves, Dr Michel Sadelain was able to introduce genes into T cells with the goal of making the body’s cells boosted cancer fighters in 1992. This was followed by Israeli immunologist Zelig Eshar engineering T cells with the first chimeric molecule, a portion of an antibody fused to part of a T cell receptor, which became known as the first generation of CARs.
In 2002, the Memorial Sloan Kettering Cancer Center (MSK) built the first effective CAR T cells, which targeted a prostate cancer antigen, and became known as the second generation of CAR T. It was able to survive, proliferate and kill prostate cancer cells in the lab, establishing the feasibility of the therapy. In 2013, MSK published the results of a clinical trial using CAR T cell therapy in adults with acute lymphoblastic leukaemia (ALL) and it was granted Breakthrough Therapy designation by the FDA the following year. In 2017, the treatment was approved by the FDA for use in children and young adults suffering from this type of leukaemia.
The unique nature of each CAR T cell therapy creates a host of manufacturing and logistical problems, and one company that has faced major difficulties is Novartis. In August 2017, their CAR T therapy Kymriah (tisagenlecleucel) was approved by the FDA for treating patients over 25 years old with B-cell precursor ALL that was refractory or in second or later relapse.
As of the end of 2019, the company had shipped these therapies to about 1,800 patients with blood cancer. Although it seems like a relatively small amount, it is an impressive milestone considering each product has to be personalised based on a patient’s own immune cells. This manual and deliberate process usually takes the company an average of 21 days to complete, with pressure being put on the timeframe due to the patients who require therapy often being very sick.
However, around 10% of the time, Novartis is not able to ship the product at all due to specification or manufacturing issues. One of the FDA requirements for Kymriah is that the product consists of at least 80% viable T cells, which was changed from the 70% threshold given in clinical trials, and is also higher than other countries where the treatment is approved. This was due to the FDA believing anything under 80% could be a potential safety hazard.
This stipulation is a source of major frustration to Novartis. There is no evidence that patients receiving doses between 60% and just under 80% fare any worse than those who receive the regulated viability of the T cells, nor have the amount of side effects been shown to increase. This is one of the major factors that contribute to limitations in shipping the product. There is also the challenge of ensuring the right personnel are available to administer the cells back into the blood cancer patient.
Helen Knight, Programme Director, Technology Appraisals and Highly Specialised Technologies at NICE, said the potential side effects of the treatment also create a logistical headache. She told Pharmafocus: “Following treatment, patients should be monitored for signs and symptoms of side effects such as cytokine release syndrome, which is a systemic inflammatory response to treatment. This response is often mild and can be managed with medication, however severe cases need intensive care treatment and may lead to other complications, such as damage to the organs.
“Therefore, the necessary infrastructure and safety measures, including extensive training for healthcare professionals, must be in place for the treatment to be available.”
The logistics of sending these treatments back to patients has also caused problems. Careful handling, storage and tracking is critical as the T cells are frozen to make their viability last longer and an accurate temperature range must be maintained. The correct documentation also needs to be carried along with the treatment. Thankfully, for corporations developing T cell therapies, specialist transport providersexist to make sure the back and forth movement of the treatment goes smoothly. However, due to all of these complications, it looks like the availability of CAR T cells will be limited in the initial years of its use in cancer patients.
While Novartis has experienced problems with the FDA regulations, the European Medicines Agency has its own rules that make the treatment’s manufacture and regulation tricky. The EMA’s Committee for Advanced Therapies considers CAR T cells as gene therapy medicinal products, but as the starting material is the patient’s own cells, they are governed by separate transplant and blood product legislation. To further complicate the issue, the final CAR T cells are classed as genetically modified organisms, which are regulated separately by each European country.
At the moment, there is no single pathway to gain approval from a regulatory perspective, and this is unlikely to change soon. This is a headache for the current manufacturers of CAR T therapies, but also something that may put off others developing products in this field.
Is it worth the cost?
T cell therapies are undeniably an improvement on previous methods of treating blood cancers. Prior to their FDA approval, diseases like lymphoma could only be treated by a combination chemotherapy regime. Depending on a variety of circumstances, this treatment can lead to long-term durable remissions in about 60% of patients. But for those who the disease has progressed past the first line phase, this is reduced to 50%.
Clinical trials for Novartis’s Kymriah showed a remission rate of 83% in leukaemia patients who did not respond to standard treatment. Gilead’s CAR T therapy, Yescarta, also induced a 72% remission rate in aggressive B cell non-Hodgkin lymphoma.
Currently, Kymriah’s list price is $373,000 for patients with lymphoma, and there is debate as to whether this enormous treatment price is actually cost-effective. In 2019, the Journal of Clinical Oncology outlined what factors would determine this price to be worth it for both Kymriah and Yescarta. They highlighted that it depends on long-term outcomes compared with chemo-immunotherapy and stem cell transplants.
