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Background: B-cell maturation antigen (BCMA) directed chimeric antigen receptor (CAR-) T cells, show high response rates in patients with highly refractory and heavily treated myeloma, and have become a standard treatment in this setting. The durability of these responses, however, has been limited with few long term remissions. One approach to potentially improve CAR T outcome is to direct these cells to alternative targets such as CD38 almost universally expressed on malignant plasma cells. In this open-label phase I multi-institutional study we explored the efficacy and safety of CAR2 anti-CD38 A2 CAR-T cells in patients with RRMM. Methods: The SOR-CART-MM-001 study was a multicenter, open-label, “3+3” dose-escalation, phase 1b trial of a single administration of a fully human antibody with lambda light chain generated by transduction of activated T cells with an anti-CD38 A2 CAR expressing retroviral vector. A single dose of CAR2 Anti-CD38 CAR-T cells was administered 2 days post lymphodepletion with single-agent cyclophosphamide 1.5 g/m 2. The primary endpoint was determination of the maximum tolerated dose (MTD) assessed by the occurrence of treatment-emergent dose-limiting toxicities during the 28-day treatment period in the dose-escalation phase of the study. Dosing was divided into three cohorts ranging from 1 × 10 5 cells/kg (Cohort 1) to 1 × 10 7 cells/kg (Cohort 3). Circulating CAR-T cells were measured at different timepoints post infusion. Key eligibility criteria included ≥3 lines of therapy with prior proteasome inhibitor, immunomodulatory IMID drug or daratumumab exposure, measurable and progressive MM per International Myeloma Working Group criteria and ECOG ≤ 2. Results: Between March 2018 and March 2022, 9 patients were enrolled and assigned to each of the three Cohorts. Patient demographics and baseline characteristics are described in Table 1. Hematologic toxicity was the most common treatment emergent adverse event experienced (6/9, 66.7%), all Grade 3 or Grade 4. All cytopenias recovered in 21 days in subjects treated with no more than MTD. Two subjects within Cohort 3 exhibited mild cytokine release syndrome (CRS) (Grade 1 and 2) with one of these two subjects also developing mild neurotoxicity (Grade 2). No CRS or neurotoxicity was observed at either of the lower dose levels. Two serious adverse events (SAEs) were reported: Klebsiella sepsis 60 days after treatment that recovered in 4 days after antibiotics and muscle weakness at 24 days after treatment that received within 1 day without treatment and neither were deemed related to the study medication. The first 2 patients in Cohort 3 met dose limiting toxicity (DLT) criteria after treatment due to grade 3 hematological toxicity and the next lower dose 1 x 10 6 cells/kg (Cohort 2) became the MTD. Pharmacokinetic data showed the percentage of the detectable circulating CAR-T cells in any subject at any time point was low with many showing no detectable cells. 4 deaths were reported after the end of the study period, and none were considered related to the investigated CAR-T cells (3 due to progression and one due to COVID-19). Overall, a total of 3 patients had a partial response (PR) and 3 patients had stable disease (SD) across 3 dose levels. PR constituted the best response in the study and the durations of objective clinical responses were each less than 3 months. These treatment responses are summarized in Table 2. Conclusion: This phase I trial demonstrated that CAR2 anti-CD38 A2 CAR-T cells were generally well tolerated at the Cohort 2 (MTD) dose and demonstrated objective though short responses even in patients progressing after daratumumab and belantamab mafodotin. More clinical studies are needed to optimize the efficacy and tolerability of CAR-T cell therapies for patients with RRMM. This study was completed, and no more patients will be enrolled. DART-RRMM-101 is a phase 1b, open-label, dose-escalation study ongoing to assess allogeneic Anti-CD38 A2 Dimeric Antigen Receptor T Cells in RRMM (ClinicalTrials: NCT05007418).

