What is CAR-T and How Does it Work?

An interview with Nicole M Trask, PharmD, a clinical consultant pharmacist at UMass Medical School and secretary of the AMCP’s Northeast Regional Affiliate.

Can you the difference between gene therapy and cell therapy? I noticed that these terms sometimes get lumped together, but from what I learned at your AMCP presentation the two therapies are not exactly the same thing.

Sure. So as you alluded to, chimeric antigen receptor T-cell (CAR-T) therapy is often referred to as gene therapy, however, it really actually falls under the umbrella cell therapy. So it probably sounds a little bit like splitting hairs, but there are some key differences between the two therapeutic approaches.

Gene therapy is used to modify an individual’s genetic material to either treat or hopefully cure the disease. There are a few different ways this can be accomplished. You can replace the defective gene, you can turn it off, or even introduce a new or modified gene that can alter the course of the disease. Cell therapy on the other hand is a treatment that involves the introduction of modified cells into the body to treat or cure disease.

Thinking about CAR-T therapy, it’s the T cells that are actually being genetically modified, not the patient’s genetic material. Those cells are then reintroduced into the body where they can fight the cancer.

Can you explain what makes blood cancer a good candidate for targeted treatment with CAR-T? Why were hematologic malignancies among the first treatments to be approved for this new mechanism?

Compared to solid tumors, hematologic malignancies have made for easy targets for CAR-T therapy for a couple different reasons.

First of all, we have better, more precise targets. So, axicabtagene ciloleucel and tisagenlecleucel, which are the first two CAR-T therapies to receive FDA approvals, both work by targeting CD-19 which is an antigen that is present on B cells. The reason this approach has been so successful is that CD-19 is almost uniformly expressed on cancerous B cells, which allows the CAR-T therapy to basically wipe out both cancer cells.

While CD-19 is expressed on the cancerous cells, it is also expressed on healthy B cells, which can lead to pretty significant collateral damage, including B-cell aplasia. 

The good news is that we can survive with low levels of B cells for a short period of time, and we can manage this depletion through administration of IV immunoglobulin as well as monitoring and treating infections that might occur.

Hematologic malignancies were first to receive FDA approval largely due to the reasons I just mentioned. They make for easier targets, and therefore have been more expensively and successfully studied thus far.

It seems like a wide-variety of conditions can be treated with a single CAR-T therapy, with expanded indications in the works for Kymriah and Yescarta, can you explain how this is possible?

The reason these therapies can work across multiple indications is the way they target specific biomarkers on the cancer cells. By engineering a patient’s own cells to be able to identify and target based on the presence of these biomarkers, the CAR-T therapy could theoretically have clinical applications across a variety of malignancies where that biomarker is implicated.

If both of the currently approved CAR-T therapies can be used to treat similar conditions, can you explain how they differ?

As I previously alluded to, both CAR-T therapies that are currently on the market work by targeted B cells that express CD-19. Both of these agents use two intracellular domains within the chimeric protein that is engineered on the service of the T cell.

The first of the two intracellular domains is a signaling domain that works to activate the T cell when it binds to the target protein. The second domain, which is referred to as the costimulatory domain, stimulates cellular replication. The main difference between the two CAR-T therapies pertains to that costimulatory domain. The axicabtagene ciloleucel utilizes the CD-28 domain, while tisagenlecleucel uses the 41-BB domain.

So, what exactly does this mean? It’s not 100% clear at this time, however, there is some data that CAR-T therapy that utilizes the CD-28 domain may have a faster initial proliferative response. The CAR-T therapy that utilizes the 41-BB domain may produce more progressive T-cell accumulation which can help balance out the less rapid immediate response that’s observed with the CD-28 domain.

I think it really remains to be seen whether this difference results in significant clinical advantages or disadvantages, so I think it’s going to be really important to keep an eye on the data that becomes available.

Which cancer conditions are not a good candidate for treatment with CAR-T therapy, and can you explain why?