In their study, they compared increased life expectancy between CAR T therapy and chemotherapy as lymphoma treatments. They used the Markov model to analyse the cost-effectiveness and budget impact of these therapies to determine progression-free survival (PFS). The model showed that Yerscarta increased life expectancy by 8.2 years at $129,000 per quality-adjusted life-year gained (QALY) when assuming a PFS of 40%. It also showed that it increased life expectancy by 6.4 years at $159,000 per QALY gained when assuming five-year PFS of 30%.
Kymriah increased life expectancy by 4.6 years at $168,000 per QALY gained when assuming five-year PFS of 35%, and by 3.4 years at $223,000 per QALY gained when assuming five-year PFS of 25%.
The results show meaningful survival gains for adults with the disease and, due to it creating long-term remissions, the treatment may be able to meet a cost-effective threshold of $150,000 per QALY.
This is obviously nowhere close to the current cost of the treatments. It is estimated that these therapies would add $2 billion annually to the spending of the American healthcare system, which is a massive increase from the $2.9 billion it spent to care for all patients with lymphoma in 2013.
To offset this cost, the authors outlined some steps that could be taken to reduce the price of the therapy, which included alternative pricing models, including payment only for patients who achieve complete remission, or a decreased price structure for CAR T therapies.
In the American context, there are several unique concerns. Due to the expense involved, it is difficult to see most insurance companies reimbursing the hospitals for carrying out these treatments. It’s even more unlikely due to the fact that many patients receiving CAR T therapy still relapse, therefore requiring more rounds of the expensive treatment.
The UK is fairing slightly better, with its socialised healthcare system approving both Kymriah and Yerscarta for use in the NHS in 2019. Through the Cancer Drugs Fund, patients will be able to access the treatment for blood cancers at several hospitals across England, but there are still long-term uncertainties about the financial viability of the therapy.
Knight believes it is currently difficult to quantify how cost-effective CAR T therapy actually is: “CAR T cell therapies are expensive. Clinical evidence suggests that people having these therapies may live for longer or have more time before their disease comes back. But longer follow-up from the studies is needed. The cost-effectiveness estimates for these therapies are uncertain because of limitations in the clinical data. Because some of these estimates are higher than NICE normally considers an acceptable use of NHS resources and are associated with a high degree of uncertainty, the CAR T cell therapies cannot yet be recommended for routine use in the NHS.”
Car T therapy and solid tumours
Though CAR T therapy has been deemed a success in treating blood cancers, it does not have a certain future in terms of treating solid tumours in other types of cancer. There are still no CAR T therapies clinically approved to treat solid tumours, due to a host of issues including the intricacies of solid tumours, and complications CAR T cells face in treating them, including tumour toxicities and undesired antigen specificity.
CAR T therapy in blood cancers works because they are malignancies of B cells which the therapy can completely wipe out, but solid tumours do not have B cell equivalents. It is a challenge to find a target on a tumour that is not present on healthy cells, which could negatively impact the patient’s chances of survival if it was wiped out.
Solid tumours do not easily allow the CAR T cells into them, especially when they are given intravenously, as these T cells get sequestered in the lung and slowly reach the tumour, meaning very few T cells can actually enter it. A further complication is that each different type of organ has a different immune microenvironment, which makes it a challenge to test CAR T in different types of cancer patients. There is not a single antigen shown in all cancer cells that is uniform.
Progress has been made, but it has lagged behind the therapy’s use in blood cancers. In September 2019, Minerva Biotechnologies began a trial using CAR T that targeted a tumour growth receptor called MUC1. Many other trials have failed to target this protein due to it being cleaved and released from the tumour’s surface, meaning any therapy that binds with it is also released. Minerva’s therapy aims to swoop in and bind to the MUC1 receptor to block growth factors from accessing the MUC1 cleavage product, which can theoretically stop a tumour from growing. The CAR T therapy will also attempt to kill any mutant cancer cells in the vicinity and send out signals to the patient’s immune system to produce more CAR T cells to shrink the tumour.
This is not the only approach being tested for this therapy in solid tumours. Scientists from the Keio Unviersity School of Medicine in Japan published their research in eLife that showed CAR T therapy destroying tumours in mice. The team developed a CAR T treatment that targeted an antigen called glycipan-1, which is found in large amounts in several types of tumour cells, and exists in low levels in normal human and mice cells. When the scientists tested this therapy on the mice bearing the tumours, they found that it effectively inhibited tumour growth without causing adverse side effects. Four out of five of the mice remained tumour-free for at least 100 days, and the team also found that the CAR T cells enhanced immune responses against other tumour antigens aside from glycipan-1.
CAR T therapy could be a game changer in the treatment of cancer. Its limited use in treating cancers of the blood has been hailed as a success, but its cost will potentially limit how widespread the treatment will be used going forward. Healthcare systems and insurance companies need to work out a more cost-effective payment programme and advancements in technology to make the therapy cheaper are needed to ensure the long-term viability of the use of this treatment in blood cancer patients, and potentially in combatting other forms of the disease in the future.
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