Resecabtagene Autoleucel

Cabaletta Bio’s stock dropped 15% over the course of Tuesday, ending the day\'s trading at $1.17.\n Analysts appeared unfazed by the news that a patient treated with Cabaletta Bio’s autoimmune CAR-T suffered a toxicity complication during a phase 1/2 trial.Cabaletta has been evaluating the CAR-T, called resecabtagene autoleucel or rese-cel, across six so-called RESET studies enrolling patients with autoimmune conditions like myositis, systemic lupus erythematosus, systemic sclerosis (SSc), generalized myasthenia gravis, multiple sclerosis and pemphigus vulgaris.In its full-year earnings report, the biotech revealed that a SSc patient had experienced a grade 3-level event of immune effector cell-associated neurotoxicity syndrome (ICANS), a potentially dangerous side effect of CAR-T treatment, nine days after receiving rese-cel.The patient\'s symptoms involved a “transient period of confusion,” and Cabaletta stressed in the release that the individual was “arousable throughout” with “no cerebral edema, seizures or motor dysfunction associated with the ICANS event.”“The ICANS resolved rapidly following treatment with dexamethasone and the patient was discharged without further symptoms,” the biotech noted.The company linked the adverse event to a failure to follow the trial protocol. Specifically, the patient had reported a fever three days before receiving rese-cel, but this information had not been passed on to the medical monitor to decide whether to proceed with the infusion.After considering the information, the trial’s independent data monitoring committee recommended that the study “proceed at the current dose without delay” and agreed with Cabaletta’s suggestion to tighten up oversight of whether participating patients had previously had a fever.William Blair analysts said that while news of the case of ICANS was “disappointing,” they argued it “underscores that the peri-infusion management of autoimmune disease patients is critical in minimizing the likelihood of severe safety events.”“Furthermore, if the patient’s fever had been reported in line with the protocol and a full work-up were performed and confirmed that the infusion should be delayed until inflammatory markers normalized, we believe the event could have been prevented,” the analysts said in an April 1 note. “Overall, we continue to view the early efficacy across multiple indications as encouraging, especially given that all patients are now off immunosuppressants and some appear to be in, or trending toward, a drug-free disease remission state,” the analysts added.Cabaletta’s investors were less positive, however, as the biotech\'s stock dropped 15% over the course of Tuesday, ending the day\'s trading at $1.17.Long a target for oncology, CAR-T has moved into immunology on the strength of academic research last year that showed a patient with lupus achieving remission after treatment.Cabaletta said it is now enrolling an average of one patient a week across the RESET program, with 33 patients having received rese-cel across the trials as of March 14. The company is aiming to share clinical and translational data at the EULAR 2025 Congress in Spain in June.“We are looking forward to meeting with the FDA to align on registrational trial designs in myositis, which affects approximately 70,000 patients in the U.S., by leveraging our emerging clinical data and our efficient development strategy,” Cabaletta CEO Steven Nichtberger, M.D., said in the earnings release.“Since presenting clinical and translational data from the RESET program demonstrating that a single weight-based dose of rese-cel was able to provide potentially transformative clinical responses after discontinuation of all immunosuppressants and while off or tapering off steroids, we have seen robust physician and patient interest in the RESET clinical program,” Nichtberger added.