Abstract Background: The National Comprehensive Cancer Network (NCCN) recommends the use of tissue-based genetic tests, such as Decipher, Prolaris, and Confirm mdx for localized prostate cancer, to help patients and caregivers make more informed treatment decisions at the time of diagnosis. However, while much enthusiasm currently exists for the burgeoning field of genomic medicine, prostate cancer disparities continue to persist in underserved communities despite the existence of evidence-based treatment guidelines. Methods: A diverse 15-member Community Advisory Board (CAB) representing rural and urban communities in Duval County, Florida were recruited from May to June 2023, to build a community-academic partnership, for the development and implementation of a genetic literacy patient-caregiver educational intervention for localized prostate cancer. The 15-member CAB was divided into groups of 5 for focus group discussions. Qualitative and quantitative data from CAB members were integrated to gain better understanding of the facilitators and barriers for prostate cancer genetic literacy in underserved communities. Results: The thematic analysis reveals several key themes related to prostate cancer, screening, treatment, and genetics. These themes reflect the diverse perspectives and experiences of the CAB members regarding prostate cancer, ranging from personal anecdotes to broader societal issues. Participants expressed thoughts related to fear, lack of knowledge, cultural beliefs, and access to healthcare. The discussion on prostate cancer and tissue based genetic testing highlighted the complexities surrounding prostate cancer and the need for further education, awareness, and access to affordable healthcare for all individuals at risk. Conclusion: CAB members emphasized the importance of improving access to information, promoting education, and addressing cultural barriers to ensure that individuals are informed about available options for prostate cancer diagnosis and treatment. Citation Format: Ewan K. Cobran, Jocelyn Turner, Folakemi Odedina, Alan H. Bryce, Christopher Williams, Jose Rodriguez, Roger Williams, Woodrow Nathan, Thomas Bryant III, LoveVonia Nathan, Laureen Husband. Community advisory board members’ perspectives on genetic literacy and patient-caregiver communication of prognostic genomics for localized prostate cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A042.

Introduction Adenosine triphosphate (ATP) is postulated to be a major player in the local control of skeletal muscle vascular tone during exercise. Exercise during hypoxic conditions significantly augments skeletal muscle blood flow and elevates venous plasma levels of ATP compared to normoxic conditions in young healthy adults. This suggests that the elevated levels of ATP during hypoxic exercise contribute to the augmented vasodilation. Nitric oxide synthase (NOS) inhibition has also been shown to blunt the effects of hypoxia on exercise vasodilation. Therefore, the aim of the current study was to evaluate the effect of NOS inhibition and hypoxia on vasodilator responses and plasma ATP levels during exercise in healthy young adults. Methods 10 young volunteers (age = 28 ± 1 years, 6 men/4 women) performed four minutes of forearm handgrip exercise at 20% of their maximal voluntary contraction (MVC). The forearm handgrip exercise was performed under normoxia and hypoxia (SpO2 = ~80%) with and without NOS inhibitor, LNMMA administered via a brachial artery catheter. Beat to beat blood pressure and heart rate were recorded. Forearm blood flow was measured using Doppler ultrasound and normalized for arterial pressure to determine forearm vascular conductance (FVC). Venous blood was obtained from a retrograde intravenous catheter at rest and during the last minute of each exercise bout. Plasma ATP was measured using the luciferin‐luciferase technique. Results During saline and normoxia FVC was 43.4 ± 8.4 at rest and 307.8 ± 22.6 ml/min/100mmHg during exercise. With hypoxia FVC increased to 59.35 ± 10.5 at rest and 370.9 ± 33.3 ml/min/100mmHg during exercise (both p<0.05 vs. normoxia). During LNMMA and normoxia FVC did not change significantly compared to saline 33.9 ± 4.4 at rest and 283.5 ± 23.2 ml/min/100mmHg during exercise. With hypoxia and LNMMA FVC was 35.04 ± 4.1 at rest (p>0.05 vs. normoxia) and 326.0 ± 23.9 ml/min/100mmHg during exercise (p<0.05 vs. normoxia). When changes from baseline are evaluated, hypoxia augmented the vasodilator responses exercise to exercise during both saline and LNMMA. ATP was higher during 20% MVC exercise with saline during hypoxia as compared to normoxia (65.6 ± 12.1 vs. 108.1 ± 23.2 versus nmol/L, p=0.058). It was also higher during 20% MVC exercise with LNMMA (81.7 ± 9.5 vs. 106.1 ± 14.7 nmol/L, p=0.055). When changes from baseline are evaluated, hypoxia augmented venous ATP concentration with exercise during both saline and LNMMA. Conclusions Our results suggest that increased endogenous ATP release during hypoxic exercise continued to evoke vasodilation during NOS inhibition. A likely source of this ATP is from red blood cells and this interpretation is consistent with findings demonstrating that NOS inhibition has limited effects on ATP mediated dilation in the human forearm. Support or Funding Information This research was supported by National Institutes of Health Research Grants HL‐119337, CTSA UL1 TR000135 and the Caywood Professorship via the Mayo Foundation

