Resetting the Immune System: Cell Therapies for Autoimmune Diseases

The advent of cell therapies, particularly those harnessing advanced cell engineering techniques initially developed for cancer treatment, offers a new frontier in the management, and potential cure, of autoimmune conditions.

Companies like Kyverna Therapeutics are pioneering in this space, focusing on targeted cellular therapies aimed at ‘resetting’ the immune system to treat autoimmune diseases. The company is developing innovative approaches to leverage the body’s immune cells to combat autoimmune diseases that have traditionally been difficult to manage with standard therapies.

Xtalks spoke with Dominic Borie, MD, PhD, President of R&D at Kyverna Therapeutics, to learn how the company is shaping the landscape of cell therapies for autoimmune diseases.

Kyverna’s platform of targeted cellular therapies addresses the complexities of the immune system, aiming at designing effective treatments to target autoimmunity and transform the standard of care.

Dr. Borie says Kyverna Therapeutics was inspired by the success of cell therapies in oncology, sparking a visionary shift to apply the approach to autoimmune diseases, where traditional therapies have often fallen short.

The core vision of the company is to harness cell therapy not just as a treatment modality but as a way to achieve sustained, treatment-free remission for autoimmune diseases. This vision is underpinned by the belief that by targeting and eliminating the immune cells responsible for the disease, it is possible to ‘reset’ the immune system, providing long-term, treatment-free disease remission, which could ultimately possibly mean a cure. Such a paradigm shift in treatment philosophy and approach offers much-needed hope for patients suffering from autoimmune diseases.

Dr. Borie explains how Kyverna Therapeutics’ research and development efforts are grounded in leveraging the immune system to target the pathogenesis of autoimmune diseases such as lupus nephritis and myasthenia gravis.

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Targeting B Cell-Driven Autoimmunity

The company’s focus on diseases such as lupus nephritis, multiple sclerosis and myasthenia gravis is driven by the recognition that B cells, a subset of lymphocytes responsible for antibody production, play a pivotal role in these conditions. Specifically, B cells may go awry, due to genetic mutations or dysregulation in networks that control B cell activity, including cytokines and regulatory T cells, which can lead to autoreactive B cells that can produce autoantibodies, antibodies against the body’s own proteins. These autoantibodies, in conjunction with other B cell-driven factors, such as inflammation-inducing cytokines, can drive the pathology of diseases like systemic lupus and myasthenia gravis, which explains the problems patients are experiencing.

Dr. Borie explains how Kyverna Therapeutics’ lead therapeutic candidate, KYV-101, is designed to “delete the bad B cells, the bad actors,” and by doing so, the hope is that it will “improve the disease not only short term, but potentially lead to a so-called ‘immune reset’ where only the ‘good B cells’ would return and not the bad actors. Reset of the immune system could be game-changing for patients with autoimmune diseases,” says Dr. Borie.

By targeting B cells, Kyverna’s cell therapy approach seeks to alleviate disease symptoms and potentially induce a lasting remission.

“What is exciting is that patients with autoimmune diseases are often young patients with their lives ahead of them. Being able to stop the disease in its tracks and give them their lives back through the resetting of their immune system is extremely compelling.”

Like KYV-101, Kyverna’s allogeneic therapeutic candidate, KYV-201, also combines a fully human anti-CD19 chimeric antigen receptor (CAR) with costimulatory domains designed to minimize cytokine release, maximize B cell depletion, and improve clinical tolerability.

Lupus nephritis is a serious kidney complication of systemic lupus erythematosus (SLE), an autoimmune disease, resulting in inflammation and potential damage to kidney tissues and kidney failure if not properly managed. Symptoms may include high blood pressure, darker or foamy urine and swelling in the legs and great fatigue. Treatment often involves medications to control the immune system and prevent further kidney damage.

Myasthenia gravis is an autoimmune disorder caused by a breakdown in the normal communication between nerves and muscles when autoantibodies attack the postsynaptic membrane of neurons, leading to impairment of the function of the neuromuscular junction (NMJ) and neuromuscular transmission. Symptoms can include difficulty in swallowing, double vision, drooping eyelids and difficulties in speech, chewing and breathing. Treatment may involve medications, surgery and other therapies aimed at improving muscle function and blocking the action of the autoantibodies with targeted monoclonal antibodies.

Cell Therapies for Autoimmune Diseases: Aims and Considerations

Developing cell therapies for diseases presents unique regulatory and clinical considerations.

Traditional clinical trial designs, which often rely on placebo controls, are not easily applicable to cell therapy trials due to the nature of the treatment, which involves collecting a patient’s cells, engineering them and reinfusing them into the patient. This makes it difficult to blind and use a placebo group. The particularities of the approach need to be addressed, explains Dr. Borie. Nevertheless, he says the possibility for transformative impact and results may support implementing innovative trial designs in which the need for a control placebo group may be less critical.

Early outcomes from Kyverna Therapeutics’ initial clinical experience with KYV-101, such as significant improvements in patients with lupus nephritis and myasthenia gravis, have been reported (see Haghikia et al. Lancet Neurology 2023;22:P1104-1105) and offer promising evidence of the potential of cell therapies to dramatically change the course of autoimmune diseases.

Dr. Borie shared that in trials of systemic lupus with CD19 CAR T cells, significant reductions in protein in the urine after a few months have been observed. Similarly, Kyverna has reported on a patient who was wheelchair-bound with myasthenia gravis and after infusion, is walking unassisted.

“These kinds of black-and-white outcomes, if verified in larger studies, would help us to address some of the challenges of developing innovative cell therapy approaches for autoimmune diseases,” says Dr. Borie.

Giving a single infusion of a cell therapy that would offer a lasting therapeutic impact for many years, if not for decades would be transformative, he explains.

“The mission at hand is that we need to verify the possibility to achieve long lasting treatment-free disease remission which would be transformative for patients with autoimmune diseases, and then find ways to make it available to many patients rapidly, ultimately implementing the approach early in their disease course rather than after they’ve developed advanced disease with irreversible organ damage. [The key is to] treat the condition at a point where it’s still reversible.”

Emerging Trends and the Future

“Cell therapy is emerging as the new modality which has potential to transform the care of patients with autoimmune disease,” says Dr. Borie.

Kyverna is aiming to expand the reach and impact of its cell therapies. The company is focused on proving the efficacy and safety of its candidate therapeutics through formal clinical trials. It also has supported providing the approach to select a few patients in need through expanded access. The goal is not just to validate cell therapy as a viable treatment option but to establish it as a standard of care for autoimmune diseases, and make it accessible and affordable to all who can benefit.

Finding ways to efficiently manufacture and reduce the cost of manufacturing the therapies, such that the cost will not be a barrier to the applicability of the approach in a large number of patients, is crucial. Making the therapies available in a safe and accessible manner is a key part of changing the course of autoimmune diseases.

The burden of current treatments associated with autoimmune diseases can be significant. People with an autoimmune disease are often reminded of their disease every day because they are taking a pill or going to an infusion center at a certain frequency every other week or every month, explains Dr. Borie.

The potential to successfully treat autoimmune diseases through cell therapy by resetting the immune system “drives us to work even harder to provide the proof that this is really the transformation that we think it’s going to be,” says Dr. Borie.

This article was created in collaboration with the sponsoring company and the Xtalks editorial team.