LeukemiaEarly Phase 1Allo-XNCT06643221
Exercise as an Immune Adjuvant for Allogeneic Cell Therapies
A Early Phase 1 study testing Exercise, Isoproterenol and Bisoprolol Fumarate Tablet 10 mg in people with Leukemia and Hematopoetic Stem Cell Transplantation, run by University of Arizona at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Leukemia, Hematopoetic Stem Cell Transplantation, Donor Lymphocyte Infusion
- What is being tested?
- Exercise, Isoproterenol and Bisoprolol Fumarate Tablet 10 mg
- Type of treatment
- Pill or oral medicine, Injection or infusion, Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 200 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Jan 2018to 31 May 2031
- Phase
- Early Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
The University of Arizona
Tucson, Arizona, 85719
Miranda Hyslop-Garza, 520-626-7053, mirandahg@arizona.edu
Mark R Morrison, MS, 520-626-7053, mrm8@arizona.edu
About this study
Official title: Exercise-induced Adrenergic Receptor Signaling 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:
Read more
- 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.
- 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.
- 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.
Read the detailed description
Background:
Allogeneic cell therapies encompass various approaches, including donor lymphocyte infusions (DLI) and engineered immune cell products like chimeric antigen receptor (CAR) T-cells, gamma delta (γδ) T-cells, cytokine-induced killer (CIK) cells, and cytokine-induced memory-like natural killer (NK) cells. These therapies are commonly employed after allogeneic hematopoietic cell transplantation (alloHCT) to prevent or treat leukemic relapse in high-risk patients. However, while these therapies have shown potential, the success rates for DLI and expanded cell products remain limited. DLI, in particular, carries the risk of inducing graft-versus-host disease (GvHD), where donor T-cells attack healthy tissues, leading to significant morbidity. Furthermore, expanded cell products face challenges related to manufacturing times, efficacy, and cost, which can limit their accessibility and effectiveness. Therefore, there is a critical need to enhance the graft-versus-leukemia/lymphoma (GvL) effects of DLI and improve the efficacy of expanded cell products to achieve better outcomes for a larger number of patients without increasing the risk of GvHD, thereby broadening their use in clinical practice.
Exercise has been shown to contribute to lower cancer risk, improve outcomes in cancer survivors, and act as an adjuvant for several cancer therapies. The present exercise model involves an acute single bout of moderate to vigorous intensity exercise lasting 20 minutes, which evokes a catecholamine-dependent mobilization and redistribution of effector lymphocytes (e.g., natural killer cells, γδ T-cells, and CD8+ T-cells). This response may enhance long-term immunosurveillance by improving the recognition and destruction of premalignant cells and contributing to the suppression of tumor growth. The overarching research question is: Can lymphocytes be collected from blood during the exercise-induced mobilization phase to generate superior cell products for cancer immunotherapy? The overall vision is to develop exercise-mobilized lymphocytes into a therapy that increases the efficacy of both DLI and expanded cell products (e.g., CAR T-cells, γδ T-cells, CIK cells, and cytokine-induced memory-like NK cells) for treating leukemia/lymphoma relapse. This novel approach, termed "DLI-X," has the potential to improve a pre-existing therapy for the treatment of blood cancers at minimal cost.
The goals of this proposal are to conduct head-to-head comparisons between standard DLI and DLI-X, both in vitro and in xenogeneic mouse models engrafted with various human hematological cancers, and to identify the underlying mechanisms driving the enhanced anti-leukemia/lymphoma response of DLI-X.
The overarching hypothesis is that DLI-X and the expanded cell products manufactured from these exercise-mobilized lymphocytes will exhibit enhanced GvL effects against multiple hematological malignancies compared to standard DLI. These effects will be driven by β2-adrenergic receptor (β2-AR)-mediated transcriptomic and proteomic changes that promote target cell recognition and cytotoxicity. Additionally, it is proposed that DLI-X will improve the efficacy of combination therapies such as blinatumomab, a bi-specific T-cell engager, and monoclonal antibodies designed to increase antibody-dependent cellular cytotoxicity (ADCC), thereby enhancing tumor growth suppression and the GvL effects of DLI.
Specific Aims:
- Evaluate how acute, single bouts of moderate to vigorous intensity exercise lasting 20 minutes influence the number, phenotype, and molecular characteristics of immune cells in the blood.
- Determine whether immune cells collected post-exercise yield superior therapeutic products compared to those collected under resting conditions from the same donor.
