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Mar 21, 2019

Dr. Marco Davila Discusses How CAR T-Cell Therapies in B-Cell Malignancies Show Promise for Other Cancers.


 I'm Lauren Davis. And joining me today is Dr. Marco Davila a medical oncologist in the Department of Blood and Marrow Transplantation and Cellular Immunotherapy at Moffitt Cancer Center. His clinical focus is utilizing cell therapies to treat patients with hematologic malignancies. Dr. Davila, welcome to the podcast.
Thanks so much for the invitation.

Today we're talking about CAR-T therapies and B-cell malignancies. Your work with targeted therapies in leukemias and lymphomas has grant great promise for patients who, historically, we would not expect to have seen such sustained responses. What do you attribute these response rates to?

Well, this is really a tremendously novel therapy. These patients that have been approved for this therapy have been deemed to be chemotherapy refractory, meaning kind of the standard treatments that you'd give these patients, the patients' malignancies have become well adapted to or are able to evade the treatments. So the immunotherapies that are being applied for these B-cell leukemias and lymphomas really are a complete paradigm shift for medical oncology as well as for the patient's cancers. So these patients' cancers, while they've been well-adapted to chemotherapies, they have not been adapted so well to CAR T-cell therapy.

Can you walk me through the process of obtaining these therapies? What's the general timeline?

Sure, so the first thing we have to do as a medical oncologist is determine that the patient is eligible for the CAR T-cell therapy, if they meet the indications in the label provided by the FDA and the drug manufacturer. So that involves mainly making sure that they have the diagnosis of an aggressive B-cell lymphoma and/or a B-cell acute lymphoblastic leukemia that has relapsed and received at least one prior therapy. So once we deem that the patient is eligible for therapy, we then arrange for the patient's peripheral blood mononuclear cells, and more specifically, T-cells, be isolated from their blood.

So this involves a apheresis procedure, where the patient comes in, usually has the large-bore needle inserted in one arm to collect the blood. It goes through a machine, filters out the cells, and returns the blood through another large-bore [INAUDIBLE] needle in the patient's other arm. So this procedure can last several hours. But afterwards, billions of cells are sent to the manufacturer for isolation of T-cells, and then genetic retargeting to the CD19 antigen present on the patient's B-cells, malignant B-cells.

Amazing-- what other cancers can be targets in the future?

So the initial approvals, as I said, have been for B-cell acute lymphoblastic leukemia and aggressive B-cell lymphoma, but there is very promising late-stage data targeting multiple myeloma, targeting the B-Cell Maturation Antigen, BCMA. And I think many of us expect that myeloma will get an approval for this treatment with BCMA-targeted CAR T-cells sometime in the next year or so. And that's going to really represent another kind of big change to a medical oncology and bone marrow transplantation programs throughout the US.

And that's because two of the major indications for autologous stem cell transplantation, so auto stem cell transplants, are aggressive B-cell lymphomas and myelomas. So many of these patients that standardly would receive an autologous stem cell transplantation may in fact be candidates for CAR T-cell therapy instead. So while myeloma is next in line, I think there's a lot of interest in adopting this technology later to, or hopefully shortly to acute myeloid leukemia as well.

What are some of the obstacles in applying this technology at a cancer center?

Well, I think probably one of the biggest obstacles is that there is a time of production, a time of [? TCQA ?] analysis to make sure that the product that's been made is safe, is not contaminated or anything like that. And sometimes the production time and the [? TCQA ?] time could be short, maybe about two to three weeks. Sometimes this lasts longer than a month.

And as I said earlier, in terms of the indications for this therapy, aggressive B-cell leukemias and lymphomas that are chemotherapy refractory, that these are patients that can't necessarily wait months for a product. So that I think is probably the biggest challenge, to be able to see a patient in the clinic and go, yes, you have very bad aggressive leukemia and lymphoma. And you meet this indication for this therapy. So we're going to collect the cells. And you know, we'll see you sometime in a few weeks or in a few months when the product is ready. That's probably the biggest challenge.