There is currently a great deal of interest in harnessing the power of CAR-T for the treatment of solid tumors in particular. Perhaps the biggest barrier in achieving that lies in identifying appropriate targets. Solid tumors are often associated with multiple potential targets and identifying any one target that is truly driving tumor growth can be extremely challenging. In addition, the collateral damage that could occur by targeting the biomarker on both the normal and cancerous cells within a solid tumor could be catastrophic. As I mentioned previously, we can survive with depleted B-cell counts that occur as collateral damage associated with the treatment of blood cancers, however, the consequences of attacking normal cells within solid organs, such as the heart, the lung, or the pancreas for example, could be deadly.

Are there currently other CAR-T or gene therapy products in the pipeline that seem promising for the treatment of hematologic malignancies, other cancers, or other serious diseases? 

This is definitely an exciting time in the pharmacy world. There are several CAR-T therapies currently in development that have the potential to improve upon what we have on the market currently. For example, one agent in particular lisocabtagene maraleucel is a CAR-T therapy that uses a fixed ratio of CD-4 and CD-8, which theoretically would allow for more precise dosing. In clinical trials, this agent was associated with rates of cytokine release syndrome as low as 1%, and rates of neurotoxicity as low as 15%. Because of the improved safety profiles, this agent is actually being studied for use in the outpatient setting rather than a lengthy hospital stay that we currently see with the available CAR-T therapies in order to manage these very severe and sometimes even deadly symptoms. There are also several off-the-self CAR-T therapies that are being studied that would use engineered cells from a health donor rather than the patients own cells. This could potentially eliminate the processing time of about 2 to 3 weeks that we see with currently available therapies and get treatments to patients more quickly. There are, of course, some concerns about potential rejection of those donor cells as well as the development of graph-versus-host-disease, and these products are still in the very early stages of development, but it is definitely something to keep an eye on.

In terms of gene therapy, this is an area that is just exploding with activity right now. There are several agents in late stage development that have the potential to significantly improve or in some cases even cure diseases such as hemophilia. It’s those extremely rare diseases that could cause significant impairments or even death such as epidermolysis bullosa or cerebral adrenoleukodystrophy just to name a couple of the disease states that are currently in late-stage development.

Can you discuss the cost challenges related to these treatments? Do you expect the upfront costs of CAR-T to decrease as more products come to the market? 

It’s certainly difficult to predict at this early stage, but I would anticipate that as more CAR-T therapies come to market, particularly those agents that may be administered on an outpatient basis or those that are considered off-the-shelf, the total cost of care per patient decrease.

There are several factors that I think will play a role in this. If we have off-the-shelf CAR-T, the processing cost would decrease drastically. The T cells would not need to be collected and engineered at the individual patient level. In addition, as safer CAR-T therapies become available, the total cost of managing the adverse effects typically associated with CAR-T would be dramatically reduced.

I’ve seen some estimates about the total costs of treatments, including the CAR-T therapy as well as the hospitalization to manage the side effects could be as high as $1.5 million per patient, which is just astounding. If safer products could eliminate or dramatically reduce that expense, that would be a huge benefit to payers and the health care system overall.

In terms of the challenges related to the cost of these treatments, some of them I already hinted at in terms of the total cost per care, but perhaps I think the biggest challenge is that the high cost of therapy is upfront, which is very different from the payment model that we are accustomed to where treatment and payment is spread out over a period of time. In addition to the upfront costs, the high cost ranging from just under $400,000 to almost half a million dollars per patient for the therapy alone, may be tough for payers to accept when there is a chance that this one-time treatment may not even work for the patient. We have already seen a lot of discussion surrounding value-based contracting as well as reimbursement if therapy does not work for the currently available CAR-T, and I really anticipate that that conversation will continue to amplify as we gather more real-world data for these agents, as well as when those additional CAR-T therapies and gene therapies come to market.