The Science Behind the Science Fiction: CAR T-Cell Therapy

In the latest ASCO in Action Podcast, ASCO CEO Dr. Clifford A. Hudis is joined by Dr. Jason Westin, member of the Government Relations Committee of the Association of Clinical Oncology, to discuss CAR T-cell therapy, a groundbreaking and lifesaving cancer treatment that comes with significant side effects, a jaw-dropping price tag, and limited locations where treatment is currently available.

“This is potentially home run therapy for patients who have decades of life left to go,” says Dr. Westin.  While he stresses that CAR T is a major step forward in ridding the world of cancer, Dr. Westin worries about the high cost of the treatment, which “is an incredible amount put upon the system.”  

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Transcript 

Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. 

Dr. Clifford Hudis: Welcome to the ASCO in Action podcast brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insights into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. 

The ASCO in Action podcast is ASCO's podcast series where we explore the policy and practice issues that impact oncologists, the entire cancer-care deliver team and the individuals we care for--people with cancer. My name is Clifford Hudis, and I'm the CEO of ASCO as well as the host of the ASCO in Action podcast series. 

For this podcast I am really pleased to have Dr. Jason Westin as my guest. Dr. Westin is a member of the Association for Clinical Oncology's Government Relations Committee. And he is the director of lymphoma clinical research in the Department of Lymphoma Melanoma within the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center. 

Today Dr. Westin and I will discuss chimeric antigen receptor, or CAR T-cell therapy. Two years ago, ASCO named CAR T-cell therapy as our advance of the year in our annual Clinical Cancer Advances Report. CAR T is a groundbreaking and life-saving treatment for children and young adults with acute lymphoblastic leukemia, and also for adults with diffuse large B cell lymphoma. 

But it comes with serious side effects, an extraordinary price tag and a limited number of places--at least in the United States--where the treatment is currently available. Today Dr. Westin and I will discuss the current state of the science on CAR T-cell therapy, as well as access issues that are facing those patients who are seeking treatment with this new modality. Welcome, Dr. Westin, and thank you for joining me today.  

Dr. Jason Westin: Thank you for having me. Before we begin, I'd like to disclose that I have clinical trial funding disclosures that are listed on the ASCO conflict of interest website. Those that I view to be specifically relevant for today's discussion include advisory work as well as clinical trial research funding for CAR T-cell companies including Kite/Gilead, Novartis and Juno. I also do clinical trial work with Celgene, Genentech, AB V, Amgen, MorphoSys, Curis, and 47 Inc.  

Dr. Clifford Hudis: Thank you very much for that. We appreciate that. Let's get into the real focus of our conversation today. And let's start, of course, with CAR T-cell therapy. What is it, for those who might not be familiar? How would you describe it? And further, what makes it so potentially transformative in oncology?  

Dr. Jason Westin: CAR T-cell therapy is an incredible breakthrough for our patients fighting cancer. The word car--c a r--stands for chimeric antigen receptor. What a CAR T-cell is taking a T-cell that's functional and in the body to fight infections, infusing a new receptor on the outside, often a receptor that has an antibody fragment fused to parts of a T-cell receptor that now allow this car T-cell to recognize the wolf in sheep's clothing that's the cancer. 

CAR T-cells are usually modified genetically using a virus to introduce new DNA into the patient's T-cell. And these are prepared in the lab, modified in a way that these can now recognize a surface marker, and then these cells are re-infused into the patient, where they can now grow. They can now find the cancer, and they can destroy it 

This has been potentially transformative because it is something that has completely different resistance mechanisms than standard chemotherapy. CAR T-cells have shown incredible promise in clinical trials and now in early days standard of care. And the sky is the limit for how this could be used in the future, targeting other markers on other types of cancer and really opening up a whole new field of how we treat cancer, much in the way that immunotherapy with checkpoint antibodies has done over the past decade or so.  

Dr. Clifford Hudis: Well, that's exciting. But you just hinted at what I think is the obvious next question. Breakthrough though this may be, clearly this has, at least for some patients, fairly significant side effects. And some of them, I understand, are somewhat different from what an earlier generation of oncologists might have been trained to recognize and to treat. Can you talk a little bit about what some of those side effects are, typically at least? And how we hope to limit that in the future? 

