CAR T cells in autoimmunity: A potential breakthrough about to explode
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First and foremost, I want to remind you that this is an editorial, which by definition offers an “opinion,” so I don’t want to be pilloried for overstating data or brandishing irrational enthusiasm.
Having said that, our cover story represents a continuation of what I promise will be ongoing coverage of what may be a tectonic shift in therapy for patients with the most severe and refractory forms of autoimmune diseases. Lupus is the sentinel disorder here, but many more disorders are now rapidly following suit, entering early-phase clinical trials.
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I am so pleased that among our esteemed panelists is Georg Schett, MD, who seized the day by capitalizing on the success of CAR T therapeutics, which are now the standards of care for a small number of lymphoreticular treatment-refractory malignancies, and building on a growing body of data exploring CAR T-cell therapy in several preclinical models of autoimmunity. He has done this by taking the giant step to treat a small number of patients with highly refractory lupus, and reporting his esteemed group’s results in detail in two of the leading medical research publications in the world.
Based on this early published experience, I have described the results in several of my recent lectures as nearly too good to be true. The patients described in these early reports were by all standards highly refractory to aggressive therapy and the clinical results, thus far, have been extraordinary. As reported, not only has the disease been controlled in all of these initial patients, but they have also, thus far, been made drug free. Finally, the therapeutic effects have endured far beyond the initial treatment period and several have lost virtually all biomarkers of autoimmunity.
Of course, the usual caveats of a small “n,” limited follow-up studies apply, but based on these results, these data demand to be duplicated and expanded — and boy is it now starting to happen.
Before I talk about the explosion, let me share a few of my biases, concerns and outlook for CAR T therapy in autoimmune diseases. In short, the primary and dominant concern has been, and must continue to be, safety.
Of highest concern is cytokine storm and immune effector cell-associated neurotoxicity (ICANS), which in the world of oncology are extremely common and life threating complications of CAR T-cell therapy. One would think that in a patient population of autoimmune diseases, these inflammatory complications would be more common but thus far we have seen the opposite. If true, I believe this is due to the lack of tumor burden and the relative ease of establishing clonal expansion, and may make us rethink the presumed mechanism of adverse inflammatory effects in CAR T-cell therapy.
Secondly, the results are profound and appear to last up to nearly 2 years — in one patient — with several of these patients with severe lupus becoming ANA negative!
Lastly, however, I am most struck by what has been the architecture of immune reconstitution and maintenance of antibody repertoire to memory antigens in the form of vaccine responses. It is as if the slate for autoimmunity has been erased, but more physiologic/homeostatic compartments of the integrated immune response have remained intact. That is what I mean about “too good to be true.”
Also occurring at the same time are next generation CAR T-cell therapies for autoimmune disease where discrete antigens are known (ie, acetylcholine receptor in myasthenia, DSG3 in pemphigus vulgaris, etc.), with more select targeting such as BCMA-expressing B cells and plasmablasts, as recently demonstrated in an RNA transfected CAR T therapeutic trial in myasthenia gravis, which offers the potential of outpatient treatment (see reference).
Finally, let me remind you this is just the beginning and the heavy lifting that lies ahead. At the moment, several dozen CAR T autoimmune disease protocols are now listed on ClinicalTrials.gov for an array of disorders ranging across conditions. Aside from lupus, they include scleroderma, Sjogren’s syndrome, antiphospholipid antibody syndrome, glomerulopathies, immune-mediated cytopenia and much more.
I recently attended a CAR T-cell session at FASEB 2023, in Boston, and was stuck at the scores of companies engaged in advanced CAR T-cell development, the majority of which I was unfamiliar with. There is now a race to investigate the potential of CAR T-cell therapy for our most refractory patients. If successful, I see the potential for this therapy to become more cost effective, as there is an entire subfield of CAR T-cell research dedicated to developing “off the shelf” allogenic cell lines, which, while not as impressive, so far have the potential to be more accessible and less expensive.
I will close by reminding you this is an editorial — and in the words of Hippocrates, “There are in fact two things, science and opinion; the former begets knowledge, the latter ignorance.” We now await the work of science.
That’s my take — what’s yours? Please share your thoughts with me at calabrl@ccf.org or at rheumatology@healio.com.
- Reference:
- Granit V, et al. Lancet Neurol. 2023;doi:10.1016/S1474-4422(23)00194-1.
- For more information:
- 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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