Axial Discovery - Using Cell Therapies to Cure Autoimmunity
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Using Cell Therapies to Cure Autoimmunity
The Schett Lab at FAU in Germany recently published research showing early clinical data (n=5) that cell therapies could be used to treat, and possibly cure, systemic lupus erythematosus (SLE). The idea of repurposing chimeric antigen receptor T-cell (CAR-T) therapies from blood cancers to autoimmunity is attractive. The technology has shown clinical success in oncology, and flipping the CAR construct has been shown to redirect T-cells to kill autoreactive B-cells versus cancer cells. Despite this promise, the heterogeneity of lupus is a major barrier to bring these potentially-curative medicines to patients.
Lupus is an autoimmune disease causing damage across several organs from the skins to the kidneys and heart. Lupus’ complexity has been a historical hurdle for drug developers. The disease has several subtypes with SLE as the most common. On top of this, a major complication of SLE is lupus nephritis, where lupus autoantibodies begin to damage the kidney. Overall, lupus drug development has been through 4 main periods:
Classical - before modern medicine, lupus (Latin for wolf) was characterized by facial lesions that resembled wolf bites.
Neoclassical - work in the late 1800s from Moritz Kaposi led to the determination that lupus was a systemic disease, not just localized to the skin
Modern - the era we are currently in catalyzed by the 1948 discovery of the lupus erythematosus (LE) cell led by Malcolm Hargraves from Mayo Clinic. This discovery started the trail of understanding the root causes of lupus, which is still an open field of research to this day. Cortisone became a standard-of-care for lupus patients along with other immunosuppressive drugs. With next-generation biologics gaining approvals in the 2010s.
Post-modern - the era lupus is entering where cures become within the realm of possibility
A family friend, who was on my high school football team, had a mom with lupus. Seeing her show up to games & practices despite various complications left an indelible mark on me. Autoimmunity tilts more toward women than men with women 10x more likely to get lupus than men. And has lagged behind all the progress that has occurred for cancer patients. A common theme for medicine is bringing the new tools from cancer precision medicine to other diseases. Cardiovascular. GI disorders. Autoimmunity. And more. At least 20K people in the US get newly diagnosed with lupus each year. With a relatively low mortality rate (~10%) there are millions of lupus patients around the world struggling to manage their symptoms and live a normal life.
Despite centuries of research, the underlying cause of lupus is not fully known. Disease associations like dsDNA autoantibodies, organ inflammation, among others helped with leads. Genomics has given glimpses here & there and has supported the development of targeted therapies but more work is left to be done. What has made this such a challenge is that a given lupus patient has a slightly different immune response, which manifests into a significant degree of disease variability. Moreover, symptoms can be non-specific to lupus and occur in other diseases, making diagnosis extremely difficult. Because of this, there is a large need for new target discovery platforms for lupus and autoimmunity in general. Seranova Bio is the category leader here.
With an increasingly deeper understanding of lupus, better therapies are emerging. Aspirin was the first FDA-approved medicine (1948) to treat lupus. Various corticosteroids were approved thereafter, and even an anti-malarial drug (hydroxychloroquine) was approved in 1955. But all of these drugs worked to suppress the immune system and manage the disease. These were important advances to relieve the pain, sores, and fatigue all lupus patients experience. However, they came with nasty side effects from suppressing the entire immune system. There are entire Reddit forums dedicated to talking about treatment combinations to reduce side effects - everything from optimizing drug cocktails they are taking through trial-and-error and also establishing the correct diet. There is a massive opportunity to also develop non-pharmacological interventions to treat autoimmunity with a model similar to Virta Health.