- Investigate the role of adrenergic receptor signaling in mediating these effects
Procedures:
Healthy participants will be recruited into three distinct arms (cohorts) of this study: (1) Exercise Cohort; (2) Exercise + Beta Blocker Cohort; and/or (3) Isoproterenol Infusion Cohort. Participants may enroll in one, two, or all three study arms. The procedures for each cohort are outlined below.
Exercise Cohort Participants in the Exercise Cohort will be scheduled to visit the laboratory for three separate sessions between 08:00 and 10:00. During each visit, staff will confirm adherence to pre-testing guidelines (e.g., 8-12 hours of fasting and no vigorous physical activity). Any participant who does not meet these guidelines will be rescheduled.
Exercise Cohort Visit 1: Screening and Graded Exercise Test Time Commitment: 60 minutes
- Informed Consent: A member of the research team will obtain written informed consent from the participant.
- Pre-screening Questionnaire: Participants will complete the AHA/ACSM pre-screening questionnaire to verify that inclusion and exclusion criteria are met.
- Anthropometric Measurements: Height and weight will be measured.
- Blood Samples: A fingerstick capillary blood sample will be collected (using a sterile spring-loaded lancet) for total cholesterol and fasting glucose quantification, using an automated handheld analyzer (Cardiocheck).
- Blood Pressure Measurement: Resting blood pressure will be measured using a manual or automated blood pressure cuff.
- Risk Stratification: Participants deemed ineligible after screening will be excluded from further participation.
- Graded Exercise Test: Participants will perform a maximal exercise protocol on an indoor stationary bicycle. They will wear a heart rate monitor and a face mask connected to a metabolic cart for continuous measurement of heart rate and respiratory gases. The test will begin at 50 Watts for females and 75 Watts for males, with power increased by 15 Watts each minute until exhaustion. Maximal oxygen uptake (VO2max), ventilatory threshold, and peak cycling power will be determined.
Exercise Cohort Visits 2 and 3 Time Commitment: 2 hours per visit Participants will return to the laboratory 3-10 days after Visit 1 and 7-14 days after Visit 2.
- Pre-Exercise Procedures: An IV catheter will be inserted into a peripheral arm vein by a trained phlebotomist. A pre-exercise blood sample (approximately 120 mL) will be collected.
- Exercise Protocol: Participants will engage in a 20-minute session of moderate-to-vigorous cycling exercise at power outputs corresponding to 50%, 60%, 70%, and 80% of their predetermined maximal oxygen uptake (VO2max) for 5-minute increments. Participants will not be exercised to exhaustion during these trials. Blood pressure measurements and ratings of perceived exertion will be collected every 5 minutes during the exercise session and immediately after.
- Blood Sampling During Exercise: Additional venous blood samples (total volume during exercise: 80 mL) will be collected through the IV catheter at various stages of the exercise protocol.
- Post-Exercise Blood Draw: A final blood draw of 15 mL will be collected 1 hour post-exercise.
Total Blood Volume: Participants will donate a total of 215 mL of blood (120 mL pre-exercise, 80 mL during exercise, and 15 mL post-exercise) per visit, for a total of 430ml across both visits. Additionally, several droplets of capillary blood (approximately 10-20 µL) will be collected during Visit 1 for screening purposes.
The procedures for Visits 2 and 3 will be identical. The rationale for two visits is to obtain sufficient blood to generate multiple therapeutic cell products from the same donor. The total time commitment for this cohort is approximately 5 hours.
Exercise + Beta Blocker Cohort
Time Commitment: 21 hours Participants in the Exercise + Beta Blocker Cohort will be scheduled to visit the laboratory for six separate sessions between 08:00 and 10:00, which will be spread over 6-10 weeks. During each visit, study staff will confirm adherence to pre-testing guidelines (e.g., 8-12 hours of fasting and no vigorous physical activity). Any participant who does not meet these guidelines will be rescheduled.
Exercise + Beta Blocker Cohort Visit 1 - Graded Exercise Test Time Commitment: 60 minutes. Participants will complete a graded exercise test on an indoor stationary bicycle to determine their maximal oxygen uptake (VO₂max) and peak cycling power. This test will ensure the appropriate intensity levels for subsequent exercise trials.
