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A treatment exists that can cure aggressive lymphoma after chemotherapy has failed. Only about two in ten eligible patients receive it. Manali Kamdar is clinical director of lymphoma services at the University of Colorado Anschutz, and Paolo Strati is an associate professor of lymphoma and myeloma at MD Anderson Cancer Center. This episode is based on their article “CAR-T therapy can cure cancer. Why is it so underused?” published on KevinMD. You will hear what this therapy asks of a patient, from cell collection through the wait for manufacturing to the weeks spent living near a treatment center. They walk through the barriers a stakeholder summit identified, including the two-week payer authorization that runs while the cancer grows, the small number of accredited centers, and the myth that eligibility works like transplant eligibility. Press play to hear why they say a relapse should trigger a referral, and why they measure success by who can deliver this treatment rather than who receives it.
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Transcript
Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast. Today, we welcome Manali Kamdar and Paolo Strati. Both of them are hematologist-oncologists. Today’s KevinMD article is “CAR T therapy can cure cancer: Why is it so underused?” Manali and Paolo, welcome to the show.
Manali Kamdar: Thanks for having us.
Paolo Strati: Thank you very much, Kevin.
Kevin Pho: All right. So I am going to ask each of you just to briefly share a story, and then we’ll jump right into the KevinMD article. So Manali, why don’t you go first and briefly tell us your story?
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Manali Kamdar: Well, I was born and raised in Mumbai, India, and I initially wanted to be a dancer, but then, as luck would have it, I eventually had to be cared for by a lot of doctors, and during that time I was really passionate about the idea of taking care of someone. That led me to pursue medicine, and subsequently I decided to pursue higher studies in the United States.
That got me to North Carolina, where I got internal medicine in my veins and blood, and through that I became quite passionate about pursuing oncology, when I saw one of my mentors taking care of somebody with metastatic breast cancer for 10 years. She led a lovely life, and she also had a peaceful end of life. So there was dignity to life and dignity to death, and I thought it was a very unique opportunity to serve mankind.
That is what led me into the world of oncology, and then I trained in New York with Dr. John Leonard, which made me more passionate about blood cancers, in particular lymphomas. It’s the most common blood cancer.
Then I went to Stanford for higher studies, where I pursued a cellular therapy and transplantation fellowship, and after that I actually went back to Mumbai and tried to set up a center there. Then, as luck would have it, I got a call from the chair of medicine and hematology at the University of Colorado to start a lymphoma program. Now, this was 12 years ago. It was an offer too hard to pass up and I took it, and I am now still in Colorado. I lead the lymphoma division here, and we are now a group of four excellent physicians in addition to me.
And yes, I think I have a life here personally as well. I married a Coloradan, and have a five-year-old daughter. So I can say that I am now quite vested in the United States.
Kevin Pho: Wonderful. And Paolo, why don’t you briefly share your story?
Paolo Strati: Well, my story is actually not much different from Manali’s. We sometimes say that we are siblings from two different mothers. I’m also an international medical graduate. I was born and raised in Italy, in the south of Italy, actually in a neighborhood and a family of very low socioeconomic status. That was probably the trigger for me to develop the empathy necessary to want to help the community, and the way I decided to help the community, in my case, was to become a medical doctor.
I also had my initial training in Italy, where I was a faculty member. Initially my focus was more internal medicine and emergency medicine, and I realized that I was really helping individuals in the short term, not in the long term, and that the way to have an impact in the long term was to do clinical research. That was the main driver for me to relocate to the United States.
As with every international graduate, that meant I had to redo my training. I went through internal medicine residency at the Mayo Clinic in Rochester, Minnesota, then eventually hematology-oncology fellowship retraining at the University of Texas MD Anderson Cancer Center in Houston, Texas, where I remain as a faculty member. I’m an associate professor. I have been on the faculty there for more than seven years, and I serve as deputy chief for indolent B-cell lymphoma. Institutionally, I help lead the CAR T-cell toxicity program.
