Ph1 T-Regulatory Cells in Amyotrophic Lateral Sclerosis

Expansion and Infusion of T-Regulatory Cells in Amyotrophic Lateral Sclerosis

Open-label pilot study to determine the safety and tolerability of autologous CD4+ CD25+ regulatory T cells infusions with concomitant subcutaneous IL-2 injections taken 3 times per week in 3 participants with ALS.

Study Overview

• Status: Completed
• Conditions: ALS (Amyotrophic Lateral Sclerosis)
• Intervention / Treatment: Biological: Autologous T-regulatory lymphocytes; Biological: Interleukin-2

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Methodist Neurological Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18 years or older.
2. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria (Appendix 1).
3. 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).
4. Capable of providing informed consent and following trial procedures.
5. Geographically accessible to the site.
6. 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.
7. Subjects must agree not to take live attenuated vaccines (including seasonal flu vaccine) 30 days before blood collection.
8. Available autologous Tregs product with greater than or equal to 50% expression of CD4, CD25 and FoxP3 determined by flow-cytometry.
9. Subjects must have been previously evaluated and followed clinically by a neuromuscular specialist at Houston Methodist Neurological Institute
10. Normal Alanine aminotransferase level (ALT)
11. Normal Serum creatinine level

Exclusion Criteria:

1. Prior use of cells therapies
2. Concurrent use of other experimental ALS therapies
3. Pregnant or breastfeeding or planning to become pregnant or planning a partner's pregnancy.
4. Other unstable medical or psychiatric illness
5. Known immune deficiency or history of lymphoma or leukemia
6. History of lymphopenia.
7. History of acquired or inherited immune deficiency syndrome, including leukopenia.
8. History of severe untreated chronic obstructive sleep apnea.
9. FVC less than 50% predicted at screening.
10. 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.
11. 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.
12. Clinically significant history of cardiac, oncologic, hepatic, or renal dysfunction, or other medically significant illness.
13. The presence of any immunologic or autoimmune disease
14. Severe cardiac dysfunction defined clinically, or as a left ventricular ejection fraction less than 40% of predicted or abnormal EKG findings.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment arm; All subjects are enrolled in the one arm consisting of infusions of autologous T-regulatory lymphocytes at a dose of 1x10 to the sixth/kg and subcutaneous injections of Interleukin-2 at a dose of 2x10 to the fifth IU/m2 three times a week.	Biological: Autologous T-regulatory lymphocytes; intravenous administration of Autologous T-regulatory lymphocytes at a dose of 1x10 to the sixth /kg.; Biological: Interleukin-2; Subcutaneous Interleukin-2 at a dose of 2x10 to the fifth IU/m2, three times a week.; Other Names: IL-2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events (CTCAE v4.0) & Medical Dictionary for Regulatory Activities (MedDRA).	Adverse events and serious adverse events related to Treg infusions were monitored throughout the study.	Adverse events related to Treg infusions at Baseline to up to two years or study participation, whichever is occurs first.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Appel ALS (AALS) Scale/Grading	The AALS is a published, validated instrument based on objective testing in five categories (bulbar, respiratory function, arm and leg function, and muscle strength) with scores ranging from 30 (normal) to 164 (maximally impaired).	Baseline and at week 15
ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised)	The ALSFRS-R (ALS Functional Rating Scale-Revised) is an orally administered validated instrument using an ordinal rating scale used to determine the a person's assessment of their capability and independence in 12 functional activities based on 10 questions related to motor, bulbar and respiratory function. Participants are asked to rate his/her impression of function regarding writing, self care, climbing stairs, and breathing. Each task is rated on a five-point scale from 0 = can't do to 4 = normal ability resulting in an overall score of 0 (worst) to 48 (best).	Baseline to week 15
T-Regulatory Cells	Treg percentage (CD4+CD25+FOXP3+ cells) within the total CD4+ population will be assessed by multicolor flow cytometry. Cluster of differentiation 4 (CD4 ) cells are also known as T cells, the white blood cells, which fight infection and play an important role in the immune system.	Mean and standard deviation represent the average of baseline and 3-month assessments.
Treg Suppression	Treg suppressive function of T-effector (Teff) cells will be assessed by [3H]-thymidine incorporation. 3H-thymidine is a radioactive nucleoside that is incorporated into a commonly used assay to measure lymphocyte proliferation. Correlation between changes in the rate of disease progression and the Treg percentage and function will be determined by Spearman's correlation analysis.	Baseline to 3 months post treatment for a total of two years from baseline
T Helper Cells Type 1 (Th1) Lymphocytes	The percentage of Tregs, Th1 lymphocytes, assessed by multicolor flow cytometry.	Baseline to 3 months post-treatment for a total of two years from baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary FVC - Exploratory Measure - Percent of Predicted FVC	FVC (Forced Vital Capacity). Reduction of pulmonary function is the primary source of morbidity and mortality in ALS. FVC testing will be used to monitor respiratory function. FVC measures the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. The intent is to report the percent of predicted FVC value.	Mean and standard deviation of the values from baseline and 3 months.
Pulmonary MIP - Exploratory Measure	MIP (Maximum Inspiratory Pressure) measures the strength of muscles used during inspiration and assessed due to decreased pulmonary function resulting in a primary source of ALS morbidity and mortality. MIP is the lowest pressure developed during a forceful inspiration against an occluded airway, measured with a device during maximal inspiration from 0 (worst) to 100 (best) and recorded as a number with the units, cm H2O (centimeters of water). Declining MIP indicates worsening of pulmonary function and maintenance of MIP over time indicates the goal of sufficient/stable respiratory strength.	At Baseline and at 3 months intervals, up to two years from baseline (or as long as participant is involved in the study).
Need for Tracheostomy- Exploratory Measure	Number of patients requiring a tracheostomy. Patients undergoing an elective, prophylactic or required tracheostomy is performed when a patient may not maintain adequate ventilation with non-invasive ventilation [such as bilevel positive airway pressure (BIPAP) or average volume-assured pressure support (AVAPS)], or could not produce adequate cough with a cough assist device to manage their secretions.	Baseline to 3 months post-treatment
Pulmonary FVC - Exploratory Measure	FVC (Forced Vital Capacity). Reduction of pulmonary function is the primary source of morbidity and mortality in ALS. FVC testing will be used to monitor respiratory function. FVC measures the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible; values less than 75% are indicative of the need for intervention and/or monitoring and optimal FVC values are greater than 76%.	Baseline to 3 months post-treatment for a total of two years from baseline

Collaborators and Investigators

• Sponsor: The Methodist Hospital Research Institute
• Collaborators: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: Stanley H Appel, MD, Houston Methodist Neurological Institute

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2016
• Primary Completion (Actual): January 5, 2018
• Study Completion (Actual): April 10, 2018

Study Registration Dates

• First Submitted: July 27, 2017
• First Submitted That Met QC Criteria: August 4, 2017
• First Posted (Actual): August 7, 2017

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: June 16, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: ALS; T-Regulatory Cells
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Nutritional and Metabolic Diseases; Amyotrophic Lateral Sclerosis; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Intercellular Signaling Peptides and Proteins; Cytokines; Interleukins; Lymphokines; Interleukin-2
• Other Study ID Numbers: Pro00013616

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No