Chapter 130
Controlling Our Immune System — 7
Our creative genius for cellular engineering is being exercised in other ways. B cell monoclonal antibodies have limited success for autoimmune disease, owing to persistence of auto-directed cells in lymph nodes and other parts of the body. The success of a single infusion of engineered T cells that bind to CD-19, a protein on the surface of all B cells, has been striking. In 2022, the first report of five patients with lupus with full resolution of symptoms was eye-opening, as was the finding that when their B cells remerged, there was no relapse. It was as if the purge of B cells acted as a computer reboot with Control-Alt-Delete. This strategy essentially kills all the B cells (inducing B cell aplasia), with disappearance of all autoantibodies. It subsequently worked exceptionally well in fifteen patients with different systemic autoimmunity (eight patients with severe lupus, four patients with systemic sclerosis, and three patients with autoimmune myositis) with drug-free remission for all during a follow-up mean of fifteen months.I The wipeout of B cells would be considered a risk for infection. However, most of the infections in this group have been mild to moderate, involving the upper respiratory tract, including COVID-19. Lawrence Steinman, a leading immunologist who is considered the father of antigen-specific therapy, said, “These results are mind-blowing, boggling, outstanding.” Another perspective was offered by Chyi Hsieh, a clinical scientist at Washington University: “I’ve been doing rheumatology for almost 25 years now, and it’s probably the most singular, impressive result that I’ve seen.”
These remarkable results with CD-19 targeting for refractory autoimmune conditions were achieved with the laborious and expensive process of engineering a person’s T cells. A much simpler, off-the-shelf approach was used successfully in several patients with autoimmune diseases, paving the way for a more practical strategy to deplete B cells.
Amore specific approach has been to target the culprit B cells, such as has been seen with pemphigus, an autoimmune skin disease, with desmoglein as the antigen protein. That specific B cell targeting strategy is the one that Cabaletta Bio is taking for myasthenia gravis and other autoimmune conditions. Many other specific B cell targets are being explored.
But B cell targeting is just one part of the story for engineering cells to restore tolerance; there are many autoimmune conditions for which other cells are the auto-directed drivers. In animal models of asthma, CAR-T targeting eosinophils were protective. Treg engineering has shown promise in multiple autoimmune conditions, with readiness for clinical trials in type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. Sonoma Biotherapeutics is moving ahead in inflammatory bowel disease and rheumatoid arthritis with a targeted Treg approach, such as CAR-reactive citrullinated antigens seen in the latter condition. Instead of the current laborious, time-consuming, and expensive way of manufacturing CAR cells outside the body, Capstan Therapeutics is pursuing an in vivo (inside the body) cell modulation approach with mRNA nanoparticle delivery.