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iwCAR-T 2024 | CAR T-cells for autoimmune diseases
David Porter, MD, University of Pennsylvania, Philadelphia, PA, discusses the potential of anti-CD19 CAR T-cell therapy for autoimmune diseases. Early clinical data shows impressive responses in this patient population, who currently have an unmet medical need. Dr Porter highlights challenges such as understanding the mechanism of CAR-Ts, the lack of long-term follow-up, and determining their place among other treatments. He also mentions the potential of allogeneic CAR-NK therapy, which could eliminate the challenges of having to make a new therapy for each individual patient. This session was filmed at the 6th International Workshop on CAR-T (iwCAR-T) held in Miami, FL.
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Transcript
I think that, CAR T-cell therapy for autoimmune diseases is the next frontier in cell therapy. The rationale for using anti-CD19 CAR T-cells, I think, is very strong. And most importantly, the early clinical data is really quite remarkable. There have been reports of using CD19 CARs in very small numbers of patients with a variety of autoimmune diseases, lupus nephritis or other manifestations of lupus, myasthenia gravis, some of the inflammatory myositis...
I think that, CAR T-cell therapy for autoimmune diseases is the next frontier in cell therapy. The rationale for using anti-CD19 CAR T-cells, I think, is very strong. And most importantly, the early clinical data is really quite remarkable. There have been reports of using CD19 CARs in very small numbers of patients with a variety of autoimmune diseases, lupus nephritis or other manifestations of lupus, myasthenia gravis, some of the inflammatory myositis. And it has been dramatically effective. Again, it’s very small numbers of patients. And I think that was emphasized in our session. But just about every patient has responded. One of the things that was very clear is that it’s early in the process. It’s early in the field. The follow-up is very short. How you monitor these patients and how you do proper disease assessments was discussed in a lot of detail. But the the initial clinical data really has been quite remarkable. The other thing is just the magnitude of the unmet medical need. There are millions of patients with some of these really awful autoimmune diseases who don’t respond to traditional therapies, who potentially could have tremendous benefit from from an approach like CAR T-cells.
I think there are a number of challenges. First of all, again, you know, what we know is that application has been very limited to small numbers of patients with limited follow-up so far. There is a different tolerance for toxicity in patients with autoimmune diseases. These aren’t patients who are rapidly dying of cancer where CAR T-cells have have initially been developed. And so there is a different tolerance for some of the toxicity involved with, say, the lymphodepleting chemotherapy and some of the side effects that go along with CAR T-cells. That said, these patients still have a awful diseases. They have many risks that lead to organ failure, things like renal failure, need for dialysis. We saw just an absolutely dramatic, heart moving video of a patient who was having trouble walking and having trouble with facial expressions, who, after receiving anti-CD19 CAR T-cells, was walking normally, her endurance was dramatically improved and then finished riding a bike down the street. And so I don’t think while the toxicity is a challenge, I don’t think we should really minimize the risks associated with some of these diseases.
Some of the challenges identified in the session is that in the initial limited clinical experience, there has been good expansion of the various CAR T-cell products, but very limited persistence. In the cancer field, persistence seems to be important, particularly in diseases like ALL, persistence is an attribute of successful CAR T-cell product. It’s not clear in autoimmunity whether persistence is going to be needed. Will lack of persistence lead to recurrence of disease? We don’t know. There was a very nice discussion about mechanisms of action and and how anti-CD19 CAR T-cells work if they’re not persisting, leading to B-cell depletion. And then this phenomenon of immune reset, normal B-cell repertoires recover. Why don’t the abnormal B-cells recover or will they recover with longer follow-up? So I think the challenge is understanding the mechanism. A challenge is going to be to really obtain good, detailed long-term follow-up on the patients initially treated.
And I think, you know, another challenge is going to be to identify the proper role for CAR T-cells in a sequence of treatment for these patients who have many different treatment options, many different B-cell directed therapies. It’s a very complicated therapy. Each drug is made individually for a patient. And where is this going to fit in the treatment paradigm of auto immune diseases? Some of the topics we learned about, regulatory T-cells that might have a real role in treating autoimmune diseases. And we learned about the potential for allogeneic NK-CAR T-cells, which would be an off-the-shelf product, and eliminate some of the challenges of having to make a new drug, a new therapy for each individual patient. So I think there are many challenges, but even early in this field, they’re already starting to be addressed and discussed in a lot of detail.
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