Unfortunately, it took over 5 decades for a new lupus drug to gain approval: Benlysta (belimumab), a monoclonal antibody (~40% response rate based on a composite index) from GSK & developed by Human Genome Sciences suppressing B-lymphocyte stimulator (BLyS) protein (a B-cell activation factor). After getting approved for SLE in 2011, the drug was approved in 2020 to also treat LN. The idea is that BLyS is elevated in lupus patients and inhibiting it could reduce the severity of the disease. Benlysta combined with the standard-of-care ultimately met its clinical endpoints and whose approval was a landmark event in lupus’ history. In previous decades, countless late-stage clinical trials failed, mainly due to various types of toxicities. For example in 2008, a drug candidate, atacicept that also interacts with BLyS was tested in LN, but the trial was ultimately halted due to a large number of infections. Similarly, ocrelizumab’s trial in LN was stopped due to fatal infections in patients taking the investigational drug. It’s thought that the patient’s prior treatment regimens in combination with the experimental drugs overly suppressed their immune system leading to more vulnerability to infection. Across 4 trials, GSK did an outstanding job at designing them and figuring out the right dosing/treatment profiles to move forward with. Benlysta is an important drug in the lupus toolbox but other drugs in development have a window to increase response rates and help patients sooner (Benlysta often takes a month or two to help patients get relief from flare-ups).
Benlysta’s approval seems to have opened the floodgates in lupus. In 2021, Aurinia’s Lupkynis (voclosporin) was approved in LN (complete renal response rate < 50%). Later that year, Saphnelo (anifrolumab-fnia) from AstraZeneca was approved to treat SLE - the drug is a first-in-class type I interferon receptor inhibitor (a response rate a little under 50%). There are several programs in progress as well, targeting IL-6, IL-17/23, CD40, CD220, and more to help lupus patients. Kezar Life Sciences is also doing interesting work in lupus developing an immunoproteasome inhibitor to build on top of the success of Proteolix/Onyx, which was acquired by Amgen in 2013 and the developer of Kyprolis, a proteasome inhibitor approved to treat multiple myeloma. The company is still working through clinical development where there are many pitfalls particularly in lupus. But Kezar’s immunoproteasome inhibitor could deplete autoantibody-secreting plasma cells and become a pipeline-in-a-pill expanding treatment options in lupus. Over the next decade, new drugs will likely gain approval in various types of lupus. These medicines are an early sign of precision medicine’s (late) entrance into lupus.
To build on top of this recent success and the progress of cell therapies in oncology, new technologies are being developed to bring potential cures to lupus patients. Various companies have sprouted up here from Cabaletta Bio to Kyverna and Sonoma. The Schett lab’s research represents forward progress for lupus patients; I think a half-century is a long enough wait for better treatments. In the paper, 5 SLE patients (4 female, 1 male) that were refractory to the standard-of-care were given autologous T-cells with an anti-CD19 (a B-cell marker) CAR construct. After lymphodepletion and dosing 1 x 10^6 cells/kg into each patient, they experienced drug-free remission after a median of 8 months. These results held up ever after the re-emergence of B-cells in ~3 months with moderate toxicity profiles, mainly cytokine-release syndrome (CRS). Despite these results, this work creates more questions than answers. Will these patients eventually relapse? Will pre-conditioning always be required? Will these cell therapies have different tolerability profiles that cancer CAR-T medicines? Can new technologies be developed to target long-lived plasma cells? Not just B-cell activation. These are opportunities for existing companies and new ones alike.
Cabaletta Bio is the first-mover here. They successfully brought one of their own cell therapies into the clinic but mixed results are an early signal that the field will face many more hurdles before success (i.e. you’re gonna need a bigger boat). Cabaletta is pioneering the use of CAAR-T cells = chimeric autoantibody receptor T-cells. Historically, the pioneers get the arrows, while the settlers get the land. Similarly, Cabaletta is opening up various avenues for startups to follow through. The company was founded in 2017 based on IP from Aimee Payne and Michael Milone at Penn with expertise in B-cell mediated autoimmunity from the former and CAR design from the latter whose work actually helped lead to the approval of Kymriah, a CAR-T therapy in cancer. Led by Steven Nichtberger (CEO), with experience from Merck and small biotechs, Cabaletta built a platform to design CAAR constructs to target and kill specific B-cells that produce autoantibodies.