Kevin Pho: All right. Both of you wrote this article, “CAR T therapy can cure cancer: Why is it so underused?” Manali, for those who didn’t get a chance to read this particular article, just tell us what it’s about. Maybe give some context for people who aren’t familiar with CAR T therapy, and then talk about the article itself.
Manali Kamdar: Absolutely. I think in general our audience is very well aware that cancer is the most common cause of mortality in the world, and one of the most common cancers is actually lymphoma. Lymphomas are of several different types, but the ones that can be quite aggressive, eventually leading to dismal outcomes and patient demise, are aggressive large cell lymphomas.
Previously, all we had in our pocket was chemotherapy. So if patients responded, good. If not, which was about 50 percent of patients, we just kept giving chemotherapy. And if that did not work, we used to take them to transplants, which were extremely toxic, and quality of life was disabling. That’s really when the advent of immunotherapy came along.
As everybody knows, chemotherapy kills normal cells as well as cancer cells, because both are fast-growing cells and it cannot really differentiate between the two. The advantage of immunotherapy is really manipulating the immune system. I think our ancestors were right that people get cancer when their immunity fails. And what does this essentially mean? It essentially means that your T cells become exhausted, or just are not able to recognize cancer as a foreign antigen.
I think one of the biggest advances in T-cell manipulation came in the form of the advent of chimeric antigen receptor T-cell therapy, CAR T-cell therapy. It’s essentially genetic engineering of the patient’s own blood. So we take a little bit of blood from the patient, take it to the lab, isolate the T cells, which are the fighter cells, and make them super T cells. So a T cell with an antenna, an antenna that can now recognize the lymphoma cell as a foreign entity. We manufacture that in the lab and then simply infuse it into the patient and let it do the job that it has forgotten to do.
With that, CAR T-cell therapy is actually curative in patients with heavily pretreated relapsed or refractory large B-cell lymphoma. So previously, about 40 to 50 percent of patients used to succumb to the disease, and those patients are now salvaged by CAR T-cell therapy.
This has also now been FDA-approved for almost a decade. You would imagine patients as well as providers would really clamor toward this treatment. However, access has been a huge issue. We do know, based on data, that about two out of ten patients who are eligible get to CAR T-cell therapy. So why do the remainder not, or cannot, get to CAR T-cell therapy?
This has been a passion project for the Lymphoma Research Foundation and for Dr. Strati and me. I do believe that is what really led us last fall to lead a stakeholder summit that was organized by the Lymphoma Research Foundation. It was convened in Washington, D.C., and it really explored many different facets. It was patients, caregivers, insurance payers, as well as regulatory providers, nurses, nurse practitioners, every single piece of this pod that really takes a patient through. This is a CAR T village, and we were really identifying what were maybe the top five reasons why patients cannot get access.
And I think what we found out was that the most common one was lack of knowledge of CAR T-cell therapy, and the time and the expense of such treatment, because clearly in the United States, even if it is an FDA-approved product, it’s a half-million-dollar enterprise. Payers have to approve it. And because it’s curative, payers approve it. But the process it takes for payer authorization to happen is about two weeks. Now, during that time, the cancer is obviously growing. And then there is obviously the manufacturing time. The cancer is obviously growing.
So we are coming up with an assessment of what it is that’s really preventing our patients from even getting to that first consult at a CAR T site. Besides that, we recognize that not everybody has a caregiver who can actually partner to travel and stay with the patient during the process. And in the U.S., I can say very few centers are still CAR T-accredited. Like I said, I think it’s not just about the ability to have it on hand, but the ability to access it.
So with that in mind, we were able to interview, host several panels, and come up with an action plan moving forward. I thought that stakeholder summit was an eye-opener, and I thank the Lymphoma Research Foundation for that.
Kevin Pho: So Paolo, tell us a little bit more about the patient experience when it comes to CAR T therapy. Just hearing what Manali said, you have to go to a CAR T-certified site. From the patient standpoint, just give us a sense of the experience of what they have to go through, in contrast to chemotherapy, if they go through the CAR T route.
Paolo Strati: Yeah, so the experience can be very different. If patients are seeking CAR T-cell therapy within a smaller academic center, maybe close to their community oncology area, or a larger academic center, it may require travel for them.
