Trial Title:
Exercise as an Immune Adjuvant for Allogeneic Cell Therapies
NCT ID:
NCT06643221
Condition:
Leukemia
Hematopoetic Stem Cell Transplantation
Donor Lymphocyte Infusion
CAR T-Cell Therapy
Lymphoma
Cell Therapy
Conditions: Official terms:
Lymphoma
Leukemia
Nadolol
Carvedilol
Bisoprolol
Isoproterenol
Conditions: 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
Study type:
Interventional
Study phase:
Early Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Crossover Assignment
Intervention 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.
Primary purpose:
Basic Science
Masking:
Double (Participant, Investigator)
Intervention:
Intervention type:
Behavioral
Intervention name:
Exercise
Description:
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)
Arm group label:
Exercise Cohort
Intervention type:
Drug
Intervention name:
Isoproterenol
Description:
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)
Arm group label:
Isoproterenol Infusion Cohort
Intervention type:
Drug
Intervention name:
Placebo
Description:
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
Arm group label:
Exercise + Beta Blocker Cohort
Intervention type:
Drug
Intervention name:
Bisoprolol Fumarate Tablet 10 mg
Description:
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
Arm group label:
Exercise + Beta Blocker Cohort
Intervention type:
Drug
Intervention name:
Nadolol (1 x 80 mg) Tablets (Invamed, Inc)
Description:
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
Arm group label:
Exercise + Beta Blocker Cohort
Intervention type:
Drug
Intervention name:
Carvedilol 50 mg
Description:
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
Arm group label:
Exercise + Beta Blocker Cohort
Intervention type:
Drug
Intervention name:
Roflumilast 500 Mcg Oral Tablet
Description:
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
Arm group label:
Exercise + Beta Blocker Cohort
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. 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.
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:
1. 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.
2. Determine whether immune cells collected post-exercise yield superior therapeutic
products compared to those collected under resting conditions from the same donor.
3. 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
1. Informed Consent: A member of the research team will obtain written informed consent
from the participant.
2. Pre-screening Questionnaire: Participants will complete the AHA/ACSM pre-screening
questionnaire to verify that inclusion and exclusion criteria are met.
3. Anthropometric Measurements: Height and weight will be measured.
4. 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).
5. Blood Pressure Measurement: Resting blood pressure will be measured using a manual
or automated blood pressure cuff.
6. Risk Stratification: Participants deemed ineligible after screening will be excluded
from further participation.
7. 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.
1. 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.
2. 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.
3. 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.
4. 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:
1. 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
2. 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.
3. 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.
4. 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.
5. Blood Sampling During Exercise: Additional venous blood samples will be collected
through the IV catheter at various time points throughout the exercise protocol.
6. 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
1. Informed Consent: A member of the research team will obtain written informed consent
from the participant.
2. Pre-screening Questionnaire: Participants will complete the AHA/ACSM pre-screening
questionnaire to verify that inclusion and exclusion criteria are met.
3. Anthropometric Measurements: Height and weight will be measured.
4. 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).
5. Blood Pressure Measurement: Resting blood pressure will be measured using a manual
or automated blood pressure cuff.
6. Risk Stratification: Participants deemed ineligible after screening will be excluded
from further participation.
7. 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.
8. 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.
9. 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.
10. 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
Criteria for eligibility:
Criteria:
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.
Gender:
All
Minimum age:
21 Years
Maximum age:
55 Years
Healthy volunteers:
Accepts Healthy Volunteers
Locations:
Facility:
Name:
The University of Arizona
Address:
City:
Tucson
Zip:
85719
Country:
United States
Status:
Recruiting
Contact:
Last name:
Miranda Hyslop-Garza
Phone:
520-626-7053
Email:
mirandahg@arizona.edu
Contact backup:
Last name:
Mark R Morrison, MS
Phone:
520-626-7053
Email:
mrm8@arizona.edu
Investigator:
Last name:
Richard J Simpson, PhD
Email:
Principal Investigator
Investigator:
Last name:
Emmanuel Katsanis, MD
Email:
Principal Investigator
Investigator:
Last name:
Forrest L Baker, PhD
Email:
Sub-Investigator
Investigator:
Last name:
Michael D Seckeler, MD
Email:
Sub-Investigator
Start date:
January 24, 2018
Completion date:
December 30, 2028
Lead sponsor:
Agency:
University of Arizona
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
University of Arizona
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06643221