Adenosine triphosphate (ATP) is postulated to be a major exercise related vasodilating metabolite. In humans, ATP infusion mimics exercise hyperemia. However, it remains unknown whether ATP can evoke the prolonged vasodilation seen during exercise. Therefore we tested two hypotheses during a three‐hour intra‐arterial infusion of a high dose of ATP (20 μgrams ·100 mL forearm vol −1 ·min −1 ): (1) skeletal muscle blood flow would wane over time (tachyphalaxis); (2) exercise hyperemic responses during ATP administration would be blunted compared to baseline. Nine healthy young participants (25 ± 1 years) performed seven rhythmic handgrip exercise bouts (20% of maximum), two during saline (control) and five during 180 minutes of continuous ATP infusion. Forearm vascular conductance (FVC; ml min −1 (100 mmHg) −1 ) and percent (%) change from control were calculated. Five minutes of ATP infusion resulted in a 710% increase in FVC (4.8±0.3 vs 35.0±1.9 ml min −1 *100 mmHg −1 , P<0.05). FVC did not wane over time with values of 35.0±1.9 and 36±2.6 ml min −1 (100 mmHg) −1 (P>0.05) seen prior to the exercise bouts at 5 vs 150 minutes respectively. With superimposed exercise FVC increased from 35.0±1.9 to 49.6±2.2 ml min −1 *100 mmHg −1 at five minutes and 36.0±2.6 to 54.5±1.1 at 150 min (P<0.05). Our findings demonstrate (1) ATP vasodilation is sustained over time without tachyphalaxis; (2) vasodilator responses to exercise during high dose ATP infusion remain intact. This latter finding questions the extent to which ATP is obligatory for exercise hyperemia. Support or Funding Information This research was supported by National Institutes of Health Research Grants HL‐119337 and by CTSA UL1 TR000135. The Caywood Professorship via the Mayo Foundation also supported this research.

High doses of adenosine (ADO) infused over a prolonged period (3 hours) produces marked vasodilation. However, this vasodilation wanes over time in an isolated canine skeletal muscle preparation. To our knowledge the waning of vasodilation with high doses of ADO has not been shown in humans. In addition, ADO plays a controversial role in exercise hyperemia. Therefore, our primary hypothesis was that in humans during a continuous three‐hour intra‐arterial infusion of a high dose of ADO (23 μgrams ·100 mL forearm vol −1 ·min −1 ) skeletal muscle blood flow would wane over time. Our secondary hypothesis was exercise hyperemic responses during ADO administration would be similar compared to control. Nine healthy young participants (29 ± 2 years) performed rhythmic handgrip (HG) exercise bouts (20% of maximum) during saline and 180 minutes of continuous ADO infusion. Forearm vascular conductance (FVC; ml min −1 (100 mmHg) −1 ) was calculated from measured forearm blood flow and mean blood pressure. FVC during minute 5 versus minute 175 during ADO infusion were 24.22 ± 3.2 versus 23.24 ± 1.95 ml min −1 (100 mmHg) −1 respectively (p>0.05). FVC during exercise increased significantly from baseline (4.78 ± 0.63 to 31.13 ± 4.17 ml min −1 *100 mmHg −1 ) during saline infusion and from (24.22 ± 3.23 to 56.33 ± 4.82 ml min −1 *100 mmHg −1 ) at five minutes and 21.99 ± 1.25 to 59.16 ± 5.21 seen at 150 minutes during ADO infusion. There was no significant difference in the delta FVC (exercise FVC – baseline FVC) between saline exercise bout versus ADO exercise bout (26.34 ± 3.75 versus 32.11 ± 5.55 ml min −1 *100 mmHg −1 ). Our findings show that contrary to the animal model, ADO vasodilatation does not wane in humans. Also, the vasodilator responses to exercise are similar during saline and prolonged ADO infusion compared to control condition. These findings suggest a minimal role of ADO in exercise hyperemia. Support or Funding Information Supported by National Institutes of Health Research Grants HL‐119337 (to M.J. Joyner and F.A. Dinenno) and by CTSA UL1 TR000135. The Caywood Professorship (M.J. Joyner) via the Mayo Foundation also supported this research.