I think, luckily, for some of these products, it seems that their production times have been relatively reasonable, maybe two to three weeks. Other kind of products have really unfortunately taken longer than a month. And those are probably one of the reasons that some of these products are favored by medical oncologists right now, because of disparate in production times. So it kind of has meant that, for some of these patients, we have to kind of keep them in the hospital to give them a bridging therapy, meaning that we try to keep their disease kind of quiet until their cells are ready. So that's probably been the biggest obstacle.

Of course, there is a financial obstacle. There is toxicity obstacles. You know, these CAR T-cell therapies are associated with a unique set of inflammatory or immune-related toxicities and neurologic toxicities, so we've had kind of, as a group of investigators, develop diagnostic and grading schemes and management schemes to manage these toxicities. And I think overall, the last few years, we've seen a lot of progress in this area. And overall, the therapy has become safer than it was maybe 10 years ago when we started developing the first clinical trials for patients with B-cell leukemias and lymphomas.
So in terms of growth, how quickly can this adapt from, say, 20 to 30 cancer centers to other hospitals?
Well, I mean, I think that's the huge need, is that we need this technology be applied at multiple centers. At the center that I'm located at, we are a major CAR T-cell therapy center for probably the Southeast, and really, in the world. We have patients from other countries that come to my institution to get this therapy because it hasn't yet been improved that their own country.
But it means that we're starting to kind of reach our own capacity to be able to provide standard of care, as well to provide know experimental cell therapies, to try to begin pushing the envelope. What's the next disease that we can use to target with these novel T-cell therapies? That means that, for us to be able to do these innovative clinical trials, we need other institutions to be able to kind of shoulder the standard of care.
So right now, there is probably about 30 sites that are providing this technology across the US. Probably the vast majority of these cell therapies really are probably given by only 10 centers. So there is a really big need to be able to go from 30, to really, close to 100 centers in the US need to be providing this therapy for patients to be able to be located close to these sites, for providers to be able to kind of start learning about this technology as well.
And I think probably the big obstacle for that is just kind of just somewhat of the infrastructure that's required to be able to provide this therapy. So institutions have to be able to have a [? FACT-accredited ?] clinical site, where they are approved to be able to collect cells, to be able ship cells, to be of a process these cells for infusion into patients. They have to be able to have multiple doses of tocilizumab, for example, to be able to manage the toxicities. They have to go through kind of an onboarding and auditing process by the manufacturers of these technologies, because it's given under a REMS program, a Risk Evaluation Mitigation Strategy mandated by the FDA.
So there is a lot of hoops that these centers have to be able to go through to provide the therapy. And I think that many of them are, but it's just taking them-- they're the second or third big groups that are going to be getting their approval to be able to provide this therapy. But I think that it's a need for patients. It's a need for the primary centers that are providing this technology right now, is to have collaborators to be able to do this. And as I said earlier, one of I think the biggest pushes that we've had for developing these kind of harmonized toxicity grading schemes, and diagnostics schemes, and management schemes, is to be able to provide this to new CAR T-cell clinicians to be able to say, this is the path you should follow in terms of managing or infusing and managing these therapies.
That brings me to my next question. And you just mentioned toxicities. What kind do you expect? And how do you manage them?
There is two well-characterized toxicities now associated with CAR T-cells. And there is the third as well that I want to mention that I think now is being a little more appreciated. The first is the Cytokine Release Syndrome, or CRS.
And this is essentially a constellation of symptoms that is associated with cardiovascular and pulmonary kind of toxicities. So patients can be hypoxic, tachycardic, hypotensive, any of these number of symptoms. And really, the hallmark of the CRS bill is a high-grade fever that can occur as early as the night of infusion.
And what's believed to be the mechanism behind this toxicity is the in-mass activation of CAR T-cells by their antigen. And with these CAR T-cells get activated, they secrete cytokines and then activate other immune cells that then can get activated and secrete other cytokines, and kind of create this rapidly escalating inflammatory kind of syndrome. And so we and the other CAR T-cell investigators across the US and the world have developed diagnostic and grading schemes to be able to classify CRS.