Dr. Jason Westin: CAR T-cell side effects are certainly unique and not overlapping in the way that we think of oncology therapies side effects. The CAR T-cell therapy side effects in the short term are broken down into two main camps. The first is something called cytokine release syndrome, sometimes abbreviated CRS. Cytokine release syndrome is effectively almost like sepsis, in that it's an overwhelming immune response where the T-cells that have been manufactured and infused into the patient release an avalanche of cytokines to effectively recruit other immune cells to come help fight the cancer.  

And in doing so, induces sepsis-like phenomenon of organ dysfunction, fever, and sometimes hypertension, which can be severe. The other acute short-term side effect that we can see from CAR T-cell therapy is a significant neurologic toxicity. And this is a new diagnosis, a new syndrome that's recently been classified by a consensus group as immune effector cell associated neurologic syndrome, or ICANS, for short. 

This can range from mild slowing of speech or mild slowing of cognition all the way to status epilepticus and anything in between. The most common troubles folks have are mild slowing, but aphasias and/or seizures can certainly occur and can be quite distressing to the patient and to the family.  

Thankfully it seems that both cytokine release syndrome and ICANS, the neurologic toxicity, appear to be fully reversible in the nearly all patients, in the vast majority of patients. The late side effects of CAR T-cells are also unique and different from what we've seen from prior chemotherapy-type induced side effects. These include, depending upon what target you're going after, an effective lack of the target expression long term.  

And for CD 19 focusing therapies, this effectively means a B cell aplasia that can sometimes be for a year or longer after the one infusion of car T-cells are administered. We know from other immune therapies that depleting certain parts of the immune system is not usually overwhelming infections or other obvious toxicities, but can result in chronic infections, inflammation and need for replacement of things like intravenous immunoglobulin to replace immunoglobulin deficiency. 

So, CAR T-cell side effects are not what we typically think of in terms of chemotherapy, of cytopenias, nausea and fatigue, or immune therapies of inflammatory responses off target from the projected cancer. These are more specific toxicities related to the extreme expansion and cytokine release of these Car T-cells during the battle against cancer as well as lingering effects from these T-cells remaining active for many months and maybe even years after the infusion. 

Dr. Clifford Hudis: There are a number of barriers right now. You've highlighted some of them. First of all, we don't have applicability yet established for a large number of diseases. That's an area for research. There are special toxicities. And it sounds like, realistically, anybody starting to do this needs to be trained and needs support staff and teams, just like you described. So there's a geographic limitation. 

But beyond all of that, there's also a more conventional limitation, which is just outright cost. And as I understand it, the cost, or at least the list price for available agents, can range from $373,000 to treat an adult with an advanced lymphoma up to 475 to treat a pediatric indication. 

And further, I think these prices do not include the additional costs of hospitalization or managing side effects, and maybe other adverse events. I'm curious, do these prices matter day to day in your practice? Do your patients need assistance navigating this? Or what's the real-world experience, given this price point? 

Dr. Jason Westin: This is a major concern for us for the future of CAR T-cell therapy. The accessibility not just based on physically being able to get it but financially being able to get these therapies, as you mentioned. The cost of the actual product itself, the one-time infusion of these T-cells that are manufactured specifically for each given patient, it's a major cost. 

But in addition to that, the actual hospitalization, which is usually a significant amount of time. For most patients that receive CAR T-cell, they're hospitalized between a week to 10 days. This is not a trivial admission for observation overnight in the hospital.  

These are huge costs. Now payers, including commercial and private payers, and now government payers, are supporting this. However, as the number of patients grow, this is going to be something that's going to increasingly strain the ability of the system to support an incredibly expensive therapy. 

This is potentially home-run therapy for patients that may, in some cases, have decades of life left to go. So, the cost is not trivial for the benefit received. But it is an incredible amount that's put upon the system, put upon the payers. Right now, through payers, it's doable. But I worry about the future of this as the number of patients who can benefit from this goes up. 

Dr. Clifford Hudis: Well, I guess if it's as transformative as you're describing, it is at least plausible that it's front-loading costs, but net actually might not be particularly more expensive than traditional, long-standing, less-effective therapies. I assume those kinds of economic models and reports are being developed. Is there anything you can say about that at this point? Or is it just too soon to make those estimates? 

Dr. Jason Westin: It's still very early days. But there are absolutely analyses being done at looking at the number of quality life years gained from these kinds of treatments. And depending upon the effectiveness of the treatment, it can absolutely be a net long-term positive of somebody getting back to health and not requiring chronic therapies, or not dying at a premature age. 