Exercise + Beta Blocker Cohort Visits 2-6 - Exercise Trials Time Commitment: 20 hours
The remaining five visits will consist of the main exercise trials, where participants will undergo the following procedures. There will be a 7-10 day period between each exercise trial visit to allow for recovery and minimize potential carryover effects from the drugs administered:
- Drug Administration: The drug trials will be conducted in a block, randomized double-blind setting to ensure that neither the experimenter nor the participant knows which trial is occurring. The randomization will be computed by a member of the research team not involved in performing the exercise trials. The timing of drug administration is based on peak plasma concentrations of each drug. At 3 hours, 2 hours, and 1 hour prior to each exercise trial, participants will be administered either a drug or a placebo pill according to the following outline: Trial 1: Placebo at all time points Trial 2: Nadolol at 3 hours Placebo at 2 hours and 1 hour Trial 3: Bisoprolol at 3 hours Placebo at 2 hours and 1 hour Trial 4: Placebo at 3 hours and 1 hour, Carvedilol at 2 hours Trial 5: Bisoprolol at 3 hours, Placebo at 2 hours, Roflumilast at 1 hour
- Pre-Drug Procedures: Prior to the ingestion of the drug or placebo, an IV catheter will be inserted into a peripheral arm vein by a trained phlebotomist. A pre-drug blood sample will be collected.
- Post-Drug, Pre-Exercise Blood Sample: After the drug or placebo has been ingested and 30 minutes before exercise begins, a post-drug, pre-exercise blood sample will be collected.
- Exercise Protocol: Participants will engage in a 20-minute session of moderate-to-vigorous cycling exercise at power outputs corresponding to 50%, 60%, 70%, and 80% of their predetermined VO₂max for 5-minute increments. Participants will not be exercised to exhaustion during these trials. Blood pressure measurements and ratings of perceived exertion will be collected every 5 minutes during the exercise session and immediately after.
- Blood Sampling During Exercise: Additional venous blood samples will be collected through the IV catheter at various time points throughout the exercise protocol.
- Post-Exercise Recovery Blood Samples: Additional blood samples will be collected during the recovery phase, at various time points ranging from 5 to 60 minutes post-exercise.
Total Blood Volume: Participants in this cohort will donate a total of approximately 220 mL of blood per visit. The cumulative total blood volume for this cohort across all six visits is approximately 1,320 mL.
Isoproterenol Cohort Participants in the Isoproterenol Cohort will be scheduled to visit the laboratory for three separate sessions between 08:00 and 10:00. During each visit, study staff will confirm adherence to pre-testing guidelines (e.g., 8-12 hours of fasting and no vigorous physical activity). Any participant who does not meet these guidelines will be rescheduled.
Isoproterenol Cohort Visit 1: Screening and Isoproterenol Infusion Time Commitment: 2 hours
- Informed Consent: A member of the research team will obtain written informed consent from the participant.
- Pre-screening Questionnaire: Participants will complete the AHA/ACSM pre-screening questionnaire to verify that inclusion and exclusion criteria are met.
- Anthropometric Measurements: Height and weight will be measured.
- Blood Samples: A fingerstick capillary blood sample will be collected (using a sterile spring-loaded lancet) for total cholesterol and fasting glucose quantification, using an automated handheld analyzer (Cardiocheck).
- Blood Pressure Measurement: Resting blood pressure will be measured using a manual or automated blood pressure cuff.
- Risk Stratification: Participants deemed ineligible after screening will be excluded from further participation.
- Pre-Infusion Procedures: The participant will be fitted with electrodes attached to an electrocardiogram (ECG; 12-lead) and will receive a resting ECG reading, which will be monitored by a physician cardiologist. The cardiologist will make the decision whether to proceed with the infusion or exclude the participant from the study. Two IV catheters will be inserted into bilateral peripheral arm veins by a trained phlebotomist. One catheter will be used for delivering isoproterenol, and one will be used for collecting blood samples. A pre-infusion blood sample (approximately 120 mL) will be collected.
- Isoproterenol Infusion Protocol: Participants will receive a continuous infusion of isoproterenol for 20-minutes at a concentration of 50ng/min/kg. Blood pressure measurements will be collected every 5 minutes during the infusion and ECG activity will be monitored continuously. A physician cardiologist will monitor the entire infusion procedure.
- Blood Sampling During Infusion: Additional venous blood samples (total volume during exercise: 80 mL) will be collected through the IV catheter during the last 5-minutes of the infusion protocol.
- Post-Infusion Blood Draw: A final blood draw of 15 mL will be collected 1 hour post-exercise.