From a practical perspective, as Manali alluded to, first and foremost, patients require what is called a leukapheresis. In many cases this requires a central venous line to be placed in their neck, which can be uncomfortable, so the white cells can be collected. And then there’s a nerve-wracking waiting time.
So Manali referred to the need for manufacturing the white cells, so that this CAR, the chimeric antigen receptor, can be genetically inserted, but that doesn’t happen overnight. It can take as short as 17 days and as long as one month, and during that timeframe about half of patients can just wait and watch, but a little bit more than that do require some sort of treatment. That could be chemotherapy or radiation or some novel biological treatments, including bispecifics. So actually, these patients may still be receiving chemotherapy and treatments overall as a bridging or holding treatment as they’re waiting for the CAR T-cell infusion.
Once they’re notified that the CAR T cells are ready, they actually have to receive chemo for three days. It’s called lymphodepleting chemo. Most of the time this is given outpatient, but for patients who are older and frail, it may require inpatient hospitalization.
And then finally, the so-called day zero happens. Now, for some CAR T-cell products that don’t grow too quickly, with what we call a costimulatory domain called 4-1BB, some centers are able to provide the CAR T-cell infusion completely outpatient, and the patient will just come back on a daily basis to be monitored for complications. But for others, those that have a costimulatory domain called CD28, most centers will require inpatient hospitalization up to day plus seven. Subsequently, if patients have no complications, and this includes cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome in addition to potential infections, then they can be discharged, but they’re still being monitored very closely.
Now, the requirement for monitoring has changed recently. Up to last year, there was an expectation, in the patient’s best interest, that they would stay in the vicinity of the academic center for about four weeks after the CAR T-cell infusion. But more recently, to facilitate that process, this has been shortened to two weeks.
Despite that, in my personal experience, and again, all of this is in the interest of patient safety, even after two weeks after CAR T-cell infusion, when patients are potentially allowed to go back to their home and their community oncologist, we first have to make sure that the community oncologist, based on their resources and their experience, is willing to take those patients back. And in my experience, as of today, very few of them are ready to do that. So at the end of the day, these patients actually end up requiring relocation for at least a month or longer from the CAR T-cell infusion.
Kevin Pho: But, Manali, one of the things that you mentioned as one of the reasons why CAR T-cell therapy isn’t used as often is a lack of knowledge. How much is it a lack of knowledge from oncologists, and how much is it a lack of knowledge from patients?
Manali Kamdar: I do have to say it’s a little bit of both. I think our field in oncology is evolving at breakneck pace, with innovations happening while we are talking today. So it’s really hard for community partners, who do not specialize in one particular cancer but are serving so many different cancers, to keep up with the field.
It may also have to do with the office pathways in the community, where they just go with the pathways, and based on that, there is no CAR T-cell referral in that pathway, so they’re not coming to us.
Third is really this myth that CAR T-cell therapy eligibility is very similar to transplant eligibility, and that is absolutely not true. I took an 89-year-old to CAR T-cell therapy. I optimized his organ function. He had a low EF. He had a low creatinine clearance. I got onco-nephrology involved and onco-cards involved, and took him through liso-cel, which is the 4-1BB construct that Paolo was talking about. He had very good caregiver support, and I essentially got him to CAR outpatient. And his only toxicity was boredom, which is what I wish everybody would say it is.
But the truth is that, yes, I think that in 97 percent of cases, if toxicities have to happen, they happen in the two weeks. As a result, we’re able to get our patients back out to the community partners sooner. But that community partner is that hub and spoke in this whole enterprise, because the referral doesn’t come to us unless it’s generated by the community partner.
And then I will say a little bit on the patients as well, and we try our best. The Lymphoma Research Foundation has had so many education seminars, and we take our personal time off to educate our patients through multiple virtual platforms like the Lymphoma Research Foundation. At this point in time, it has definitely enhanced knowledge of CAR T-cell therapy.
But I do believe that googling does not help. I feel it’s very easy for patients to just type and look at the dismal outcomes, the toxicities with CAR T-cell therapy, get overwhelmed, and even if they have a caregiver, not actually get to that consult to even discuss it with the CAR T expert.
