Ph1 T-Regulatory Cells in Amyotrophic Lateral Sclerosis

This is Pilot Study will consist of 3 people diagnosed with amyotrophic lateral sclerosis (ALS), who will undergo 4 infusions of autologous expanded Tregs and concomitant subcutaneous injections of Interleukin-2 [IL-2] (2 x 105 IU/m2) 3 times weekly, for 52 weeks or unless the interim analysis confirms or negates the investigational product (IP = Tregs) use.

During the enrollment period up to three research participants will be recruited from patients in our ALS Clinic for screening, baseline measures and leukapheresis. The Treg cell manufacturing will be performed in a current Good Manufacturing Practice (cGMP) laboratory. The first subject will receive infusions of their expanded Tregs (1x106 /kg) with concomitant subcutaneous IL-2 injections (2 x 105 IU/m2) 25 days (+/- 2 days) post leukapheresis. The 2nd subject will begin after the first subject has completed the first 4 weeks and has experienced no untoward effects during this period. Once subjects #1 and #2 have completed the first 4 weeks and no toxic events have occurred they will therefore be considered safely past the first milestone and subject #3 will begin infusions.

Research Participants #1, 2 and 3 will repeat the leukapheresis (under a separate protocol) and undergo Treg infusions at the modified schedule of every 4 weeks, with concomitant subcutaneous injections of IL-2 (2 x 105 IU/m2) 3 times weekly. The subjects will be called on Day 7, and 21. Office visits will be completed on the day after infusions and every two weeks while the subjects are undergoing Treg infusions for clinical evaluation, scoring, and blood draws. The subjects will then be seen during office visits once per month for one year total from their initial baseline visit for clinical evaluation, scoring, and blood draws

Monthly interim analyses will monitor the subjects using validated ALS scales such as the ALS Functional Rating Scale-Revised (ALSFRS-R) and Appel ALS Grading Scale (AALS), which incorporates muscle strength and dysfunction, activities of daily living and pulmonary function. The analyses will also include interim medical history and physical exam, an electrocardiogram (ECG) when indicated, pulmonary function tests (PFTs) such as Forced vital capacity (FVC) and Maximum Inspiratory Pressure (MIP or MIPS), safety labs (such as a complete blood count (CBC), chemistry, liver function, thyroid tests-T4 and TSH) as well as more technical research labs such as T Regulatory Cell and related markers (Th1 and Th17 counts, FoxP3 RNA expression), and Treg Suppression Assays. A prothrombin time (PT) and partial thromboplastin time (PTT) will be performed only if the subject has an abnormal coagulation result at baseline or if the subject is on anti-coagulation therapy.

Adverse Events (AEs) and Serious Adverse Events (SAEs) will be monitoring from the time of consent until end of study or AE/SAE resolution.

Inclusion criteria

• Age 18 years or older.
• Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria (Appendix 1).
• Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at least 30 days (riluzole-naïve subjects are permitted in the study).
• Capable of providing informed consent and following trial procedures.
• Geographically accessible to the site.
• Women must not be able to become pregnant (e.g. post-menopausal, surgically sterile, or using adequate birth control methods) for the duration of the study and three months after study completion. Adequate contraception includes: abstinence, hormonal contraception (oral contraception, implanted contraception, injected contraception or other hormonal (patch or contraceptive ring, for example) contraception), intrauterine device (IUD) in place for ≥ 3 months, barrier method in conjunction with spermicide, or another adequate method.
• Subjects must agree not to take live attenuated vaccines (including seasonal flu vaccine) 30 days before blood collection.
• Available autologous Tregs product with greater than or equal to 50% expression of CD4, CD25 and FoxP3 determined by flow-cytometry.
• Subjects must have been previously evaluated and followed clinically by a neuromuscular specialist at Houston Methodist Neurological Institute
• Normal Alanine aminotransferase level (ALT)
• Normal Serum creatinine level

Exclusion criteria

• Prior use of cells therapies
• Concurrent use of other experimental ALS therapies
• Pregnant or breastfeeding or planning to become pregnant or planning a partner's pregnancy.
• Other unstable medical or psychiatric illness
• Known immune deficiency or history of lymphoma or leukemia
• History of lymphopenia.
• History of acquired or inherited immune deficiency syndrome, including leukopenia.
• History of severe untreated chronic obstructive sleep apnea.
• FVC less than 50% predicted at screening.
• Exposure to any other agent currently under investigation for the treatment of subjects with ALS (off-label use or investigational) within 30 days of the Baseline Visit.
• The presence of unstable psychiatric disease, cognitive impairment, or dementia that would impair ability of the subject to provide informed consent, according to the PI's judgment, or a history of active substance abuse within the prior year.
• Clinically significant history of cardiac, oncologic, hepatic, or renal dysfunction, or other medically significant illness.
• The presence of any immunologic or autoimmune disease
• Severe cardiac dysfunction defined clinically, or as a left ventricular ejection fraction less than 40% of predicted or abnormal EKG findings.