Total Blood Volume: Participants will donate a total of 215 mL of blood (120 mL pre-infusion, 80 mL during infusion, and 15 mL post-infusion) during this visit. Additionally, several droplets of capillary blood (approximately 10-20 µL) will be collected during Visit 1 for screening purposes.
Outcome Measures:
The outcome measures for all three cohorts will be identical as described in the 'Outcome Measures' section of this protocol
- Conditions
- Leukemia, Hematopoetic Stem Cell Transplantation, Donor Lymphocyte Infusion, CAR T-Cell Therapy, Lymphoma, Cell Therapy
- Being tested
- Exercise, Isoproterenol, Placebo, Bisoprolol Fumarate Tablet 10 mg, Nadolol (1 x 80 mg) Tablets (Invamed, Inc)
- 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
- Medical subject headings
- Leukemia, Lymphoma, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ExerciseBehavioural
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)
IsoproterenolDrug
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)
PlaceboDrug
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
Bisoprolol Fumarate Tablet 10 mgDrug
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
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
Carvedilol 50 mgDrug
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
Roflumilast 500 Mcg Oral TabletDrug
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
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: 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 Receives: 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) Receives: Drug: Isoproterenol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: up to 120 days
Secondary outcomes (4)
Single-Cell Secretome
We will assess the functional phenotype of purified cell types, including CD4+ and CD8+ T cells as well as natural killer (NK) cells, isolated from blood lymphocytes or expanded cell products. This will be accomplished using the Isoplexis single-cell platform and a multiplexed analysis of over 32 cytokines. Polyfunctionality will be evaluated by quantifying the number of distinct cytokines secreted by individual cells (ranging from 0 to 32) after a culture period of 4 to 18 hours. Each assay will include controls: unstimulated cells as a negative control, tumor cells to represent a target, and phorbol myristate acetate (PMA) as a positive control.
Measured: immediately after the intervention
CITE-Seq Analysis of Immune Cell Populations
We will use CITE-Seq to analyze transcriptional and surface protein differences in key human immune cell populations in response to exercise, with and without in vitro tumor challenge. Cell clusters will be annotated using the Azimuth package based on reference human PBMCs. Additionally, we will conduct differential gene expression (DE) analysis and perform Gene Set Enrichment Analysis (GSEA) using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms, applying fold-change and difference metrics for all major immune cell clusters defined by the Azimuth multimodal atlas. We will also sequence various chains of the T-cell receptor (alpha, beta, gamma and delta) to determine T-cell clonal characteristics and antigen specificity using public databases (e.g. VDJdb).
Measured: immediately after the intervention
Human Cell Engraftment and Immune Reconstitution:
In xenogeneic mice, peripheral blood counts and flow cytometry will be performed on days +7, +14, +21, +28, and +35 following tail bleeding into heparinized capillary tubes. This will assess human CD45+ cell engraftment (% of total human and mouse CD45+ cells) and differences in human immune cell reconstitution using a limited panel of lineage markers due to the restricted blood volumes in mice. If necessary, selected experiments will involve euthanizing mice to evaluate differences in human CD45+ cell and lymphocyte subsets in the bone marrow and spleen.
Measured: up to 120-days
Pathology and Immunohistochemistry
In additional experiments, tissues-including the large and small intestine, liver, lung, and skin-from xenogeneic mice will be harvested for pathological evaluation of xenogeneic graft-versus-host disease (xGvHD). Immunohistochemistry will be performed to assess the types of infiltrating human cells present in the mouse tissues. The quantification of immune cells will be conducted using image analysis software to count the number of positive-staining cells per field of view, allowing for a comparison of immune cell infiltration across different tissues and experimental conditions.
Measured: up to 120-days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Oct 2024
- Study start24 Jan 2018
- Primary completion31 May 2031 (estimated)
- Study completion31 May 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- 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.
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Arizona
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06643221
- Sponsor's protocol ID
- 1801161041
- Other IDs
- 5R01CA277493-02
- Acronym
- Allo-X
- Status last verified
- Feb 2026
- First submitted
- 8 Oct 2024
- Last updated
- 5 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Filioglou 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.
PubMed 40672109Baker 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.
PubMed 38592213Smith 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.
PubMed 40311885McDougal 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.
PubMed 40574863Batatinha 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.
PubMed 40940923Batatinha 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.
PubMed 41194247Batatinha 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 Apr 14;10(7):2565-2577. doi: 10.1182/bloodadvances.2025018345.
PubMed 41538301Zuniga 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.
