Taking Lessons Learned With CAR-T in Oncology to the Autoimmune Space

David Porter, MD

Investigations with chimeric antigen receptor (CAR) T-cell therapy are entering a new field: autoimmune disease. 2023 saw a record number of investigational chimeric antigen receptor T-cell (CAR-T) therapies enter clinical trials for the treatment of autoimmune diseases, mostly focusing so far on lupus nephritis (LN) and systemic lupus erythematosus (SLE). Trials are investigating CAR T-cell therapies in B-cell-driven autoimmune diseases like SLE and LN, with a growing list of trials entering the space including Kyverna Therapeutics’ KYV-101 and Nkarta’s NKX019 in LN, ImmPACT Bio’s IMPT-514 and Gracell Bio’s GC012F in SLE, and Cabaletta Bio’s CABA-201 and Artiva Bio’s AB-101 being investigated in both SLE and LN.

CGTLive® spoke with David Porter, MD, director of Cell Therapy and Transplant and Jodi Fisher Horowitz Professor in Leukemia Care Excellence, University of Pennsylvania Medicine, to learn more about the expansion of CAR T-cell therapy to the field of autoimmune disease. He discussed what enabled this expansion and lessons learned from their use in oncology.

CGTLive: What lessons has the field learned with CAR T therapies from their use in oncology?

David Porter, MD: CAR T-cell therapies have been really revolutionary for patients with a number of hematologic malignancies, particularly B-cell malignancies, lymphomas, multiple myeloma, and even chronic lymphocytic leukemia. They have had a dramatic impact, particularly in patients who have run out of effective treatment options. What they all have in common is that the current most successful CAR T-cells are really good at targeting B-cells in B-cell malignancies, although also normal B-cells.

There are many autoimmune diseases that we know are either caused by or certainly affected by auto antibodies, and those auto antibodies come from B-cells. Many of these diseases can be treated with therapies that target B-cells that are immunosuppressive, or that directly deplete a patient's own B-cells. But many patients, just like patients with cancers, don't respond well, or they become resistant, or just the burden of so much immunosuppression over time, causes really unacceptable morbidity. So, it's logical to think about using anti B-cell directed therapy that potentially is much more potent than available therapies. That's a one and done therapy that doesn't require lifelong immune suppression. And so, the idea came using the available CART-cell approach to target B-cells to get very, very deep B-cell depletion to prevent production of auto antibodies, and potentially treat autoimmunity.

There are a few, but dramatic reports of patients with a number of autoimmune diseases that have responded very well to CART-cell therapy, anti B-cell directed CART-cell therapy, specifically anti CD19 targeting, with the most experience right now in lupus nephritis. It is auto antibody mediated. And you can show deep depletion of B-cells even in patients who hadn't responded well to other anti B-cell therapies and patients going into complete remission. So, I think this is the next frontier in CART-cell therapy. Right now, the success has been with anti CD19 directed therapy but there are clinical trials with other B-cell targets and other aspects of cells that result in auto immunity, targeting other types of B-cells targeting specifically the auto antibody, or even targeting other aspects of cell immunity.

What do you think enabled that transition from going from oncology to now being in auto immune diseases?

Porter: First, we needed the experience of using these cell therapies in patients with malignancies, initially testing it in patients who really had no other effective treatment options, and then really understanding not just the mechanism of action but also understanding the toxicity and how to manage the toxicity. So, over a number of years, CART-cells have become increasingly safe. In fact, in many cases, they can be used in an outpatient setting for much of the episode of care. And as they became safer, and the toxicity and toxicity management became more understood, it became logical to think about applying them in other situations.

In the world of cancer therapies, that means using these CART-cells, perhaps earlier in lines of therapy, maybe not as a last line when patients have run out of every other option, but maybe sooner as a second line therapy or potentially even first line therapy and in high-risk patients. But then, it became clear if they are effective and you can use them safely in B-cell malignancies, perhaps they could be used safely in other diseases that are caused by B-cell abnormalities and, in the case of autoimmune disease, caused by abnormal B-cells producing auto antibodies, for instance. So, I think the ability to use them, to understand the toxicity and use them in a safe manner, really has led to the ability to apply CAR T-cell therapy to autoimmune diseases.

This transcript has been edited for clarity.