CAR T cells one year later: What have we learned?
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Nearly 1 year ago, I wrote my first editorial about the emergence and excitement surrounding the early experience with CAR T cells — CAR T Cells in Autoimmunity: A Potential Therapy About to Explode.
That excitement had been driven by the pioneering work of Georg Schett, MD, which at that time was based on the experience of a single patient with refractory lupus put in deep, drug-free remission through the administration of an autologous CD19-targeting T-cell therapy. The buzz surrounding this carefully studied single patient was indeed explosive, yet naturally left many unanswered questions.
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In the interim period, Dr. Schett and colleagues have reported on their subsequent experience regarding 15 patients with lupus, scleroderma and myositis, which have continued this streak of impressive and even dramatic outcomes with no safety surprises yet. As I have just returned from EULAR 2024, I wanted to do a gut check on where we currently stand in this rapidly evolving and expanding field.
In this issue, we have gathered an esteemed group of discussants including Dr. Schett, Allen P. Anandarajah, MBBS; Michelle Petri, MD; Christopher Palma MD, ScM; and Ronald van Vollenhoven, MD, PhD; who candidly discuss both the promise and threats confronting this emerging field.
In Vienna, there were more than 20 abstracts from numerous countries and continents, as well as several well-done industry-sponsored symposia, replete with patient testimonies reporting on further early work with cellular therapies, each moving the needle a bit to improve our understanding of the field.
Some of my reflections include that I now think we should speak more broadly beyond CAR “T cells,” and propose we refer to the field as “cellular therapy.” I base this on the observation that we are now seeing an emergence well beyond autologous T cells. Several dozen companies and more than 40 active clinical trials on www.clinicaltrials.gov are now examining autologous and allogeneic, or “off the shelf,” T-cell therapeutics. We are also seeing the early entry of several NK cell therapeutics, which are also allogeneic.
Furthermore, there are myriad variations of cellular constructs, with varying degrees of “armoring,” designed to protect and prolong the effectiveness, as well as enhance effector functions, of these therapies. Additionally new to our emerging field is the entry of dual CAR targeting, or cells with anti-CD19 plus a second targeting molecule, such as anti-BCMA, anti-CD20 and others.
Overall, the general results of these many abstracts can be summarized as showing continued remarkable efficacy. Unsurprising, the results have not been 100% positive, but it has been close. There have also been no new safety signals. So, at 1 year the field of cellular therapies continues to exceed expectations.
Finally, I want to end with a more sober reflection and urge you to read an outstanding viewpoint published in the June issue of Annals of the Rheumatic Diseases, by Andrea R. Daamen, PhD, and Peter E. Lipsky, MD, critically outlining the potential pitfalls of cellular therapies. These include the potential for long-term toxicities, such as infections and secondary T-cell cancers, which are now under active investigation by the FDA. The authors further reflect — and I agree — that the limitations of the numerous noncontrolled pilot studies now underway are unlikely to alone provide adequate data to optimize the use of cellular therapies in the clinic in the near future. There are many other lessons I could reflect on, but I will save these for another time. For now, despite the limitations, the field is moving on — and we are cautiously and critically following it. That’s my current take on “cellular therapy.” What’s yours? Please share your thoughts with me at calabrl@ccf.org or at rheumatology@healio.com.
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- Leonard H. Calabrese, DO, is the Chief Medical Editor, Healio Rheumatology, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic.
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