PubMed 36189306Zuniga 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.
PubMed 36719647Batatinha 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.
PubMed 37077913Sullivan JL, Leite G, Cruz NS, Batatinha H, Swanson KA, Filioglou D, McKenzie GM, Kistner TM, Arunachalam PS, Baker FL, Katsanis E, Simpson R. Exercise-Mobilized Donor Lymphocytes Enhance Blinatumomab Activity Against B-ALL. Res Sq [Preprint]. 2026 Aug 13:rs.3.rs-10395685. doi: 10.21203/rs.3.rs-10395685/v1.
PubMed 42845554Chou L, Valenzuela AM, McDougal LM, Baker FL, Katsanis E, Simpson RJ. Exercise-mobilized lymphocytes enhance antibody-based immunotherapy in multiple myeloma through CD16+ NK cell-mediated cytotoxicity. J Transl Med. 2026 Mar 3;24(1):483. doi: 10.1186/s12967-026-07888-7.
PubMed 41776652
Study at a glance
From the registry record, last updated by the sponsor on 5 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Exercise-induced Adrenergic Receptor Signaling as an Immune Adjuvant for Allogeneic Cell Therapies
- ClinicalTrials.gov ID
- NCT06643221
- Acronym / sponsor ID
- Allo-X / 1801161041
- 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
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- University of ArizonaUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- 24 Jan 2018 (actual)
- Primary completion
- 31 May 2031 (estimated)
- Study completion
- 31 May 2031 (estimated)
- First posted
- 16 Oct 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
- 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.
- 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.
Detailed description
Background:
Allogeneic cell therapies encompass various approaches, including donor lymphocyte infusions (DLI) and engineered immune cell products like chimeric antigen receptor (CAR) T-cells, gamma delta (γδ) T-cells, cytokine-induced killer (CIK) cells, and cytokine-induced memory-like natural killer (NK) cells. These therapies are commonly employed after allogeneic hematopoietic cell transplantation (alloHCT) to prevent or treat leukemic relapse in high-risk patients. However, while these therapies have shown potential, the success rates for DLI and expanded cell products remain limited. DLI, in particular, carries the risk of inducing graft-versus-host disease (GvHD), where donor T-cells attack healthy tissues, leading to significant morbidity. Furthermore, expanded cell products face challenges related to manufacturing times, efficacy, and cost, which can limit their accessibility and effectiveness. Therefore, there is a critical need to enhance the graft-versus-leukemia/lymphoma (GvL) effects of DLI and improve the efficacy of expanded cell products to achieve better outcomes for a larger number of patients without increasing the risk of GvHD, thereby broadening their use in clinical practice.
Exercise has been shown to contribute to lower cancer risk, improve outcomes in cancer survivors, and act as an adjuvant for several cancer therapies. The present exercise model involves an acute single bout of moderate to vigorous intensity exercise lasting 20 minutes, which evokes a catecholamine-dependent mobilization and redistribution of effector lymphocytes (e.g., natural killer cells, γδ T-cells, and CD8+ T-cells). This response may enhance long-term immunosurveillance by improving the recognition and destruction of premalignant cells and contributing to the suppression of tumor growth. The overarching research question is: Can lymphocytes be collected from blood during the exercise-induced mobilization phase to generate superior cell products for cancer immunotherapy? The overall vision is to develop exercise-mobilized lymphocytes into a therapy that increases the efficacy of both DLI and expanded cell products (e.g., CAR T-cells, γδ T-cells, CIK cells, and cytokine-induced memory-like NK cells) for treating leukemia/lymphoma relapse. This novel approach, termed "DLI-X," has the potential to improve a pre-existing therapy for the treatment of blood cancers at minimal cost.
The goals of this proposal are to conduct head-to-head comparisons between standard DLI and DLI-X, both in vitro and in xenogeneic mouse models engrafted with various human hematological cancers, and to identify the underlying mechanisms driving the enhanced anti-leukemia/lymphoma response of DLI-X.
The overarching hypothesis is that DLI-X and the expanded cell products manufactured from these exercise-mobilized lymphocytes will exhibit enhanced GvL effects against multiple hematological malignancies compared to standard DLI. These effects will be driven by β2-adrenergic receptor (β2-AR)-mediated transcriptomic and proteomic changes that promote target cell recognition and cytotoxicity. Additionally, it is proposed that DLI-X will improve the efficacy of combination therapies such as blinatumomab, a bi-specific T-cell engager, and monoclonal antibodies designed to increase antibody-dependent cellular cytotoxicity (ADCC), thereby enhancing tumor growth suppression and the GvL effects of DLI.