Exercise‐induced rapid onset vasodilation produces a temporary rise in skeletal muscle blood flow in humans. The underlying mechanisms for this rapid hyperemia and regulation of muscle blood flow with single contraction are still not well understood. We tested the hypothesis that during a prolonged high dose intrarterial infusion of adenosine triphosphate (ATP; 20 μgrams ·100 mL forearm vol −1 ·min −1 ), the rapid onset vasodilatory response post‐single exercise contraction would be reduced compared to that of adenosine (ADO; 23 μgrams ·100 mL forearm vol −1 ·min −1 ). 14 healthy young participants (30 ± 1 years) performed a forearm single contraction exercise (20% of maximum) at minute 75 of either ATP (N=8) or ADO (N=6) continuous infusion. Artery diameter and blood velocity were measured using Doppler ultrasound. Forearm vascular conductance (FVC; ml·min −1 ·100 mmHg −1 ), time to peak, and area under curve were calculated. The mean resting FVC was higher during ATP (307.15 ± 50.56) and ADO (353.23 ± 43.98) infusion compared to saline infusion (45.17 ± 5.61 and 47.14 ± 5.57) (p<0.05). Compared to ADO, ATP infusion had a lower delta FVC from post‐ to pre‐contraction (174.06 ± 30.75 vs. 276.53 ± 24.90, p<0.05). Area under the curve and time of peak FVC did not significantly differ between drugs. These results suggest a prolonged ATP infusion may have blunted the rapid vasodilatory response more‐so than ADO. Thus, our findings indicate that ATP may be necessary but not obligatory in the rapid onset vasodilation response post‐single muscle contraction in humans. Support or Funding Information Supported by National Institutes of Health Research Grants HL‐119337 (to M.J. Joyner and F.A. Dinenno) and by CTSA UL1 TR000135. The Caywood Professorship (M.J. Joyner) via the Mayo Foundation also supported this research.

OBJECTIVE Men and women differ in cardiac output. We hypothesize a sex by genotype interaction may exist during a low‐dose adrenaline infusion affecting the β2 adrenergic receptor. METHODS Subjects: Ten males (mean ± SD: age=27.8±6.6, height=178.5±8.0cm, weight=83.9 ±12.4kg, BMI=26.3±2.9kg/m^2, BSA=2.0±0.2) and fourteen females (mean ± SD: age=26.3±5.9, height=164.3±7.0cm, weight=60.8±6.2kg, BMI=22.5±2.1kg/m^2, BSA=1.7±0.1) were studied. Three males were homozygous for Arginine (Arg/Arg) and 7 males were homozygous for Glycine (Gly/Gly) at position 16. In the female cohort, eight females were Arg/Arg and six females were Gly/Gly, at position 16. Procedure: A 1‐hour epinephrine infusion dosed at 5ng/kg/min was administered. BP was measured via an arterial catheter and HR via EKG. Stroke volume and Cardiac output were estimated via Modelflow and TPR was calculated. Plasma samples were collected at time: 0, 30, 45, 60, and 70 minutes and catecholamines measured using HPLC with electrochemical detection. Population Pharmacokinetic‐Pharmacodynamic Analysis: Plasma epinephrine concentrations and cardiac output responses were analyzed using the Nonlinear Mixed Effects (NLME) Stochastic Approximation Expectation‐Maximization (SAEM) algorithm in MATLAB® Simbiology TM (version 2015a, Mathworks, Natick, MA). The Visual Predictive Check was conducted using the R statistical software (version 3.2.2, The R Foundation for Statistical Computing, Vienna, Austria). RESULTS Epinephrine pharmacokinetics were well‐described using a one‐compartment model with an ‘effect compartment’ and elimination from the central compartment. The population mean estimates for the volume of distribution and elimination rate were 22.81 L (CV=27.52%) and 8.77 L/hour (13.00%), respectively. Cardiac Output was modeled using the Hill Stimulation Equation and resulted in mean population estimates of E0=4.94 L/min (13.56%) for baseline, Emax=34.86 L/min (38.61%), and EC50=2486.23 ng/L (CV=5.54%). Bodyweight (mean=70kg) and Sex:Genotypes were the main covariates for the model. A visual predictive check revealed adequate central tendency for the linked PK/PD model. Dosing (300ng/kg/hour for a 70kg individual) simulations resulted in a PK/PD profile stratified for the population mean and Sex:Genotype covariates. Plasma Concentration‐Response curves produced subpopulation (Male Arg/Arg, Male Gly/Gly, Female Arg/Arg, and Female Gly/Gly) differences. CONCLUSION Based on the plasma concentration‐response curves, the interaction of sex and genotype influences the ability to increase cardiac output during an infusion of low‐dose epinephrine. Support or Funding Information NIH T32 Clinical Pharmacology Fellowship Grant GM008685‐17.

Abstract Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young‐to‐middle‐aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging‐related conditions. Using plasma specimens from the Comprehensive Assessment of Long‐term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA‐IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA‐sequencing data from a subset of participants, we observed a significant reduction in a senescence‐focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.