So, there is no doubt that the cost of this is high, but the benefit is also very high. But if this continues long term to scale up for more and more patients, even net long-term success and long-term neutrality of a cost, if you're paying more now and getting less costs later, it can still strain the system, if the upfront cost is substantial. 

So, I think this is something that's going to have to be looked at in terms of, what is the true cost of making CAR T-cells? And potentially bringing those costs down as we try to scale up for more patients over time.  

Dr. Clifford Hudis: So, you spoke about getting approval, and it sounded like you were talking about conventional commercial payers. Last year, the Centers for Medicare and Medicaid Services, or CMS, announced that Medicare would cover CAR T nationwide and we at ASCO were really delighted with that. 

But we recognize that, while the drugs are being reimbursed, that reimbursement remains at a level well below the actual acquisition costs. So, I think this is another version of the same question, but how is that shortfall impacting patients? And how is it addressed? Or is that just something that the institutions have to eat? 

Dr. Jason Westin: It's different from different institutions, depending upon their status with CMS and if they're grandfathered into older systems, or if they're not protected in that way, it is certainly a problem. And it's something that the approval for this to be funded by CMS was absolutely great for our patients. However, the reimbursement, as you mentioned, that's proposed for that approval is quite low. 

It's not close to the price for the product as well as for the inpatient stay. And so many hospitals are treating commercial patients with the idea that they are reimbursed at a higher level to cover patients who are treated and covered by government payer systems. The government payer systems also have temporary funding that's associated with the new technology, the end-tap mechanism, where there's an initial bump in the reimbursement that's not permanent.  

This is--these add-on payments are helping hospitals who are at risk of having a net loss financially for doing CAR T-cells. But these are only usually two years in length, meaning that this is not going to be a cost assistance for those hospitals for the long future of CAR T-cells. This is short term.  

So, this is something that is new to government payers. This took quite a while after approval for CMS to make a determination on where this would be supported or not. It's all brand new. And it takes time to figure out the potential benefit, the potential long-term reimbursement levels. 

But the current reimbursement levels are not going to be sustainable from government payers to hospitals, as a modality to keep this viable therapy for patients. We've already seen some hospitals that are not able or willing to treat patients who are on a government health-care system, actually sending them to larger systems that are treating many commercial patients to try and subsidize this net loss for a patient on Medicare or Medicaid. 

This is something that is a big problem that's in addition to the cost of it. The substandard reimbursement is going to be a strain on the system in the long run. 

Dr. Clifford Hudis: Well, that's interesting. I mean before the CMS coverage announcement came out, we at ASCO actually submitted comments to the agency, and this included our perspective on both appropriate coverage and reimbursement for CAR T as well as an overarching description of ASCO's principles on approval coverage and getting the right treatment to the right patients at the right time. That's really the underlying principle that we try to rely on.  

I mention that because I know you have some familiarity with policy making in government, and then you've been--we've been--lucky, I think, that you're serving on the government relations committee right now. From the perspective of that, GRC, I wonder if you care to just expand a little bit on the importance of ASCO coming out and taking a stand on an issue like this?  

Dr. Jason Westin: I think it's essential for organizations like ASCO to advocate on behalf of our patients to try and educate policymakers and lawmakers about exciting new breakthroughs and why this matters for our country, as well as for our future. This technology is so new and so innovative. So different than what we've done before in terms of treating diseases with medications or with antibodies, that it is sometimes a shock to the system about what exactly is this CAR T-cell. What exactly does that mean? 

And having lawmakers and policymakers learn from organizations of experts like ASCO. And having policy statements and comments made on potential proposed recommendations. If we don't speak up for our patients, then our patients are going to suffer. And so, I applaud ASCO and the team at ASCO that works on these recommendations and policy statements. 

Because this really is essential for us to speak up and to be seated at the table in a way that we can advocate for our patients. It's sometimes difficult for lawmakers or for policymakers to know what to prioritize. Or if this is something that's real, or if this sounds too good to be true, and therefore we shouldn't learn much about it or pay attention to it. 

As mentioned earlier on this podcast, this is the beginning of a new era of therapy for fighting cancer. And we need to make sure that our policymakers and our lawmakers are aware this is coming, and aware that this is something that's going to be potentially transformative. And therefore, legislating and making policy in a way to allow patients dealing with cancer to have access to these incredible new treatments. 