Specific Aims:
- Evaluate how acute, single bouts of moderate to vigorous intensity exercise lasting 20 minutes influence the number, phenotype, and molecular characteristics of immune cells in the blood.
- Determine whether immune cells collected post-exercise yield superior therapeutic products compared to those collected under resting conditions from the same donor.
- Investigate the role of adrenergic receptor signaling in mediating these effects
Procedures:
Healthy participants will be recruited into three distinct arms (cohorts) of this study: (1) Exercise Cohort; (2) Exercise + Beta Blocker Cohort; and/or (3) Isoproterenol Infusion Cohort. Participants may enroll in one, two, or all three study arms. The procedures for each cohort are outlined below.
Exercise Cohort Participants in the Exercise Cohort will be scheduled to visit the laboratory for three separate sessions between 08:00 and 10:00. During each visit, staff will confirm adherence to pre-testing guidelines (e.g., 8-12 hours of fasting and no vigorous physical activity). Any participant who does not meet these guidelines will be rescheduled.
Exercise Cohort Visit 1: Screening and Graded Exercise Test Time Commitment: 60 minutes
- Informed Consent: A member of the research team will obtain written informed consent from the participant.
- Pre-screening Questionnaire: Participants will complete the AHA/ACSM pre-screening questionnaire to verify that inclusion and exclusion criteria are met.
- Anthropometric Measurements: Height and weight will be measured.
- Blood Samples: A fingerstick capillary blood sample will be collected (using a sterile spring-loaded lancet) for total cholesterol and fasting glucose quantification, using an automated handheld analyzer (Cardiocheck).
- Blood Pressure Measurement: Resting blood pressure will be measured using a manual or automated blood pressure cuff.
- Risk Stratification: Participants deemed ineligible after screening will be excluded from further participation.
- Graded Exercise Test: Participants will perform a maximal exercise protocol on an indoor stationary bicycle. They will wear a heart rate monitor and a face mask connected to a metabolic cart for continuous measurement of heart rate and respiratory gases. The test will begin at 50 Watts for females and 75 Watts for males, with power increased by 15 Watts each minute until exhaustion. Maximal oxygen uptake (VO2max), ventilatory threshold, and peak cycling power will be determined.
Exercise Cohort Visits 2 and 3 Time Commitment: 2 hours per visit Participants will return to the laboratory 3-10 days after Visit 1 and 7-14 days after Visit 2.
- Pre-Exercise Procedures: An IV catheter will be inserted into a peripheral arm vein by a trained phlebotomist. A pre-exercise blood sample (approximately 120 mL) will be collected.
- Exercise Protocol: Participants will engage in a 20-minute session of moderate-to-vigorous cycling exercise at power outputs corresponding to 50%, 60%, 70%, and 80% of their predetermined maximal oxygen uptake (VO2max) for 5-minute increments. Participants will not be exercised to exhaustion during these trials. Blood pressure measurements and ratings of perceived exertion will be collected every 5 minutes during the exercise session and immediately after.
- Blood Sampling During Exercise: Additional venous blood samples (total volume during exercise: 80 mL) will be collected through the IV catheter at various stages of the exercise protocol.
- Post-Exercise Blood Draw: A final blood draw of 15 mL will be collected 1 hour post-exercise.
Total Blood Volume: Participants will donate a total of 215 mL of blood (120 mL pre-exercise, 80 mL during exercise, and 15 mL post-exercise) per visit, for a total of 430ml across both visits. Additionally, several droplets of capillary blood (approximately 10-20 µL) will be collected during Visit 1 for screening purposes.
The procedures for Visits 2 and 3 will be identical. The rationale for two visits is to obtain sufficient blood to generate multiple therapeutic cell products from the same donor. The total time commitment for this cohort is approximately 5 hours.
Exercise + Beta Blocker Cohort
Time Commitment: 21 hours Participants in the Exercise + Beta Blocker Cohort will be scheduled to visit the laboratory for six separate sessions between 08:00 and 10:00, which will be spread over 6-10 weeks. During each visit, study staff will confirm adherence to pre-testing guidelines (e.g., 8-12 hours of fasting and no vigorous physical activity). Any participant who does not meet these guidelines will be rescheduled.
