Exercise as an Immune Adjuvant for Allogeneic Cell Therapies

NCT06643221 | Recruiting Early Phase 1 DMC FDA Drug

• 2 other identifiers: 18011610415R01CA277493-02
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to improve the treatment of blood cancer by using exercise to collect healthier immune cells from donors. Allogeneic adoptive cell therapy is a treatment where immune cells from a healthy donor are given to a cancer patient, usually to help prevent or treat cancer relapse after a stem cell transplant. These donor cells can either be directly infused into the patient or grown in a lab to create more specialized immune cells that target and kill cancer. While this therapy has been helpful for many patients, there is a need to make it more effective for a larger group and reduce side effects like graft-versus-host disease (GvHD), where the donor's immune cells attack the patient's healthy tissue. This Early Phase 1 trial will test whether exercise can help produce better immune cells from donors. The investigators will recruit healthy participants for three study groups:

1. 1.Exercise Group: Participants will complete a 20-minute cycling exercise session. The investigators will collect blood samples before, during, and after exercise to study the number and quality of immune cells. The investigators will also use the collected cells to create immune therapies and test their ability to kill cancer cells in the lab and control cancer growth in mice.
2. 2.Exercise and Beta Blocker Group: In this group, participants will complete up to five cycling sessions, with at least a week between each session. Before each session, participants will take either a placebo or a drug (beta blocker) that blocks stress hormones like adrenaline. The investigators will collect blood samples before and during exercise to see how blocking these hormones changes the effect of exercise on immune cells.
3. 3.Isoproterenol Group: Participants in this group will receive a 20-minute infusion of isoproterenol, a drug that mimics the effects of adrenaline. The investigators will collect blood samples before, during, and after the infusion to see if the drug causes similar immune changes to those caused by exercise.

Conditions

Leukemia; Hematopoetic Stem Cell Transplantation; Donor Lymphocyte Infusion; CAR T-Cell Therapy; Lymphoma; Cell Therapy

Keywords

exercise; cell therapy; beta-blockers; immune function; phosphodiesterase inhibitor; CAR T-cells; NK-cells; cytokine-induced killer cells; cytokine-induced memory-like NK-cells; monoclonal antibodies; leukemia; lymphoma; donor lymphocyte infusion; gamma-delta T-cells

Outcome Measures

Primary Outcomes (5)

• Immune Cell Enumeration and Phenotyping

  Whole blood samples will be analyzed for complete blood counts and to quantify lymphocyte and monocyte subtypes using flow cytometry and a comprehensive immunophenotyping panel. This panel is designed to identify major immune cell populations, as well as markers related to differentiation, exhaustion, migration, activation, and inhibition. Specific cell types expressing a surface protein, or combinations of surface proteins, will be reported as the percentage of cells positive for expression and/or by mean fluorescent intensity (MFI). For descriptive purposes, the cell counts of all major lymphocyte and monocyte subtypes will be expressed as cells per microliter (cells/µL) of whole blood. Additionally, isolated peripheral blood mononuclear cells (PBMCs) and expanded cell products will be quantified and phenotyped in a similar manner.

  immediately after the intervention

• Cytolysis in vitro

  We will assess whether lymphocytes collected during or after exercise, as well as cell products manufactured from these lymphocytes, are more effective at killing hematologic cancer target cells. Using in vitro assays, such as flow cytometry and bioluminescence-based assays, we will compare the cytolytic activity of both the collected lymphocytes and the manufactured cell products to those obtained under resting conditions. Results will be measured as the time required to achieve 10%, 20%, 30%, 40%, and 50% cytolysis, or as the percentage of target cells killed at specific time points (e.g., 4, 8, 24, and 48 hours). We will also evaluate the impact of combination therapies, such as monoclonal antibodies targeting the tumor model, as appropriate.

  immediately after the intervention

• Tumor Burden and Tumor Free Survival

  Tumor burden will be evaluated in immunocompromised mice engrafted with human tumors by measuring the size, number, and progression of tumors using imaging techniques such as bioluminescence, MRI, or CT scans, along with physical measurements where applicable. Overall tumor burden will be assessed through metrics like peak tumor size and photon intensity in bioluminescence imaging. Tumor-free survival will be defined as the time from treatment until either the recurrence of detectable tumors or the last follow-up without tumor recurrence. Data will be reported as overall tumor reduction (e.g., percentage decrease in tumor size or number), peak tumor burden, and photon intensity, as well as the duration of tumor-free survival in days. Additional analyses will explore the effects of treatment on delaying tumor progression and improving overall survival.

  up to 120-days

• Clinical xGvHD Score

  The development of xGvHD (xenogeneic graft-versus-host disease) will be assessed using a clinical scoring system with a possible aggregate score ranging from 0 to 10. Animals will be monitored regularly, and a total score of 5 or higher on two consecutive assessment days will indicate the presence of moderate xGvHD. This scoring system allows for the systematic evaluation of disease severity and progression in response to treatment.

