Excited by the prospect of doing research that led to new therapies for autoimmune diseases, rheumatologist James Chung spent two years at Pfizer working on small molecules and 17 years at Amgen working on monoclonal antibodies. Despite progress in some areas, he noticed that rare autoimmune diseases remained untreatable, and existing therapies for other autoimmune disorders fell short. Today, he serves as the Chief Medical Officer at Kyverna Therapeutics and is leading the clinical trials to test CAR T cells in patients with multiple sclerosis (MS). “At Kyverna, I saw an opportunity in cell therapy to get to that next level of efficacy for a lot of these diseases,” he said. “So far, the data looks promising…There is potential to make a discernible difference in long-term outcomes for patients.”
Why does CAR T cell therapy make sense for MS?
The idea that depleting B cells influences autoimmune disease has been around for a while. Monoclonal antibodies against the B cell protein CD20, for instance, are effective in many autoimmune diseases, including MS. Some of the early data on monoclonal antibodies for relapsing remitting MS were very promising. They were also effective in progressive MS, but not as much as people hoped. Unlike monoclonal antibodies, CAR T cells can go into tissues, so they can cause a greater degree of B cell depletion than monoclonal antibodies. There is a real opportunity to use CAR T cells to test the hypothesis about B cell depletion in a more complete way and evaluate if there could be unprecedented levels of efficacy.
How did Kyverna Therapeutics become involved in CAR T cell therapy for autoimmune disease?
It started in early 2020. We were looking for the right CAR construct and found it at James Kochenderfer’s lab, a clinician at the National Cancer Institute who specifically designed it to be safer than YESCARTA®, a CAR T cell therapy for large B cell lymphoma. This work resulted in KYV-101, an autologous CD19 CAR T-cell therapy that Kyverna Therapeutics tested in a Phase 1 study of two multiple sclerosis patients. We found CAR T cells in the cerebral spinal fluid of both study participants, with no signs of neurotoxicity, together with a decrease in antibodies produced by B cells in the CNS (1). We are still in the early days, but these were promising results.
How does KYV-101 reach the brain, and how many doses does a patient need?
We administer KYV-101 intravenously and let nature do its thing. T cells are designed to find their targets anywhere in the body. The exciting thing about CAR T cell therapy is that it's a one-time administration. We are looking for long-term remission or long-term disease control without background immunosuppression. With monoclonal antibodies or small molecules that dampen inflammation, you're maintaining not only the chronic administration of that drug, but also background immunosuppression. So far, the data show that whether it's lupus or other autoimmune disease, a single dose will lead to good disease control without background medications. We know that this probably won't be the case for every disease, or for every patient. But the premise is that with one administration, you can get what we call “immune reset” which allows long-term disease control and durable remission without the need for concomitant medications. There may be patients who need retreatment, and a remaining question is which patients would need it, and which CAR therapies would allow that. For instance, Kyverna’s CAR construct is fully human. But there are other CAR constructs that may be immunogenic, which may prevent redosing.
What is the status of KYV-101’s clinical development?
There is a real opportunity to use CAR T cells to test the hypothesis about B cell depletion in a more complete way and to see if there could be unprecedented levels of efficacy.
- James Chung, Kyverna Therapeutics
There are currently two Kyverna-sponsored Phase 1 trials for lupus nephritis in the US and Germany. The safety profile looks good, and the therapy has been well tolerated. In lupus nephritis patients, we are seeing a good safety profile and evidence that it is having an impact on biomarkers of disease activity and some early evidence of clinical efficacy. We also have regulatory clearance to begin a Phase 1/2 study on systemic sclerosis. And we are starting a Phase 2 study for myasthenia gravis and multiple sclerosis.
What patients are you recruiting for a KYV-101 Phase 2 trial, and what do you hope to find?
For the MS trial, we are recruiting patients whose disability continues to progress even though they are being treated with anti-inflammatory agents. These include patients with primary and secondary progressive MS who have relapsing remitting disease. This is the most difficult to treat disease type, and we lack good therapies. We want to see a reduction in disease progression. We know that monoclonal antibodies like ocrelizumab slow disease progression, but not as much as we'd like. Through this trial, we hope to show that CD19 CAR T cell therapy depletes B cells in the tissues and covers a broader set of B cells than a CD19 monoclonal antibody, which should have a greater effect in slowing disease progression.
How is Kyverna Therapeutics monitoring for CAR T cell therapy side effects such as brain toxicity?
For the first ten days, the patients are in the hospital so we can monitor them closely for cytokine release syndrome, neurotoxicity, and immune effector cell-associated neurotoxicity syndrome (ICANS). These are expected side effects, and physicians who administer CAR T cell therapy know how to manage these well. So far, it looks like the safety profile of CAR T cell therapy in patients with lupus or MS is different from what you see in oncology where you have significant cytokine release syndrome and severe ICANS. Although you do see these in MS and lupus patients, they occur much less frequently and are also less severe. After ten days, patients leave the hospital and are enrolled in a follow up study to monitor them for the next 15 years.
What are you most excited for in terms of the future of autoimmune disease research at Kyverna Therapeutics?
We’re just at the beginning stages of what could be a transformation in how we treat patients with autoimmune diseases who are refractory to current therapies. It's complex; it's a lot of work; but we’re going one by one through these diseases. So far, the results seem promising. We look forward to being a leader in this field, continuing to push the boundaries, going into multiple indications, and looking at other ways of delivering cell therapies. In addition to our autologous CAR T cell program, we have an allogeneic CAR T cell program using the same CAR construct and cells from healthy donors, which should make the therapy more patient-friendly. We hope to dose patients with allogeneic CAR T cells by the end of the year in partnership with Intellia Therapeutics. They have a CRISPR/Cas9 technology for generating allogeneic CAR T cells without immunogenic protein sequences that could lead to rejection. This strategy is an elegant way of allowing CAR T cells to survive sufficiently long to deplete B cells effectively. We're also developing a new process that will shorten the manufacturing process and make it less costly and more accessible to more patients.
This interview has been condensed and edited for clarity.
Reference
- Fischbach, F. et al. CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis. Med N Y N S2666-6340(24)00114–4 (2024).