Exercise + Beta Blocker Cohort Visit 1 - Graded Exercise Test Time Commitment: 60 minutes. Participants will complete a graded exercise test on an indoor stationary bicycle to determine their maximal oxygen uptake (VO₂max) and peak cycling power. This test will ensure the appropriate intensity levels for subsequent exercise trials.
Exercise + Beta Blocker Cohort Visits 2-6 - Exercise Trials Time Commitment: 20 hours
The remaining five visits will consist of the main exercise trials, where participants will undergo the following procedures. There will be a 7-10 day period between each exercise trial visit to allow for recovery and minimize potential carryover effects from the drugs administered:
- Drug Administration: The drug trials will be conducted in a block, randomized double-blind setting to ensure that neither the experimenter nor the participant knows which trial is occurring. The randomization will be computed by a member of the research team not involved in performing the exercise trials. The timing of drug administration is based on peak plasma concentrations of each drug. At 3 hours, 2 hours, and 1 hour prior to each exercise trial, participants will be administered either a drug or a placebo pill according to the following outline: Trial 1: Placebo at all time points Trial 2: Nadolol at 3 hours Placebo at 2 hours and 1 hour Trial 3: Bisoprolol at 3 hours Placebo at 2 hours and 1 hour Trial 4: Placebo at 3 hours and 1 hour, Carvedilol at 2 hours Trial 5: Bisoprolol at 3 hours, Placebo at 2 hours, Roflumilast at 1 hour
- Pre-Drug Procedures: Prior to the ingestion of the drug or placebo, an IV catheter will be inserted into a peripheral arm vein by a trained phlebotomist. A pre-drug blood sample will be collected.
- Post-Drug, Pre-Exercise Blood Sample: After the drug or placebo has been ingested and 30 minutes before exercise begins, a post-drug, pre-exercise blood sample will be collected.
- Exercise Protocol: Participants will engage in a 20-minute session of moderate-to-vigorous cycling exercise at power outputs corresponding to 50%, 60%, 70%, and 80% of their predetermined VO₂max for 5-minute increments. Participants will not be exercised to exhaustion during these trials. Blood pressure measurements and ratings of perceived exertion will be collected every 5 minutes during the exercise session and immediately after.
- Blood Sampling During Exercise: Additional venous blood samples will be collected through the IV catheter at various time points throughout the exercise protocol.
- Post-Exercise Recovery Blood Samples: Additional blood samples will be collected during the recovery phase, at various time points ranging from 5 to 60 minutes post-exercise.
Total Blood Volume: Participants in this cohort will donate a total of approximately 220 mL of blood per visit. The cumulative total blood volume for this cohort across all six visits is approximately 1,320 mL.
Isoproterenol Cohort Participants in the Isoproterenol Cohort will be scheduled to visit the laboratory for three separate sessions between 08:00 and 10:00. During each visit, study staff will confirm adherence to pre-testing guidelines (e.g., 8-12 hours of fasting and no vigorous physical activity). Any participant who does not meet these guidelines will be rescheduled.
Isoproterenol Cohort Visit 1: Screening and Isoproterenol Infusion Time Commitment: 2 hours
- Informed Consent: A member of the research team will obtain written informed consent from the participant.
- Pre-screening Questionnaire: Participants will complete the AHA/ACSM pre-screening questionnaire to verify that inclusion and exclusion criteria are met.
- Anthropometric Measurements: Height and weight will be measured.
- Blood Samples: A fingerstick capillary blood sample will be collected (using a sterile spring-loaded lancet) for total cholesterol and fasting glucose quantification, using an automated handheld analyzer (Cardiocheck).
- Blood Pressure Measurement: Resting blood pressure will be measured using a manual or automated blood pressure cuff.
- Risk Stratification: Participants deemed ineligible after screening will be excluded from further participation.
- Pre-Infusion Procedures: The participant will be fitted with electrodes attached to an electrocardiogram (ECG; 12-lead) and will receive a resting ECG reading, which will be monitored by a physician cardiologist. The cardiologist will make the decision whether to proceed with the infusion or exclude the participant from the study. Two IV catheters will be inserted into bilateral peripheral arm veins by a trained phlebotomist. One catheter will be used for delivering isoproterenol, and one will be used for collecting blood samples. A pre-infusion blood sample (approximately 120 mL) will be collected.
- Isoproterenol Infusion Protocol: Participants will receive a continuous infusion of isoproterenol for 20-minutes at a concentration of 50ng/min/kg. Blood pressure measurements will be collected every 5 minutes during the infusion and ECG activity will be monitored continuously. A physician cardiologist will monitor the entire infusion procedure.