  up to 120-days

• Survival

  Survival will be monitored as a critical endpoint in this study. Death will be recorded when any of the following criteria are met: (1) the animal experiences greater than 20% weight loss compared to its baseline weight at two consecutive weigh-ins, indicating significant deterioration in health; or (2) the animal exhibits signs of severe morbidity, characterized by an xGvHD score exceeding 7. These criteria ensure that any adverse effects related to treatment or disease progression are accurately captured, allowing for a comprehensive assessment of the survival outcomes in the context of xGvHD.

  up to 120 days

Secondary Outcomes (4)

• Single-Cell Secretome

  immediately after the intervention

• CITE-Seq Analysis of Immune Cell Populations

  immediately after the intervention

• Human Cell Engraftment and Immune Reconstitution:

  up to 120-days

• Pathology and Immunohistochemistry

  up to 120-days

Study Arms (3)

Exercise Cohort

EXPERIMENTAL

After an initial maximal graded exercise test to determine maximal oxygen uptake and peak cycling power, healthy participants will undergo a 20-minute graded exercise test at intensities corresponding to 50, 60, 70 and 80% VO2max (5-minutes per stage)

Behavioral: Exercise

Exercise + Beta Blocker Cohort

PLACEBO COMPARATOR

Healthy participants will complete a 20-minute graded exercise test at intensities ranging from 50-80-% of the maximal oxygen uptake under the following conditions: (1) Placebo; (2) 10mg bisoprolol ingestion; (3) 80ng nadolol ingestion; (4) 50ng carvedilol ingestion; (5) 10mg bisoprolol + 100mcg roflumilast ingestion. All drugs and placebo will be ingested 2-3h prior to exercise. Trial conditions will be double-blind and cross over with each participant serving as their own cntrol

Drug: Placebo; Drug: Bisoprolol Fumarate Tablet 10 mg; Drug: Nadolol (1 x 80 mg) Tablets (Invamed, Inc); Drug: Carvedilol 50 mg; Drug: Roflumilast 500 Mcg Oral Tablet

Isoproterenol Infusion Cohort

EXPERIMENTAL

To determine if pharmacological activation of beta-adrenergic receptors evokes an immune respponse akin to exercise, healthy participants will receive an intravenous infusion of isoproterenol (50ng/kg/min)

Drug: Isoproterenol

Interventions

Exercise BEHAVIORAL

After an initial maximal graded exercise test to determine maximal oxygen uptake and peak cycling power, healthy participants will undergo a 20-minute graded exercise test at intensities corresponding to 50, 60, 70 and 80% VO2max (5-minutes per stage)

Exercise Cohort

Isoproterenol DRUG

To determine if pharmacological activation of beta-adrenergic receptors evokes an immune respponse akin to exercise, healthy participants will receive an intravenous infusion of isoproterenol (50ng/kg/min)

Isoproterenol Infusion Cohort

Placebo DRUG

Healthy participants will consume the placebo 2-3h prior to completing a 20-minute graded exercise test at intensities ranging from 50-80-% of the maximal oxygen uptake

Exercise + Beta Blocker Cohort

Bisoprolol Fumarate Tablet 10 mg DRUG

Healthy participants will consume a 10mg Bisoprolol Fumerate tablet 2-3h prior to completing a 20-minute graded exercise test at intensities ranging from 50-80-% of the maximal oxygen uptake

Exercise + Beta Blocker Cohort

Nadolol (1 x 80 mg) Tablets (Invamed, Inc) DRUG

Healthy participants will consume a 80mg Nadolol tablet 2-3h prior to completing a 20-minute graded exercise test at intensities ranging from 50-80-% of the maximal oxygen uptake

Exercise + Beta Blocker Cohort

Carvedilol 50 mg DRUG

Healthy participants will consume a 50mg Carvedilol tablet 2-3h prior to completing a 20-minute graded exercise test at intensities ranging from 50-80-% of the maximal oxygen uptake

Exercise + Beta Blocker Cohort

Roflumilast 500 Mcg Oral Tablet DRUG

Healthy participants will consume a 500mcg Roflumilast tablet and a 10mg Bisoprolol tablet 2-3h prior to completing a 20-minute graded exercise test at intensities ranging from 50-80-% of the maximal oxygen uptake

Exercise + Beta Blocker Cohort

Eligibility Criteria

• Age: 21 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participants must:
• Be between 21 and 55 years of age.
• Be classified as 'low-risk' for graded exercise/stress testing according to ACSM-AHA criteria.
• Have no contraindications for the use of isoproterenol, carvedilol, bisoprolol, nadolol, or roflumilast as per FDA guidelines.

