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Jeffrey Sparks @jeffsparks – @jeffsparks.bsky.social

Jeffrey A. Sparks is a rheumatologist and Associate Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts. Dr. Sparks serves as the Director of Immuno-Oncology and Autoimmunity and Associate Program Director for the Rheumatology Fellowship of the Division of Rheumatology, Inflammation, and Immunity. His research focuses on using patient-oriented and epidemiologic methods to evaluate the etiology, outcomes, and public health burden of rheumatic diseases.

Competitors for the CAR-T for Kidney Disease Region

Team 1: CAR-T for Autoimmune Diseases

vs

Team 2: CAR-T Side Effects

Image generated by Evan Zeitler using DALLE-E 3, accessed via ChatGPT at http://chat.openai.com, February 2025. After using the tool to generate the image, Zeitler and the NephMadness Executive Team reviewed and take full responsibility for the final graphic image.

This is personal for me! It is quite an honor to be involved in this year’s NephMadness, and some may say it is years in the making.

First, I have been hearing about NephMadness from my brother, Dr. Matthew Sparks, from its inception. Growing up in Arkansas, we were devout fans of the Arkansas Razorbacks men’s college basketball team, culminating in the 1994 NCAA national championship. This meant that “March Madness”, the NCAA tournament, was a major event in the Sparks household. In fact, we were so into that we would make a “tournament” for everything from our favorite movie to favorite meal. So, it was natural that Matt would one day apply this to nephrology for NephMadness and a similar program for rheumatology called RheumMadness. I have played in both every year–and never come to close to winning. Maybe this is my year?

Second, I direct our institution’s “RheumOnc” program that offers expedited oncology referrals to rheumatology and investigates autoimmune toxicities from immune checkpoint inhibitors. This also was years in the making, starting off as a hospitalist on the bone marrow transplant service at Washington University in St. Louis and as a moonlighter on oncology teams at Brigham and Women’s Hospital and Dana-Farber Cancer Institute. We have used this infrastructure to investigate rheumatic immune-related adverse events as well as mortality and flares of pre-existing rheumatic disease after immunotherapy. I also co-lead our CAR-T cell therapy program to enroll patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We recently reported safety of CAR-T cell therapy for cancer in patients with pre-existing autoimmune diseases. It is fascinating how some cancer therapies may induce autoimmunity, while CAR-T cell therapy may treat them!

Now to this year’s CAR-T cell region in NephMadness. This boils down to the natural clinical question of risk (CAR-T Side Effects) vs benefit (CAR-T for Autoimmune Diseases).

The “benefit” side of the equation is evidenced by an explosion of case reports and case series hinting at truly impressive efficacy for CD19-targeted CAR-T cell therapy to treat autoimmune diseases such as SLE, systemic sclerosis, and myositis. There are now ongoing CAR-T cell clinical trials across almost every rheumatic disease. I will emphasize that none of the currently published prospective studies include a control arm. While you would typically take results of a single-arm trial “with a grain of salt”, the outcomes have shattered our expectations. For example, we are only rarely able to stop immunosuppressant therapies in rheumatic diseases, since this typically results in a flare. However, CAR-T therapy, particularly for lupus nephritis, have resulted in drug-free remission after only a single dose. The clinical researcher in me wants a truly controlled and blinded study. However, the clinician in me has never seen such impressive outcomes from any therapy. So, the “benefit” side of the equation may be one of the most exciting developments in rheumatology in recent memory.

The “risk” side of the question remains important and only partially answered. We know that cytokine release syndrome and neurotoxicity are the acute outcomes to worry about. We see this frequently in cancer patients and expect to see also see this in rheumatic patients. The jury is still out on how rheumatic patients may fare. Tumor burden is a strong predictor of outcomes in cancer patients, so it may be that patients without cancer fare as well or even better. However, they will have an activated immune system and may be on immunosuppression when cellular therapy is given. This could result in worse outcomes. Also, there are other side effects such as infection, cytopenias, acute kidney injury, and hypogammaglobulinemia. Rarely, some cancer patients have died from CAR-T side effects. There are also some reports of lymphomas from the engineered CAR and/or viral vector. Of course, the rheumatic clinical trials will collect safety data but may be too small to make definitive conclusions. Finally, it should be mentioned the incredible costs needed to perform apheresis, engineer cells, give lymphodepleting therapy, and hospitalize the patient for a week or more. Clearly, we will need to scale this therapy and work on making this easier to administer related to lymphodepletion and length of hospitalization. Safety is certainly important, but even the known toxicities in cancer patients have not tempered enthusiasm for CAR-T cell trials in rheumatic patients.

So what is my pick? I am 100% going with “CAR-T for Autoimmune Diseases” to run this region. I think it will be unanimous by the Blue Ribbon Panel, similar to a 1-seed trouncing a 16-seed in the first round of the NCAA tournament. In fact, I pick this team to make a Cinderella run and win the entire NephMadness. I am also picking “CD-19 CAR T” to win the “B-Cell Breakaway” region in RheumMadness. I predict CAR-T will be the first to be the dually crowned victor of both NephMadness and RheumMadness. Two shining moments for this special team!

I will conclude with reflecting on how truly exciting CAR-T therapy is in rheumatology. This seems like a paradigm shift in our expectations and an entirely new platform for therapy. We had been happy with remission while on long-term therapy. How exciting will it be to give a single dose of a therapy that essentially cures a patient! Related to the platform, we could choose different antigens and different types of cells. This feels like the advent of a new “Cellular Therapy Era”, analogous to the “Biologic Era” for rheumatic diseases that started around 2000. Work has already begun to help scale this to allogenic “off the shelf” therapies or to give bi-specific T cell engagers that have CAR-T-like effects but are administered like other biologics.

CAR-T for Autoimmune Diseases for the win!

– Guest Post written by Jeffrey Sparks

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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