Scientific advancements have enabled novel ways to foster the therapeutic potential of adoptive cell therapies beyond oncology. Recently, clinical case studies have sparked significant investor and industry interest in the use of chimeric antigen receptor T cells (CAR-Ts) for autoimmune disorders, potentially expanding CAR-Ts’ utility beyond oncology. Roberto Caricchio, M.D., the Myles J. McDonough Chair in Rheumatology, professor of medicine, and chief of the division of rheumatology in the department of medicine at the University of Massachusetts Chan Medical School, recently opined, “The potential of cell therapy to reset the immune system and provide long-term, drug-free remissions for patients with severe autoimmune disease may represent the biggest medical breakthrough in the last 50 years of rheumatology,” in a Nkarta press release dated October 17, 2023.

In the latest edition of CELLect Horizons, biotech analysts Sami Corwin, Ph.D., and Matt Phipps, Ph.D., provide an overview of the known biological underpinnings of autoimmunity and rationale for using CAR-T as a therapeutic, review the clinical data generated to date by CAR-Ts in autoimmune disorders, provide an overview of the cell therapy competitive landscape in select autoimmune indications, analyze the potential market opportunity for these therapies, review recent business development and financing activity in the space, and provide their outlook on the field.

Autoimmune diseases are characterized by aberrant immune system activity toward host cells or tissues, resulting in inflammation and/or organ dysfunction. Although the underlying cause of autoimmune diseases is unclear, genetic predisposition and environmental factors (i.e., viruses, bacteria, medications, pollutants, hormones, and stress) have been linked to the onset of symptoms. Autoimmune diseases are broadly classified as B-cell mediated disorders or T-cell mediated disorders based on the underlying driver of immune system dysfunction; however, given the crosstalk between immune cells, often both T and B cells contribute to the pathophysiology of the autoimmune disease. There are over 100 known autoimmune diseases that are estimated to affect 15 million to 20 million Americans and 4.5% of the world population, with increasing incidences due to environmental factors and improved surveillance and diagnosis. Despite the high prevalence of these disorders, suboptimal treatments exist for the majority of autoimmune disorders, with immunosuppression and steroids remaining treatment staples despite often not being curative, requiring chronic use, and being associated with safety concerns and negative side effects such as increased susceptibility to infections, weight gain, diabetes, and bone atrophy. Direct medical care costs for these disorders results in a substantial economic burden, which NIH estimates at $100 billion in aggregate in the U.S. (Roberts et al. Autoimmune Rev. 2021).

In oncological applications, anti-CD19 CAR-T therapies have demonstrated the ability to induce deep and complete depletion of both circulating and tissue-resident B cells. The ability of CAR-T therapies to provide clearance of B cells raises the possibility that CAR-T cells could be an effective treatment for B-cell mediated autoimmunity. In addition, CAR-T cells can enact deeper B-cell clearance and eliminate B cells in more compartments in cancer indications compared to mAbs, which suggests that if proven to be safe and effective, CAR-T therapies could provide long-term remission from an autoimmune disease with a one-time treatment.

A landmark study published by Dr. Georg Schett, professor and head of the department of internal medicine 3 and vice president of research at Friedrich-Alexander University, Erlangen-Nürnberg in Germany, in 2021 demonstrated administration of CD19 CAR-T cells to a patient with lupus led to the elimination of autoantibodies and durable drug-free remission with successful B-cell reconstitution (Mougiakakos et al. N. Engl. J. Med. 2021). Subsequently, Dr. Schett’s group has shown that CD19 CAR-T therapy has induced durable drug-free remission in eight lupus patients with follow-up beyond two years, three myositis patients with up to one year of follow-up, and four systemic sclerosis patients with up to six months of follow-up. These initial case studies suggest that CAR-T could be used to transiently and deeply deplete B cells in patients with various autoimmune diseases without the loss of protective antibodies to vaccine/pathogen-specific antigens, effectively resetting the immune system.

Over 30 companies have announced that they are pursuing the development of an engineered cell therapy for the treatment of autoimmune diseases. While some companies were founded on the premise of developing cellular therapeutics for autoimmune indications, many have repurposed their respective clinical-stage oncology assets for the autoimmunity space.

We estimate there are over 70 cell therapy programs in development for the treatment of autoimmune disorders, with CARs targeting clinically validated and de-risked antigens that induce B-cell and/or plasma-cell depletion (targeting CD19 and/or BCMA) being the most advanced and making up the lion’s share of approaches. We believe CD19 CAR-T therapies are the most de-risked based on the data generated to date, with the need, benefit, and risks of targeting long-lived plasma cells with BCMA still unclear.

The most common indication being pursued is systemic lupus erythematosus (SLE), which we view as largely de-risked based on the clinical data generated, but we note a high level of interest in indications that have not been clinically de-risked yet but present a potentially larger commercial opportunity, such as multiple sclerosis (MS) and rheumatoid arthritis (RA). We also believe companies will quickly expand their pipelines into additional autoimmune indications as initial clinical proof of concept is established. In addition, we believe companies developing Treg-based therapeutics will first pursue the prevention of organ transplant rejection but could increasingly pivot into other autoimmune indications if their technologies prove safe and efficacious.

We have identified at least 33 ongoing clinical trials evaluating cell therapies for the treatment of at least 13 different autoimmune indications, underscoring the breadth of opportunity. We also highlight that the first clinical trial evaluating CAR-T for an autoimmune disease (Cartesian’s Phase I trial of Descartes-08) was initiated in 2019, highlighting how rapidly the competitive landscape has evolved.

In this edition of CELLect Horizons, titled “The Hammer Finds a Bigger Nail: Cell Therapy for Autoimmune Disorders,” Dr. Corwin and Dr. Phipps provide a thorough analysis of the field and reach the following conclusions:

  • Initial clinical data has demonstrated CAR-T therapies can yield durable, drug-free remission across multiple autoimmune indications, but more data is needed to assess the full extent of response durability.
  • Safety will be paramount.
  • Long-term cell persistence may not be necessary for durable efficacy.
  • The independent therapeutic effect and importance of lymphodepletion is still unclear.
  • Vein-to-vein time is less crucial, but manufacturing scalability could be a major determinant of who will be successful in the space.
  • There is uncertainty as to whether the FDA will require registrational trials to be placebo controlled, but we see the concern as overblown.
  • Antigen selection and depth of B-cell, T-cell, and plasma cell depletion remains debated.
  • Allogeneic therapies and in vivo CAR-Ts could be advantageous.
  • Success in tissue transplantation could open the door for CAR-Treg therapies to pursue other autoimmune-mediated disorders.
  • Success in autoimmunity could open the door to CAR-Ts’ effective use in additional indications.

To request a copy of the full length CELLect Horizons—The Hammer Finds a Bigger Nail: Cell Therapy for Autoimmune Disorders report, or for more information on the companies from each analyst’s coverage list, please contact us  or your William Blair representative.