Dr. Clifford Hudis: So, on the question, again, of access, maybe going in a slightly different direction. We've talked a good bit just now about the science. We've talked a little bit about the toxicities. And we've spoken about the geographic limitations as well as payment. But addressing the geography issue. 

Obviously with scale and familiarity, it's at least conceivable that more centers could offer this, and they might offer it on an entirely outpatient basis. What do you think about that as a near-term potential? And what do you think we have to maybe accomplish? What advances might be needed in order to facilitate that? Or you could say, I guess, not going to happen. So, what do you think is coming in that regard? 

Dr. Jason Westin: I think that the CAR T-cell delivery has such a special need for both monitoring as well as anticipation of management of troubles, that this is not something that I see the current generation of CAR T-cells being administered widely in settings that don't have experience with this, or settings that don't have experience with prior transplant-type treatments. 

This is treatment which has potential danger to go sideways in a hurry. And if you've never done this before, you may not anticipate that, and not be able to help your patients. So, there are current geographic limitations, and centers that do this and centers that don't. And I think that's probably for good reasons at this point and should not be something that we try and break down those walls and have this available at every oncology clinic until we work out ways to make this safer and less dangerous. 

So, it's been a significant challenge to try to transition the current generation of CAR T-cells from an inpatient setting to outpatient setting. We are working on that, as others are. And there are some CAR T-cell products that may lend themselves to easier use as an outpatient, either because of less toxicities or less severe toxicities projected.   

So, this is not something that's going to be a forever problem. But to the current generation of the FDA-approved products, the vast majority are administered inpatient, which is a strain on the hospital systems as well as on patients who prefer not to be cooped up in the hospital for a week to 10 days, if they don't need to be. So, I think this will change as we get better technology, as we get systems in place to monitor patients through telemedicine system as an outpatient. And hospitals have more direct lines from the hotel to the inpatient service, if you have a toxicity. That's coming, but it's been a challenge. 

Dr. Clifford Hudis: I think that's a great place for us to start to wrap this up. I have to ask though, reflecting on what we've covered, is there any area of CAR T science or clinical use that we've neglected to surface in this conversation? Or anything else you want to convey to the listeners?  

Dr. Jason Westin: I think the CAR T-cell story is an incredible advance. When I describe it to my patients, I describe it as almost a science fiction-like therapy where we're able to take your immune system, modify it in a way that it can now see the wolf in sheep's clothing, and get back and re-infuse these cells back in your body. And get them to work to effectively eliminate the cancer that they've not been able to do thus far.  

This is a therapy that works incredibly well for relatively rare cancers at this point. And so I think, as we're smarter and as we learn how to better manipulate the immune system in therapeutic ways, the sky is the limit for how we can both treat cancers and hopefully, even as we get further afield, maybe even prevent cancers from ever developing. 

If we know somebody has a genetic risk that is a high probability of developing a cancer, teaching their immune system new tricks, so that we can have the sky be the limit and really work to try to end cancer, to try and conquer cancer. This is something that is obviously a goal for many researchers and many people who focus on cancer. But this new advance of cell therapy, of CAR T-cell therapy, is a major step forward in our efforts to try and rid the world of cancer. 

Dr. Clifford Hudis: Well, I mean that's just a great way to wrap this up, I think. And I want to again thank you, Dr. Westin for taking the time to speak with me today and for providing so much clear and understandable information. I'm sure this will be useful for a lot of people. Really appreciate it. 

Dr. Jason Westin: Thank you very much for having me. 

Dr. Clifford Hudis: And I do hope that all of our listeners have enjoyed this conversation on CAR T-cell therapy, an exciting and developing area of cancer care. I hope you also see, woven through this, the way in which we are able to take evidence-based advocacy to policymakers to support the kinds of cutting-edge, scientific advances that are members and all of our listeners contributed to through their research and their study.  

And I think that this is something that highlights the connected nature, again, of all of our work and the importance of our engagement. For those of you who want to learn more about CAR T and also breaking cancer policy news, we have that for you at ASCO in action on our website. 

And again, as a reminder, that's ASCO.org/ASCOaction. And in this case, ASCO action is all one word. Until next time, I want to thank everyone for listening to this ASCO in Action podcast. If you enjoyed what you heard today, please don't forget to give us a rating or a review on Apple podcasts or wherever you listen. 

And while you're there, please make sure you subscribe, so you never miss an episode. The ASCO in Action podcast is just one of ASCO's many podcasts. You can find all of our shows at podcast.asco.org.