iStock/ Jian Fan Having established success in cancer, biopharma is now looking to leverage CAR T therapies against a new target, autoimmune disorders, with several early- to mid-stage readouts expected this year. In September 2022, an intriguing report went up on Nature Medicine. Though the study was small, its impact on biopharma has been huge. The study enrolled five patients with systemic lupus erythematosus (SLE), a chronic autoimmune condition where the immune system targets the patient’s own body. SLE triggers inflammation in organs across the body and can manifest as a wide variety of symptoms, including fevers, blood clots, swollen extremities, fatigue and mouth sores. There is currently no cure for SLE, but the Nature Medicine paper sparked hope that one might be near. The study tested a relatively new technology called CAR T cell therapy, which often uses a patient’s own immune T cells, modifying them outside of the body to make them more potent against certain target cells and then injecting them back into the patient. This approach has already seen success in cancer, with several therapies having earned the FDA’s approval: Gilead’s Yescarta, Johnson & Johnson’s Carvykti and Novartis’ Kymriah, to name a few. The Nature Medicine study hinted at similar promise in autoimmune diseases—all five treated patients hit and maintained remission for an average of eight months and no longer needed other treatments to keep SLE at bay. Two years later, the New England Journal of Medicine published a slightly larger study —including 15 patients—that confirmed these findings and pointed to even broader benefits. CAR T therapy not only elicited remission in SLE patients but also resulted in encouraging response rates in those with idiopathic inflammatory myositis or systemic sclerosis. “Cell therapies are the only modality that appear to provide a prolonged period of drug-free remission, which can be transformative for [a] patient’s quality of life,” Sami Corwin, an analyst at William Blair, told BioSpace in an email. The CAR T approach, in particular, offers a one-time treatment option and is “not associated with chronic side-effects,” as compared with other modalities, Corwin added. Though T cell engagers and NK cells are also being eyed as autoimmune treatments, CAR T therapies are leading the charge—for good reason. “CAR T therapies have already demonstrated remarkable success in conditions like lupus and systemic sclerosis by selectively depleting autoreactive B cells, resulting in sustained immune reset,” Katy Rezvani, head of the Institute for Cell Therapy Discovery & Innovation at MD Anderson, told BioSpace in an email. The biopharma industry is now seeking to expand on this early success, with Bristol Myers Squibb, Kyverna, CRISPR Therapeutics and more progressing CAR T therapies in a wide range of indications, including SLE, multiple sclerosis and stiff person syndrome. Here, BioSpace reviews five of the most advanced players in this space and how they’re harnessing—and innovating on—CAR T technology to address autoimmune diseases. BMS Brings CAR T Cancer Expertise to SLE A leader in CAR T therapies for cancer, Bristol Myers Squibb is now leveraging its cell therapy expertise to address autoimmune diseases. The pharma is working on CD19 NEX-T , an investigational CAR T therapy designed to seek out the cell surface protein CD19, which is highly expressed in B cells. Once it binds to CD19, the CAR T construct activates, releasing a cocktail of inflammatory cytokines and other chemicals that destroy the target B cell. This approach is similar to how BMS’ CAR T therapy Breyanzi works—only this time, the pharma is using this mode of action not to kill cancerous B cells in lymphomas but to deplete defective immune cells that mistakenly attack healthy cells. In an email interview with BioSpace , Rosanna Ricafort, vice president and head of late development, hematology and cell therapy at BMS, called CD19 NEX-T a “top priority” for the pharma, with which it plans to “push the boundaries in immune-mediated diseases.” In service of this goal, the pharma is running the Phase I Breakfree-1 and Breakfree-2 studies of CD19 NEX-T in SLE. At the 66th Annual Meeting of the American Society of Hematology in December 2024, BMS presented early data from both trials showing that three patients followed for at least six months were able to stop all other therapies without showing new signs of disease activity. One patient hit the definition of disease remission at six months. Aside from SLE, BMS is also advancing CD19 NEX-T for multiple sclerosis (MS), for which it unveiled early data last month, pointing to encouraging safety and tolerability. The pharma expects to provide additional early-stage data from the Phase I CD19 NEX-T program this year, building up to pivotal trials as soon as the data allow. “Our ultimate goal is to target the root cause of disease and drive long-term, treatment-free disease control for patients with severe forms of these autoimmune diseases,” Ricafort said. Kyverna Targets First CAR T Therapy for Stiff Person Syndrome This year, Kyverna Therapeutics is anticipating several key milestones for its investigational CAR T therapy KYV-101. Like BMS, Kyverna’s approach targets CD19 to eliminate dysfunctional immune cells, leading to what the biotech calls an “ immune reset ” in patients with autoimmune diseases. KYV-101 is unique in that it is designed specifically to avoid cytokine release syndrome and improve tolerability. Kyverna is testing KYV-101 for three target conditions : Stiff person syndrome (SPS), myasthenia gravis and lupus nephritis. Of these, the most mature indication is SPS, for which Kyverna expects to complete enrollment of a Phase II trial by mid-2025, building up to a topline readout in early 2026, CEO Warner Biddle told BioSpace in an email. Typically afflicting women more than men—and more frequently diagnosed in people 20 to 60 years of age—SPS is a rare disorder that arises