Last month, I covered: 1) The types of immuno-oncology (IO) therapy; 2) Roadblocks to cellular therapies; 3) What are CAR-T cells and how do they work; and 4) How well does CAR-T therapy works. If you haven't had a chance to read it, click
This month, I will cover: 1) What is the side effect profile; 2) Why CAR-T therapies will be expensive; 3) Does CAR-T therapies justify the cost? and 4) Questions still facing the CAR field?
What is the side effect profile?
One of the potentially lethal side effect with CAR-T therapy is cytokine release syndrome (CRS) which involves elevated levels of several cytokines including interleukin (IL)-6 and interferon γ. Clinical symptoms include fever, hypotension, respiratory insufficiency and neurological changes such as delirium, global encephalophathy, aphasia and seizure like activities/seizure. This particular side effect was not evident in mice models, and was presented only when it was infused into humans.
There were several cases of CRS at Children's Hospital of Philadelphia (
) with significantly elevated levels of IL-6 which made the patients extremely ill. After a cytokine blockade failed, one 8 mg/kg dose of an IL-6 receptor antagonist, Tocilizumab, and the IL-6 levels returned to normal. IL-6 is a classic feedback loop mechanism possessing a network effect and one needs to interrupt multiple nodes or block the IL-6 mechanism to halt this toxicity.
It was also found that by measuring the percentage of bone marrow blast (BMB) (%), defined as disease burden, correlates with the severity of CRS for children. Those with no disease burden are characterized as having BMB below 50%, and those with disease burden (yes) have greater than 50% BMB. Those who have a "yes" for disease burden have a greater likelihood and severity of
. It is more advantageous to deploy therapy in patients with a low burden of disease resulting in less toxicity. The more BMB, the more severe the CRS. This could be also applied to adults as they have a mature immune system compared to children who are still developing their immune system.
Why CAR-T therapies will be expensive
People want to live longer with a better quality of life. To achieve this, scientist have gone into uncharted waters in understanding the etiology or mechanism of action of diseases which is not an easy feat. In order to achieve this, drug development has gotten longer and longer and therefore, more and more expensive. On average, according to a 2013 study published by
Center for the Study of Drug Development, it takes 11 (range 10-15) years to develop a drug from research to approval with a cost on average of $2.6 billion dollars.
IO therapy is far more complex than small or large molecule. Scientists understand how our immune system works, but not thoroughly enough to know how the immune system will react when one starts to manipulate the human immune system.
In order to administer CAR-T therapy, scientists had to figure out the following steps to manufacturing this therapy:
- Depending on the type of cancer, design a CAR with the best external and internal signals (Signal 1 and Signal 2); and
- Design it with the best viral vector to transmit the gene to the T-cell and proliferate;
- Get the CAR-T cells to expand ex. vivo in order to infuse it back to the patient;
- Get the reprogram cells to expand in the host and persist for unlimited amount of time in order for the patient to remain cancer free;
- Collect T-cells from the patient;
- Reprogram the patient's T-Cell to CAR-T cells;
- Infuse it back into the patient.
All these steps takes an extraordinary amount of scientific knowledge, experimentation and time for each individual. This is truly personalized medicine. CAR-T therapy is uncharted territory and no one knows whether this will work for every individual even if it is using an individual's own immune system.
|Comparison Study of three different CAR-T Therapies for ALL and CLL.
In the comparison study of SKMCC, NCI, and UPenn for leukemia, the therapy worked for ALL in a small number of patients, but not very well for CLL. The expression of CAR-T cells only lasted for 30 days in the SKMCC and NCI which may account for why the response rate was poor for CLL. However, even with an expression rate of greater than 4 years in the UPenn study, the overall response rate was 57% vs. 90% with ALL.
For patients who achieved a partial response or is nonresponsive to the CAR-T therapy, doctors and scientists have to figure out why the patient didn't have a complete response. It may mean going back to the drawing board in designing a different CAR, using a different viral vector, or using a different type of T-cell. This path adds on cost to the CAR-T therapy. Or they may decide to either add another drug or go with a different class of agents.
In calculating the cost to produce this therapy, because the process described has be done separately for each individual, it becomes very costly. Production cost only comes down when there is economy of scale, and with CAR-T therapy, there is no economy of scale since it's personalized to each individual. The cost of this therapy can only be determined by the biotech company that is actually developing the CAR-T therapy.
This is the dilemma. Society wants personalized medicine yet who is going to pay for the cost of personalize medicine? Insurance providers will not pay for CAR-T therapy because it is unproven by regulatory standards right now as well as their standards, the side effect profile is risky even though it can be remedied and it is very expensive. Today, most insurance companies will only pay for the standard treatments and only when all therapies fail, will the insurance company consider adoptive cellular therapy with special circumstances.
Does CAR-T therapies justify the cost?
The obvious answer is "yes." If one can use their own immune system to fight cancer, this is ideal and the therapy would be a one dose cure as oppose to traditional treatments including checkpoint inhibitors, another IO therapy, where the patient would have to take the drug/biologic for a specific period of time and hope the cancer is eradicated. Any inhibitor, is only viable for a limited period of time compared to a programmed T-cells which could be expressed for an unlimited time period.
In non-CAR-T therapy, the cancer could return and the same or different drug/biologic would have to be administered again similar to a maintenance therapy vs. a cure which is less expensive in the long run. And as each episode of a relapse occurs, the odds of survival is diminished significantly because the body gets weaker and the cancer get smarter in terms of resistance.
But the real answer relies on the payer. The insurance company will not pay for a new therapy unless it is proven that CAR-T therapy works and is a cure, by their standards, not just FDA approval, it's safe and it saves the insurance company money. But in order to determine this, health economic data must be collected over a determined length of time to demonstrate not only efficacy and safety, but the therapy saves the company money compared to standard treatment which many times are generic versions of the drug or biosimilar of a biologic.
If the insurance company won't cover the therapy, and the patient or family wants the therapy, they will have to pay for it. If the patient can afford to pay for it, they will. But most patients and families can't afford it and they will have to rely on standard treatment and hope for the best.
Questions still facing the CAR field?
The development of CAR-T therapy is at the beginning of its era. There are still many questions facing the
- Persistence: Correlates with outcome?
- Is long term persistence of CAR cells desired?
- Which approaches give durable persistence of CAR-Ts?
- What is the best vector to introduce the CAR: retroviral, lentiviral or non-viral vectors?
- scFv or endodomain construction?
- What is the optimal T cell type and composition of the infused product?
- How can checkpoint therapy and Car T therapy be combined?
In addition to questions facing the CAR field, there are clinical questions such as degree of disease burden, pre and post infusion therapy that can affect how well the CAR-T therapy works.