CARs in cancer are made up of 2 major parts: (1) an extracellular domain to bind the target made up of an antibody fragment specific to a cancer antigen and (2) an intracellular signaling domain to induce T-cell stimulation - common domains are CD3 ζ to initiate cytotoxicity and CD137, which enhances T-cells durability. The premise of Cabaletta was to repurpose this technology to focus on autoreactive B-cells. Versus CARs, double-A CARs or CAARs display an antigen on the extracellular domain instead of an antibody fragment. The antigen is meant to lure in pathogenic B-cells closer to T-cells to be killed.
Recently, Cabaletta reported phase 1 clinical data (n=16) for their lead product, a CAAR-T cell to treat mucosal-dominant pemphigus vulgaris (mPV). The drug candidate failed to generate a response even at the high-end of dosing of 7.5 x 10^9 cells. This may be due to residual autoreactive B-cells within lymphatic organs and other inflamed tissues that are not accessible. One patient showed a positive signal and there weren’t dose-limiting toxicities. This data has motivated the company to prioritize pre-treated patients in efforts to maximize odds of a response. Then to diversify, Cabaletta now has a CD19 CAR-T preclinical program. These initial results unveil a few interesting opportunities to develop cell therapies for autoimmunity:
Autoantigen discovery platforms to map out new targets for cell therapies to engage for the over 80 autoimmune diseases from lupus to rheumatoid arthritis (RA) and multiple sclerosis (MS)
New approaches around dosing and T-cell activation before reinfusion into a patient. Cabaletta has established that high doses could work in autoimmune patients without severe side effects like CRS that are often found in cancer patients treated with CAR-T. The current results suggest that B-cell depletion wasn’t robust enough to generate a response - this is why pre-conditioning might always be a requirement in this field, but there are also interesting opportunities to play around with activation states of T-cells put into patients. Also, tapering steroid treatments might end up being an important driver of success, which helped the efficacy signal of Saphnelo to be more easily detectable.
Once you can systematize target ID and dosing, the hardest problem to solve is manufacturing. CAR-T prices (~$1M) in cancer won’t work in autoimmunity - the patient population is too large and the mortality rates too low versus oncology. As a result, new tools are needed to lower the cost of cell therapy manufacturing before they have a large impact on autoimmunity. Given the current pace of biomanufacturing of cell therapies in cancer, it might be another decade before they can be cost competitive for diseases like lupus.
Trial design is the intangible opportunity for all drug developers in lupus. The disease is highly variable with most patients on at least 2 medications already. Prior treatments could mask the effects of a tested drug. This requires various forms of treatment tapering to reduce the background noise of past medications to improve the quality of the clinical data.
Then diagnosis is essential to define lupus heterogeneity: the core issue in lupus. It will also be very important feeding into clinical trial recruitment and disease control. Lupus is pretty mysterious. And current tests primarily focus on symptoms. There is an anti-nuclear antibody test to measure antibodies that attack self tissue, but it only indicates a risk for lupus not the actual disease. New tests need to be developed that catch patients earlier and more precisely. This would be a massive boon for lupus drug development because clinicians can be more confident of a diagnosis and disease activity to determine if a patient should be enrolled in a placebo-controlled trial.
Treatments for lupus started broad and have slowly become more precise toward an era of potential cures. This will be an all hands on deck moment requiring new drugs from biotech as well as collaborations between various medical specialties from rheumatologists to cardiologists, dermatologists, and nephrologists. The bar for cell therapies in autoimmunity will be much higher than cancer. The net benefits will need to be higher in terms of relapse rates and costs because current treatments for autoimmunity can already manage symptoms decently well. These problems are opportunities for startups to bring cures and fulfill the promise of selectively destroying destructive B-cells in autoimmune patients.
