Taking CAR-T for a Test Drive Save

When the ACR Convergence 2024 abstract site went live, the first query I typed into the search bar was, “CAR-T.” I consider myself a CAR-T skeptic and would be surprised if the magical results from this NEJM case series replicate at scale, but it seems likely that CAR-T will revolutionize the care for (some) patients with rheumatic diseases. What is CAR-T? How can you get a healthy dose of it at ACR? And what does it mean for the future? Read on to find out!

CAR-T may still be unfamiliar for many rheumatologists. For a comprehensive and well-written run-down, I recommend starting with this excellent piece in Nature Reviews: Rheumatology. In brief, however, The “CAR” stands for “chimeric antigen receptor” and refers to artificially-created transmembrane receptor proteins; the “T” refers to T-cells, which are the most common current vector. Most current platforms use autologous T-cells (i.e. from the patient themselves), which are given the CAR and then re-infused to a patient who has undergone lymphodepletion with cyclophosphamide and fludarabine. Because most current platforms target CD-19 or BCMA, the re-infused CAR-T cells bring about a profound depletion of B-cells.

What new data will be presented at ACR? The most exciting abstracts will all be presented on Sunday, November 17th at 2024 in “Abstracts: SLE – Treatment I: Cellular Therapy” from 3:00-4:30PM EST.

Thus far the vast majority of clinical experience in this area comes from Georg Schett’s group, who published the aforementioned NEJM case series and is reporting (as far as I can tell) all of the clinical data at this year’s meeting. I find that a little disappointing; it would be nice to see their approach and experience generalized to a wider study population.

In Abstract 1749 (and I think Abstract 1750 - unclear if the same population) they have updated their initial experience to include 30 total patients (19 from the patient used program, 11 in the Phase 1 CASTLE trial). This included 18 patients with systemic lupus erythematosus (SLE), 7 with systemic sclerosis (SSc), and 5 with idiopathic inflammatory myopathies (IIM).

Similar to their prior reporting, CAR-T fixed everyone and allowed them to go off therapy (DORIS remission in lupus, no progressive ILD in SSc, ACR/EULAR major response in IIM). Importantly, therapy was well tolerated, with half of patients having tolerable cases of cytokine release syndrome, none having immune effector cell-associated neurotoxicity syndrome, and only a few “mild” infections. 

The same group also shared a “next-generation” process for CAR-T in Abstract 1753, which purportedly has a shorter manufacturing time and improved potency. Neither the manufacturing time nor the potency were compared to prior products in the abstract, but similar to prior reports, all 9 patients who received the investigational agent improved and were able to discontinue rheumatic disease therapies.

If these results do not scale or safety issues become more problematic, other CAR-T or CAR-T adjacent therapies may fill the void. Two abstracts that I found particularly interesting targeted autoreactive 9G4 idiotope B cells, which generate many of the relevant pathologic antibodies in SLE. They approached these in two ways, using targeted CAR-T cells (Abstract 1751, CAR-T against 9G4 B cells) or bispecific antibodies (Abstract 1752). Both abstracts demonstrated success in selectively depleting autoreactive B cells in SLE, which opens the door for “precision” medicine – i.e. killing the “bad” B cells while leaving the “good” ones alone.

CAR-T has great promise, but additional studies with comparator groups and studies from other research groups will be necessary. Long term side effects and the logistics of administration will need to be studied. That said, CAR-T has great promise and any session discussing it will be well worth your time!