Cell-based therapy to suppress neuroinflammation and slow disease progression in ALS


Clinical Trials

Poster Number: 59


Stanley Appel, MD, Jason Thonhoff, MD,PhD, Ericka Simpson, MD, James Berry, MD, Merit Cudkowicz, MD


1. Houston Methodist, Houston, Texas, 2. Houston Methodist,Houston, Texas, 3. Houston Methodist, Houston, Texas, 4. MAssachusetts General Hospital, Boston, MA, 5. Massachusetts General Hospital, Boston, MA

Background- In ALS neuroinflammation plays a prominent role in mediating disease progression, and is characterized by a non-cell-autonomous pathological process dependent upon the interaction of injured motoneurons and surrounding glia as-well-as dysregulated central and peripheral immune systems. Tregs are a subpopulation of T-lymphocytes consisting of CD4+CD25highFOXP3+ cells that suppress proinflammatory responses, and are thus an important source of neuroprotection. However, in ALS Treg populations, FoxP3 expression, and Treg suppressive functions are reduced and the dysfunction correlates with the extent and rapidity of disease progression. Expansion of the dysfunctional ALS Tregs ex vivo in the presence of IL-2 and rapamycin restores their ability to suppress Tresp proliferation.
Objective – To determine whether autologous infusions of expanded Tregs into patients with amyotrophic lateral sclerosis (ALS) are safe and well-tolerated during early and later stages of disease.
Results – Autologous infusions of expanded Tregs into 3 ALS patients formed the basis of a first in man FDA approved Phase 1 pilot study of safety and tolerability. Following leukapheresis, isolation, and expansion, Tregs were administered intravenously at early stages of disease (4 doses over 2 months) and later stages of disease (4 doses over 4 months). Concomitant interleukin (IL)-2 was administered subcutaneously 3 times weekly over the entire study period. Infusions of Tregs were safe and well-tolerated in all participants. Treg numbers and suppressive function increased after each infusion. 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 higher the Treg suppressive function, the slower the progression of the disease. These results demonstrated safety, feasibility and the potential benefit of Treg infusions. However, the clinical benefit of the infused Tregs did not last, and it became clear that multiple infusions with a monthly infusion protocol might be required to sustain benefit. To accomplish this goal, we needed to develop and implement an optimized manufacturing process for the expansion and cryopreservation of Tregs, including production from one expansion phase of large numbers of highly suppressive Tregs that maintained cell viability, integrity and suppressive function when frozen and thawed. All of these goals have been accomplished in a GMP facility.
An FDA approved Phase IIa trial is now in progress exploring the biological activity, safety and tolerability of autologous Treg infusions in combination with low dose IL-2 in a larger number of patients (12 total) over a longer period of time (monthly infusions for 12 months). The Tregs are expanded ex vivo at our facility, cryopreserved, and then thawed and administered at two sites, Houston Methodist Hospital (HMH) and Massachusetts General Hospital (MGH). The trial was separated into a two-period study. The first period is a 6-month multicenter, randomized, double-blind placebo-controlled trial evaluating infusions of expanded autologous Tregs in combination with subcutaneous IL-2 versus placebo in 12 adults with ALS (3/6 ALS patients at each site on placebo, 3/6 receiving autologous infusions). The second period is a 6-month open-label extension in which all 12 participants receive autologous Tregs infusions in combination with subcutaneous IL-2. To date 6 patients have been enrolled and the autologous infusions appear to be safe and well tolerated.
Conclusions – We have successfully initiated the study of Treg therapy as a potential treatment for patients with ALS. We demonstrated the safety and therapeutic potential of the adoptive transfer of autologous Tregs as a treatment for ALS in a Phase I study of 3 patients. There was clear clinical benefit, but the effect did not last. An FDA-approved Phase IIa monthly infusion trial is underway in 12 ALS patients (6 from HMH and 6 from MGH) that includes a 6 month placebo arm followed by a 6 month dose escalation in all 12 patients. If clinically effective, the new manufacturing process and effective cryopreservation protocol would permit the scalability of ALS-derived autologous Tregs for extended treatment times with successive doses of an “off-the-shelf” immune-privileged Treg therapy.

Supported by MDA, ALSFAC, and the ALS Association