Exercise as an Immune Adjuvant for Allogeneic Cell Therapies

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. 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. 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. 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. Participants can join one, two, or all three groups. This research will help understand whether exercise can improve immune cell therapies for treating blood cancer and reduce the risk of GvHD, making these treatments safer and more effective.

Sex

All

Minimum age

21 Years

Maximum age

55 Years

Procedures are in place for protecting against or minimizing the risks to the healthy volunteers recruited for this study. Physical risk to volunteers and matched related donors will be protected through health screening to determine study eligibility, and medical monitoring with an established test termination criterion during the exercise and isoproterenol infusion trials.

To protect against the remote risk of an adverse cardiac event occurring during exercise and isoproterenol infusion, the study will only enroll volunteers who are considered "low risk" for maximal stress testing in accordance with the guidelines published by the American College of Sports Medicine (ACSM) and American Heart Association (AHA). Individuals who are considered "low risk" are men and women who are asymptomatic and have no more than one risk factor for cardiovascular disease (CVD). The risks to subjects are therefore extremely low. All infusions will take place in the Clinical and Translational Sciences Research Center (CATS) Infusion Suite, which is a designated University of Arizona campus facility for infusion trials and equipped with appropriate medical personnel and monitoring equipment (i.e. ECG). The graded exercise tests and isoproterenol infusions procedures will be performed under the direction of a licensed and board-certified cardiologist

Inclusion Criteria:

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.

Exclusion Criteria:

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.

Additionally, participants who meet the inclusion criteria but present with more than one of the following cardiovascular disease (CVD) risk factors will be excluded unless cleared by a cardiologist:

* Family History: Myocardial infarction, coronary revascularization, or sudden death before 55 years of age in a father or male first-degree relative, or before 65 years of age in a mother or female first-degree relative.
* Hypertension: Systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg.
* Dyslipidemia: Total serum cholesterol exceeding 200 mg/dl.
* Pre-diabetes: Fasting blood glucose levels between 100 mg/dl and 126 mg/dl.

• BACKGROUNDFilioglou D, Leite GSF, Batatinha H, Santa-Cruz N, Davini DW, Baker FL, Simpson RJ, Katsanis E. Cytokine-induced memory-like NK cells combined with Tafasitamab demonstrate efficacy against B-cell acute lymphoblastic leukemia. Immunother Adv. 2025 Jul 16;5(1):ltaf025. doi: 10.1093/immadv/ltaf025. eCollection 2025. PMID 40672109
• RESULTBaker 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
• RESULTSmith KA, Batatinha H, Niemiro GM, Baker FL, Zuniga TM, Diak DM, Mylabathula PL, Kistner TM, Davini D, Hoffman E, Colombo JN, Seckeler MD, Bond RA, Katsanis E, Simpson RJ. Exercise-induced beta2-adrenergic receptor activation enhances effector lymphocyte mobilization in humans and suppresses lymphoma growth in mice through NK-cells. Brain Behav Immun. 2025 Aug;128:751-765. doi: 10.1016/j.bbi.2025.04.040. Epub 2025 Apr 29. PMID 40311885
• RESULTMcDougal LM, Baker FL, Gustafson MP, Katsanis E, Simpson RJ. Exercise-mobilized donor lymphocyte infusions enhanced with cytokine stimulation for the prevention and treatment of leukemic relapse after allogeneic hematopoietic cell transplantation. Front Immunol. 2025 Jun 12;16:1563972. doi: 10.3389/fimmu.2025.1563972. eCollection 2025. PMID 40574863
• RESULTBatatinha H, Pena NA, Hoskin GA, Kistner TM, Diak DM, Niemiro GM, Katsanis E, Simpson RJ. Exercise Delays Human Leukemia Progression and Mitigates Graft-Versus-Host Disease After Donor Lymphocyte Infusion in Xenogeneic Mice. Cancers (Basel). 2025 Aug 29;17(17):2826. doi: 10.3390/cancers17172826. PMID 40940923
• RESULTBatatinha H, Niemiro GM, Pena NA, Hoskin GA, Zuniga TM, Smith KA, Baker FL, Diak DM, Mylabathula PL, Kistner TM, Seckeler MD, Katsanis E, Simpson RJ. Isoproterenol infusion enhances composition and function of G-CSF mobilized allogeneic peripheral blood hematopoietic cell grafts. Stem Cell Res Ther. 2025 Nov 5;16(1):614. doi: 10.1186/s13287-025-04725-4.