In a phase 1 study in 3 humans with amyotrophic lateral sclerosis (ALS), the safety and therapeutic potential for autologous transfusion of proinflammatory T cells (CD4+CD25highFOXP3+) has been demonstrated. Although there was clear clinical benefit from transfusion of autologous expanded proinflammatory T cells, these benefits were not maintained in the absence of continued infusions. Phase 2 trials that include longer-term regular infusions are now underway.
Neuroinflammation plays a prominent role in disease progression in ALS by a noncell-autonomous process that is dependent upon interactions between injured neurons and surrounding glia as well as dysregulation of the central and peripheral immune systems. Regulatory T cells (Tregs) suppress these inflammatory responses but are dysfunctional in ALS.
When dysfunctional Tregs are purified from plasma of people with ALS and expanded with interleukin 2 (IL-2) and rapamyacin, the Treg function is restored. These cells can then be reinfused intravenously to the individual. In this study, autologous expanded Tregs were administered intravenously in 4 doses over 2 months and then in 4 doses over 4 months. Interleukin 2 (IL-2) was administered subcutaneously 3 times per week over the entire study period.
The infusions slowed progression rates during early and later stages of disease, and the increased Treg suppressive function correlated with slowing of disease progression. The disease-modifying effect, however, was not sustained when infusions stopped, making it clear that a monthly infusion protocol might be required to sustain benefit. To allow for long-term monthly infusions of autologous expanded Tregs, an optimized manufacturing process for expansion and cryopreservation was developed. With this process, the function and viability of the expanded Treg cells was maintained.
A phase 2a trial of monthly infusions of autologous proinflammatory T cells is underway in 12 individuals with ALS. This trial includes a 6-month placebo arm followed by a 6-month dose escalation. If this trial shows efficacy, the new manufacturing and cryopreservation protocols will permit scalability of this treatment.
The T cells used in these transplants are taken from the plasma of the individual with ALS and then expanded in the presence of interleukin 2 (IL-2) and treated with rapamycin to restore function before being infused back into the individual.
Brad Klein, MD, MBA, FAAN, FAHS, FAANEM, and Raissa Villanueva MD, MPH, FAAN
Jennifer Robblee, MD, MSc; Amaal J. Starling, MD; Rashmi B. Halker Singh, MD, FAHS, FAAN; and Nina Riggins, MD, PhD
Michael S. Cartwright, MD, MS, and Hwajin Lee, MD