So I think my plea to community partners is, if you think someone’s relapsing, just look for the CAR T site and refer. That’s all we ask for. My plea to patients is that social media platforms are great. It’s definitely a bonding, a community, a sense of “He is going through the same thing as I am going through. We are in this together.” But I don’t believe that individual patient experiences can be replicated across all human bodies.
We have such better tools to take our patients to. We optimize their health so much better that truly CAR T-cell therapy is way easier on the body than chemoimmunotherapy. If someone has gone through chemoimmunotherapy and relapsed and is now seeking CAR T expertise or a consult, I will tell you that it’s going to be a whole lot easier on you.
So I think it’s really education. It starts with education, and multiple times over. America is a huge country, and I think Paolo and I definitely represent academic sites that just see these referrals, but the true America is living in the rural areas. How do we get this innovative, curative treatment implemented at these sites is really the next challenge that we are all ready to take on. We just have to keep identifying what are the points that we can work on.
Kevin Pho: Paolo, for those community oncologists who may be listening to us now, tell us a type of common scenario where they should be thinking about CAR T therapy that typically would come up.
Paolo Strati: So I want to start by saying that both Manali and I have a lot of respect for our community oncology partners and collaborators, because we understand that, differently from us, they are able to take care of multiple types of cancers, whereas Manali and I are currently very specialized in lymphoma. So there’s no expectation for them to necessarily know exactly what type of lymphoma patient should be considered eligible for CAR T.
So the message that I would like to convey is that for any patient with a B-cell malignant lymphoma, which is currently the subtype where we have FDA approvals for CAR T today, an initial collaboration with us may help. The reason I’m saying this is that while CAR T-cell treatments are currently approved by the FDA when it comes to large B-cell lymphoma that relapses after a first line of anthracycline-based chemotherapy, there could be in the near future an approval for patients who have a suboptimal response to frontline treatment and have high-risk features. So actually starting that collaboration even at an initial diagnosis of large B-cell lymphoma, and other subtypes of B-cell lymphoma, can be very helpful, because it can provide some guidance.
And all of this is in light of the fact that, differently from the other cancers that the community oncologists take care of so well in the community, the solid tumors, those are very frequent. You will have one case in every hundred individuals in the U.S. every year. But when it comes to lymphoma, that’s one case in every hundred thousand, every million sometimes if you consider marginal zone lymphoma. So I think the cooperation from the beginning between academia and community oncology can be very helpful both for patients and providers.
Kevin Pho: We’re talking to Manali Kamdar and Paolo Strati. Both are hematology-oncologists. Today’s KevinMD article is “CAR T therapy can cure cancer: Why is it so underused?” Now I’m going to end with just asking each of you to share some take-home messages to the KevinMD audience. Paolo, why don’t you go first, and then we’ll end with Manali.
Paolo Strati: So the first one is that working together is going to be the key to success. And when I’m referring to together, I’m referring to community oncology, academia, but also, most importantly, patient partner organizations. PPOs such as the Lymphoma Research Foundation can be a one-stop shop where both providers and patients can have access to more knowledge about lymphoma and more knowledge about resources available, both in terms of financial support, insurance support, and overall integration between their providers.
Kevin Pho: And Manali, we’ll end with you, your take-home messages.
Manali Kamdar: I think my take-home is that a relapse should trigger a referral to a site which has access to CAR T-cell therapy. We’ll take care of it all. We just need to see the patient ASAP.
I do believe that we need to move from center-based excellence to more system-wide capability. I think the measurement of success is not about who just receives CAR, but who can deliver it. So we need to align stakeholders. That will include not just clinicians, community partners, referral providers, payers, industry, and regulators, as well as patients. I think around this, we need to build access as a quality metric. I do believe that the future of CAR T-cell therapy is not just innovation; it is implementation, scalability, and access.
Kevin Pho: Manali and Paolo, thank you so much for sharing your perspective and insight, and thanks again for coming on the show.
Manali Kamdar: Thank you.
Paolo Strati: Thank you very much for having us.
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