And while maybe 10 years ago, the standard of management of CRS was really kind of trying to withhold therapy until-- there was concern that the patient was at high risk of death, over the last few years, we moved an early intervention program, where we really kind of intervene at grade two levels of CRS, whereas maybe 10 years ago, it was grade four CRS. And I think that had a really huge impact at making the technology much safer. The concern was that, by intervening, you may be impacting the efficacy of the CAR T-cells, but luckily, that has not borne true.
The second major toxicity is considered to be a neurologic toxicity. So these are, again, another constellation of symptoms that can range from mild kind of confusion, difficulty speaking, to sometimes grand mal seizures and the patients completely obtunded to the point where that they need to be intubated to protect their airway. And this one, while there is, I think, again, a good uniform harmonization of the way we grade these neurologic toxicities, in the way we intervene them, there is still not a great understanding of what's the mechanism behind this toxicity.
So our interventions really rely only mostly on steroids. And some of course will get tocilizumab as well. But we're not certain if how well these agents are at actually mitigating some of these toxicities, or not certain how to treat neurologic toxicity also in the setting of a patient with cytokine release syndromes. There is guidelines, but we're not certain in terms of how effective those guidelines are, probably because we don't necessarily have objective markers to follow with neurologic toxicity. So I think that's a huge area of need right now for CAR T-cell research.
And the last one that we're starting to learn about, at least, again, based on the FDA-approved therapies, is B-cell aplasia. Since this CD19 antigen that's been targeted on malignant B-cells is also expressed on normal B cells, that means patients' normal B-cells will be killed by this therapy as well. So you can have patients that have six months, nine months after treatment, or sometimes years after treatment that, when you check their peripheral blood or their bone marrow, they actually have no B-cells.
And they have very, very low gamma goblin levels, which are the antibodies that are secreted by B-cells, and that these patients can be prone to developing infections. And so I've seen a few patients in my own clinical experience coming back to the hospital six months, a year later with these recurrent infections. Then, lo and behold, it turned out that they have hypogammaglobulinemia. They have B-cell aplasia, that these patients that required longer course of antibiotics, and potentially IVIG to help kind of support them through these periods of infections.
And that's something that really has to be kind of-- what I'm working on is trying to make sure that this is communicated well to the primary medical oncologist, because those are the patients that are really going to be following the patient's long term. So most of these CAR T-cell centers evaluate the patient, and treat the patient, and kind of get the patient through that first month or so after CAR T-cell infusion. But it's ultimately the patient's primary medical oncologist that is going to be managing the patient long term, and it's going to be likely then that's going to be managing the complications of B-cell aplasia long term.
How about clinical trials? Are there any trials that are looking towards the future to move the field forward?
Absolutely, so there are trials, as I said before, targeting AML. There is NKG2D-based CAR technology that already been part of a report that's shown patients with objective responses with this therapy. So we're really excited about that technology.
There is also TCR-based gene therapy as well, going on for multiple different solid-tumor malignancies. There are CARs that are being clinically evaluated for glioblastoma multiforme. And there are also CAR-T developed for any number of other malignancies, such as mesothelioma, prostate cancer. So these are all things that are in the clinical pipeline already there. And there is a next iteration of technologies where, really what we're seeing is the clinical application of the technologies that were developed probably 5 or 10 years ago.

But there is a whole new pipeline of exciting innovations or refinements of CAR T-cells, so bringing in a kind of third generation or armored CAR design, where you add in a cytokine secreting element to it, or where you have a molecular switch so that you can finally control the expression of the CAR or the downregulation of the CAR for safety issues. So these are things that I imagine are going to reach the clinic in the next year or two. And there is a lot of excitement for it, because that's going to really add to our CAR toolkit for the future, to be able to make this technology more efficacious, but also more safe.

That's fantastic. Again, my guest today has been Dr. Marco Davila of Moffitt Cancer Center. Thank you so much for being on our podcast.

My pleasure.

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