- Blood Sampling During Infusion: Additional venous blood samples (total volume during exercise: 80 mL) will be collected through the IV catheter during the last 5-minutes of the infusion protocol.
- Post-Infusion Blood Draw: A final blood draw of 15 mL will be collected 1 hour post-exercise.
Total Blood Volume: Participants will donate a total of 215 mL of blood (120 mL pre-infusion, 80 mL during infusion, and 15 mL post-infusion) during this visit. Additionally, several droplets of capillary blood (approximately 10-20 µL) will be collected during Visit 1 for screening purposes.
Outcome Measures:
The outcome measures for all three cohorts will be identical as described in the 'Outcome Measures' section of this protocol
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Exercise Cohort | Experimental | Behavioral: ExerciseAfter 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 + Beta Blocker Cohort | Placebo comparator | 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 TabletHealthy 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 |
| Isoproterenol Infusion Cohort | Experimental | Drug: IsoproterenolTo 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) |
Who may qualify
- Ages
- 21 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (20 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ExerciseAfter 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) | Behavioural | Exercise Cohort |
| IsoproterenolTo 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 Infusion Cohort |
| PlaceboHealthy 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 | Drug | Exercise + Beta Blocker Cohort |
| Bisoprolol Fumarate Tablet 10 mgHealthy 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 | Drug | Exercise + Beta Blocker Cohort |
| Nadolol (1 x 80 mg) Tablets (Invamed, Inc)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 | Drug | Exercise + Beta Blocker Cohort |
| Carvedilol 50 mgHealthy 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 | Drug | Exercise + Beta Blocker Cohort |
| Roflumilast 500 Mcg Oral TabletHealthy 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 | Drug | Exercise + Beta Blocker Cohort |
Primary outcome
Immune Cell Enumeration and Phenotyping
Time frame: immediately after the intervention
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.
Cytolysis in vitro
Time frame: immediately after the intervention
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.
Tumor Burden and Tumor Free Survival
Time frame: up to 120-days
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.
Clinical xGvHD Score
Time frame: up to 120-days
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.
Survival
Time frame: up to 120 days
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.
4 secondary outcomes
Single-Cell Secretome
Time frame: immediately after the intervention
CITE-Seq Analysis of Immune Cell Populations
Time frame: immediately after the intervention
Human Cell Engraftment and Immune Reconstitution:
Time frame: up to 120-days
Pathology and Immunohistochemistry
Time frame: up to 120-days
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Jun 2026.
- Background: PubMed 40672109Filioglou 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.
- Results publication: PubMed 38592213Baker 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.
- Results publication: PubMed 40311885Smith 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.
- Results publication: PubMed 40574863McDougal 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.
- Results publication: PubMed 40940923Batatinha 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.
- Results publication: PubMed 41194247Batatinha 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.
- Results publication: PubMed 41538301Batatinha 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 Apr 14;10(7):2565-2577. doi: 10.1182/bloodadvances.2025018345.
- Results publication: PubMed 36189306Zuniga 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.
- Results publication: PubMed 36719647Zuniga 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.
- Results publication: PubMed 37077913Batatinha 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.
- Derived from this study: PubMed 42845554Sullivan JL, Leite G, Cruz NS, Batatinha H, Swanson KA, Filioglou D, McKenzie GM, Kistner TM, Arunachalam PS, Baker FL, Katsanis E, Simpson R. Exercise-Mobilized Donor Lymphocytes Enhance Blinatumomab Activity Against B-ALL. Res Sq [Preprint]. 2026 Aug 13:rs.3.rs-10395685. doi: 10.21203/rs.3.rs-10395685/v1.
- Derived from this study: PubMed 41776652Chou L, Valenzuela AM, McDougal LM, Baker FL, Katsanis E, Simpson RJ. Exercise-mobilized lymphocytes enhance antibody-based immunotherapy in multiple myeloma through CD16+ NK cell-mediated cytotoxicity. J Transl Med. 2026 Mar 3;24(1):483. doi: 10.1186/s12967-026-07888-7.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Exercise, Isoproterenol and Bisoprolol Fumarate Tablet 10 mg in people with Leukemia and Hematopoetic Stem Cell Transplantation, run by University of Arizona at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 5 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Immune Cell Enumeration and Phenotyping (time frame: immediately after the intervention). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06643221, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jun 2026.