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Throughout 2023, interest in the application of CAR-T and other cell therapies to autoimmune disease skyrocketed, with a multitude of clinical trials being initiated by various companies.
In continuation of a trend that initially got rolling at the tail-end of last year, 2023 saw a record number of investigational chimeric antigen receptor T-cell (CAR-T) therapies enter clinical trials for the treatment of autoimmune diseases.1 These newly initiated studies, many of which are recruiting patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN), seek to push the boundaries of a therapeutic modality that originally proved itself in the field of oncology.
Currently, there are 6 FDA-approved CAR-T therapies, all of which are currently indicated exclusively for the treatment of hematological malignancies like large B-cell lymphoma and multiple myeloma.2 When it comes to B-cell malignancies, CAR-T therapies function by targeting antigens typically found on B-cells and releasing cytokines to destroy them; the intention is to wipe out cancerous B-cells, though healthy B-cells will inevitably be destroyed as well. This mode of action thus has potential to be repurposed for the treatment of B-cell driven autoimmune diseases like SLE.1,3
In November 2022, Kyverna Therapeutics announced that KYV-101, its investigational autologous CD19-directed CAR-T therapy, had been cleared for the phase 1 KYSA-1 trial (NCT05938725) clinical trial in patients with LN. Throughout 2023, several other companies reached the same milestone with their CAR-T and other cell therapy products for lupus. Among these were investigational new drug application clearances for Cabaletta Bio’s CABA-201, a CD19-directed CAR-T, in SLE and LN; ImmPACT Bio’s IMPT-514, a bispecific CD19/CD20-directed CAR-T in active, refractory SLE (rSLE); Artiva Biotherapeutics’ AlloNK (AB-101), an unengineered allogeneic natural killer (NK) cell therapy forming part of a combination therapy with antiCD20 monoclonal antibody rituximab, in SLE and active LN; Nkarta’s NKX019, an allogeneic CD19-directed CAR NK cell therapy, in LN; and Gracell Biotechnologies’ GC012F, an autologous BCMA/CD19-directed CAR-T, in rSLE.4-8
“Despite advances over the last few decades, treatment options for SLE remain inadequate,” David J. Chang, MD, the chief medical officer of Cabaletta Bio said in a May 2023 statement.9 “There are currently no curative options available that achieve durable disease remission. Existing therapies typically result in general immunosuppression, require chronic administration, and are often administered in conjunction with steroids and other immunosuppressive medications to reduce disease burden, which can leave patients with continued disease activity, treatment-associated side effects, and impaired quality of life.”
Several of the aforementioned therapeutics have been previously evaluated for the treatment of hematological malignancies or use constructs similar to those previously used for that purpose.4-9 Although most of these companies initially made the leap to autoimmune disease clinical trials with SLE and/or LN, several of them have now expanded their investigations into other autoimmune diseases. For example, KYV-101 was subsequently cleared by the FDA for trials in diffuse cutaneous systemic sclerosis (scleroderma) and myasthenia gravis, CABA-201 was cleared for trials in active idiopathic inflammatory myopathy (also referred to as myositis), systemic sclerosis, and generalized myasthenia gravis.10-14
In response to this rising interest in cell therapy for autoimmune diseases, 2023 also saw the birth of a new medical conference dedicated specifically to the topic: the inaugural Cell Therapy for Autoimmune Disease Summit, held November 28-30 in Philadelphia, Pennsylvania. CGTLive™ attended the emerging conference in order to speak to experts in the space and learn more about the promise and challenges presented by this novel treatment modality for autoimmune disease. During the course of the meeting several themes emerged.
One of these motifs was the need for an increased focus on safety during autoimmune disease trials in comparison to trials that evaluate CAR-T for patients with late-stage cancers. “I think [an] aspect that physicians will find very important is the safety of these cell therapies since that has become a big question as a whole for cancer,” Tiffany Chen, PhD, the vice president of discovery at GentiBio, told CGTLive at CTADS.
“The risk tolerance is just better there because patients have cancer—they have limited time—and so they're willing to take these,” Chen continued. “[For] autoimmune disease patients, that might not necessarily be the case. As such, ensuring there's really good safety in these cell therapies is very important.”
Another important theme emphasized by multiple attendees at the conference was the increased need for collaboration between different parties during the development of these therapeutics. The input of oncologists, who have experience treating patients with the use of CAR-T, and input from doctors who treat patients with autoimmune diseases but lack experience with CAR-T, will both be essential for biotech companies, academic institutions, and treatment centers to consider during the early stages of this field’s development.
“We're very used to working within a group of oncologists, hematologists, and blood and marrow transplant physicians to treat patients with cancer,” David Porter, MD, the director of cell therapy and transplant at Penn Medicine, told CGTLive at CTADS. “But historically, our cell therapy group doesn't necessarily work with the physicians and their staff that treat autoimmune diseases: the rheumatologists, the nephrologists, dermatologists, neurologists, etc. We certainly have relationships—we know each other, and we share patients back and forth—but we don't have the same experience having a joint program.”
“I think it’s a very exciting time seeing cellular therapies, in particular CAR T-cells, transition from the oncology setting into the autoimmune setting,” Tom Van Blarcom, PhD, the senior vice president and head of research at Kyverna Therapeutics, told CGTLive in a separate interview at the conference. “One of the main things we're learning is that this [effort] has to be a really big partnership between oncology physicians who've been treating patients with CAR T-cells and these new physicians in rheumatology and neurology who have less or little-to-no experience with cellular therapies. Bringing both those communities together, as well as companies like [Kyverna] who are trying to develop these drugs, is a huge 3-way partnership...”
Peter A. Merkel, MD, MPH, the chief of the Division of Rheumatology and a professor of medicine and professor of epidemiology at Penn Medicine, concluded his interview with CGTLive at CTADS with a word of cautious optimism for the future of this emerging field. “I think we are certainly hopeful that some forms of cell-based therapy will help some forms of autoimmune disease and hopefully substantially,” Merkel told CGTLive.
"We need to do this right, we need to move it forward, but I think we're very enthused,” Merkel continued. “We need to see how this plays out and this will take some time. I also think patients will be interested. We need to remember that the goal is to help patients and that's what we're trying to do. We want to be able to raise the bar and help our patients even more than we've been able to so far.”