when the body makes antibodies that attack the enzyme glutamic acid decarboxylase, which plays a role in the production of a neurotransmitter involved in muscle control. Common symptoms include muscle stiffness and painful spasms. If all goes well for Kyverna this year, the biotech expects to file a Biologics License Application for KYV-101 for SPS next year. “We believe this focused approach in SPS will enable us to deliver the first CAR T cell therapy in autoimmune disease to the market,” Biddle said. Beyond SPS, Kyverna is also looking forward to several catalysts in myasthenia gravis this year, including aligning with the FDA on a registrational path for the CAR T therapy in the first half of 2025, followed by a topline mid-stage readout in the latter half of the year. Kyverna’s autoimmune CAR T program is comprehensive, with the company having treated the most patients with a CAR T cell therapy so far, according to Biddle. CRISPR Homes in on Off-the-Shelf CAR T Market Seeking to build on the momentum from its Vertex Pharmaceuticals–partnered gene therapy Casgevy, CRISPR Therapeutics is now moving its allogeneic next-generation CAR T therapy CTX112 through clinical trials in various autoimmune diseases. The key advantage for CTX112 is its off-the-shelf availability, CRISPR Therapeutics Chief Medical Officer Naimish Patel told BioSpace in an email. “The drawbacks of autologous CAR T cell therapies”—those that draw cells from the patients themselves—“are that they are very expensive, require patients to stop their immunomodulatory therapy to get T cells harvested, are not widely available … and are associated with potentially severe side effects.” CRISPR Therapeutics is evaluating the potential of CTX112 in various autoimmune diseases, supported by safety, pharmacokinetic and pharmacodynamic data from cancer studies. The asset is currently in Phase I development for SLE, but at the 43rd J.P. Morgan Healthcare Conference in January, CEO Samarth Kulkarni bared the company’s plans to expand testing to other autoimmune indications. In its fourth-quarter and full-year 2024 business report last month, CRISPR Therapeutics revealed it had expanded its basket trial for CTX112 to include systemic sclerosis and inflammatory myositis. Updates for study are expected mid-2025, as per the biotech. “We see incredible potential for our allogeneic CAR T program, and we are looking forward to sharing a broad program update on CTX112 mid-year 2025,” Patel said. Autolus Awaits Q1 SLE Readout for Obe-Cel The only therapy on this list with an FDA approval under its belt is Autolus Therapeutics’ obecabtagene autoleucel, also called obe-cel, which was cleared by the regulator in November 2024 for relapsed/refractory B cell acute lymphoblastic leukemia. In this indication, obe-cel is marketed as Aucatzyl. Like most of the other assets in this class, obe-cel targets the CD19 epitope. Autolus is seeking to set its candidate apart from the rest of the space through a unique CAR construct that has what it calls a “ fast-off ” kinetic mechanism, which, unlike the traditional approach, enables the controlled binding of the CAR molecule to its target, in turn activating T cells in a similarly controlled manner. According to Autolus, this fast-off scheme closely mirrors the physiological interactions of T cells with their corresponding receptors. Results from a Phase Ib/II study of obe-cel in B-cell acute lymphoblastic leukemia, published in the New England Journal of Medicine in November 2024, suggest that Autolus’ fast-off approach improves T cell persistence and lowers exhaustion, leading to better clinical outcomes. More than half of patients achieved complete remission after obe-cel treatment, with an estimated 12-month overall survival rate of 61.1% Autolus still doesn’t have such detailed data for obe-cel in autoimmune diseases. The biotech is currently running the Phase I CARLYSLE study in advanced SLE, for which initial data are expected in the first quarter of this year, as per a November 2024 company presentation . Cabaletta Anticipates Multiple Catalysts for Rese-Cel in 2025 Cabaletta Bio—which launched in November 2018 with a stated focus on autoimmune disease—was ahead of the curve in this space. It is also the only company on this list that is developing its investigational cell therapy exclusively for autoimmune diseases. CABA-201 , also called resecabtagene autoleucel or rese-cel, is an investigational CAR T therapy that also targets CD19. What makes rese-cel unique is that it contains a 4-1BB domain, which is a protein commonly expressed on activated T cells that helps enhance their activity . Recent preclinical evidence has pointed to the potential of targeting 4-1BB to address autoimmune diseases. Cabaletta is testing this approach in the clinic with its Phase I/II RESET program, which is assessing rese-cel in a wide variety of autoimmune disorders, including myositis, SLE, systemic sclerosis, myasthenia gravis, MS and pemphigus vulgaris. Of these indications, the biotech named as primary focuses myositis, SLE and systemic sclerosis, for which rese-cel’s mechanism has the potential to “achieve robust improvement in clinical disease activity within 3 months of treatment,” according to its website . In a corporate presentation last month, Cabaletta unveiled initial clinical data from the RESET program, touting “consistent and deep” depletion of B cells 22 days after infusion. Additionally, treatment with rese-cel resulted in strong treatment response, pointing to the potential to achieve drug-free remission in patients with refractory disease. Similarly, rese-cel showed the potential of a “drug-free clinical response” in systemic sclerosis, while early data for SLE pointed to promising rates of remission. Cabaletta has several other rese-cel milestones lined up for 2025 , including more clinical and translational readouts throughout the year and a meeting with the FDA to align on a registrational path for the asset.