You may not qualify if:

• Participants will be excluded if they:
• Currently use tobacco products or have quit within the last 6 months.
• Have a body mass index (BMI) greater than 34 kg/m² or waist circumference exceeding 102 cm for men and 88 cm for women.
• Use any medications known to affect the immune system or regularly take ibuprofen/aspirin, antidepressants, or medications that alter blood pressure or cardiovascular function.
• Use of hormone replacement therapy.
• Are pregnant or breastfeeding.
• Have chronic or debilitating arthritis or have been bedridden in the past three months.
• Experienced a common illness (e.g., colds) within the past 6 weeks.
• Have central or peripheral nervous disorders, a history of stroke, or major affective disorder.
• Are infected with HIV or hepatitis or have any autoimmune disease.
• Have known cardiovascular disease or contraindications for the use of isoproterenol, carvedilol, bisoprolol, nadolol, or roflumilast.
• Use any prescription medications or have an allergy to beta-blockers.
• Have a resting heart rate of less than 50 beats per minute.
• Suffer from asthma, emphysema, bronchitis, kidney disease, pheochromocytoma, diabetes, overactive thyroid, or a history of severe anaphylactic reactions.
• Are scheduled for surgery.

Sponsors & Collaborators

• University of Arizona: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

The University of Arizona

Tucson, Arizona, 85719, United States

RECRUITING

Related Publications (5)

• Zuniga TM, Baker FL, Smith KA, Batatinha H, Lau B, Gustafson MP, Katsanis E, Simpson RJ. Acute exercise mobilizes NKT-like cells with a cytotoxic transcriptomic profile but does not augment the potency of cytokine-induced killer (CIK) cells. Front Immunol. 2022 Sep 14;13:938106. doi: 10.3389/fimmu.2022.938106. eCollection 2022.

  PMID: 36189306 RESULT

• Zuniga TM, Baker FL, Smith KA, Batatinha H, Lau B, Burgess SC, Gustafson MP, Katsanis E, Simpson RJ. Clonal Kinetics and Single-Cell Transcriptional Profiles of T Cells Mobilized to Blood by Acute Exercise. Med Sci Sports Exerc. 2023 Jun 1;55(6):991-1002. doi: 10.1249/MSS.0000000000003130. Epub 2023 Jan 26.

  PMID: 36719647 RESULT

• Batatinha H, Diak DM, Niemiro GM, Baker FL, Smith KA, Zuniga TM, Mylabathula PL, Seckeler MD, Lau B, LaVoy EC, Gustafson MP, Katsanis E, Simpson RJ. Human lymphocytes mobilized with exercise have an anti-tumor transcriptomic profile and exert enhanced graft-versus-leukemia effects in xenogeneic mice. Front Immunol. 2023 Apr 3;14:1067369. doi: 10.3389/fimmu.2023.1067369. eCollection 2023.

  PMID: 37077913 RESULT

• Baker FL, Smith KA, Mylabathula PL, Zuniga TM, Diak DM, Batatinha H, Niemiro GM, Seckeler MD, Pedlar CR, O'Connor DP, Colombo J, Katsanis E, Simpson RJ. Exercise-induced beta2-adrenergic Receptor Activation Enhances the Antileukemic Activity of Expanded gammadelta T-Cells via DNAM-1 Upregulation and PVR/Nectin-2 Recognition. Cancer Res Commun. 2024 May 13;4(5):1253-1267. doi: 10.1158/2767-9764.CRC-23-0570.

  PMID: 38592213 RESULT

• Batatinha H, Valenzuela AM, Filioglou D, Wilde P, Leite G, Kistner TM, Baker FL, Katsanis E, Simpson RJ. Exercise-Mobilized Lymphocytes Enhance the Function of Cytokine-Induced Memory-like NK-cells Against Myeloid Leukemia. Blood Adv. 2026 Jan 15:bloodadvances.2025018345. doi: 10.1182/bloodadvances.2025018345. Online ahead of print.

  PMID: 41538301 DERIVED

MeSH Terms

Conditions

Leukemia; Lymphoma; Motor Activity

Interventions

Exercise; Isoproterenol; Bisoprolol; Nadolol; Carvedilol; Roflumilast; Tablets

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Behavior

Intervention Hierarchy (Ancestors)

Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenoxypropanolamines; Propanolamines; Propanols; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring; Dosage Forms; Pharmaceutical Preparations

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This trial has two main approaches: 1. Single Group - Blood samples collected from healthy participants during and after an acute exercise bout (or isoproterenol infusion) are compared to the 'resting' sample of the donor. 2. Crossover - Blood samples collected from healthy participants during and after an acute bout of exercise (or isoproterenol infusion) are compared across different conditions involving a placebo, selective beta-antagonists, non-selective beta-antagonists and phosphodiesterase inhibitors. In this model, all participants act as their own controls and a wash out period of at least 7-days is interspersed between each trial.

Study Record Dates

• First Submitted: October 8, 2024
• First Posted: October 16, 2024
• Study Start: January 24, 2018
• Primary Completion (Estimated): December 30, 2028
• Study Completion (Estimated): December 30, 2028
• Last Updated: October 16, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)