Autoimmune

After years of treating autoimmune diseases with chronic doses of biologics or small molecules, recent studies from academic researchers suggest that long-term remission is possible with one-time immune cell therapies.¹ Using gene editing, CRISPR Therapeutics aims to engineer immune cell therapies that target the root cause of many autoimmune diseases in a scalable way with the hope of producing long-term durable remissions while avoiding many toxicities of traditional treatments.

The immune system is the body’s defense against infection and injury. Autoimmune diseases occur when immune cells confuse “self” (healthy organs and tissues) with “non-self” (pathogens like viruses and bacteria). In many autoimmune diseases, B cells, a type of white blood cell, play a critical role in starting and sustaining this self-directed immune attack.

Self-directed pathologic B cells play a key role in driving a variety of autoimmune diseases including systemic lupus erythematosus (SLE), Systemic Sclerosis (SSc), and idiopathic immune myositis (IIM).² The treatment for these diseases traditionally has been chronic immunosuppressive therapies that are often associated with a variety of side effects.

Understanding CAR T cell therapy

Chimeric antigen receptor (CAR) T cell therapy aims to remove pathologic B cells after a single therapy with the goal of long-lasting improvement in symptoms without the need for other long-term medicines to suppress the immune system.

In 2023, academic researchers performed the first studies showing the promise of using a patient’s own (autologous) T cells to make CAR T cells that eliminate unhealthy B cells and reset the immune system, thus producing long-term remissions in diseases such as SLE, SSc, and IIM.¹

Follow-up data from the same academic researchers have shown that autologous CAR T cell therapy can eliminate unhealthy B cells from areas of the body where other treatment modalities, such as biologics, have not demonstrated an effect.³ Additionally, in another early-stage clinical trial, allogeneic CAR T cell therapy has shown early signs of efficacy in certain autoimmune indications.⁴

While the autologous CAR T cell therapy approach has shown early signs of clinical benefit, this autologous approach has limitations. For example, autologous CAR T cells are 1) expensive to manufacture as they must be made specifically for each patient, 2) require highly specialized centers for administration, and 3) are associated with potentially severe side effects. These aspects of autologous CAR T cell therapy significantly reduce the availability of CAR T cell therapy.^{5 6}

Leveraging CRISPR technology

We believe that CRISPR-based gene editing could drive the next generation of therapies for autoimmune diseases. Using CRISPR-based gene editing, we can manufacture CAR T cell therapies from healthy donors (allogeneic) that offer several potential advantages:

• Immediate availability and broader access: administered off-the-shelf with no need for patient apheresis or individualized manufacturing per patient, which could also reduce the cost of treatment
• Greater consistency and manufacturability: each batch can yield many doses using starting material derived from healthy donors
• Precision therapy: targeted gene insertion using CRISPR technology could mitigate risks associated with random gene insertion

We are investigating this approach for autoimmune diseases such as SLE with the potential to expand into other B cell mediated autoimmune diseases.

REFERENCES:

1. Müller, F. et al. N Engl J Med. 2024; doi: 10.1056/nejmoa2308917.
2. Martin F, Chan AC. Immunity. 2024; doi: 10.1016/S1074-7613(04)00112-8.
3. Tur C, et al. Ann Rheum Dis. 2024; doi: 10.1136/ard-2024-226142.
4. Wang X, et al. Cell. 2024; doi: 10.1016/j.cell.2024.06.027.
5. Scheffer Cliff ER, et al. Am Soc Clin Oncol Educ Book. 2023; doi: 10.1200/EDBK_397912.
6. Mikhael J, et al. JCO Oncol Pract. 2022; doi: 10.1200/OP.22.00315.