Advances in cancer immunotherapies.

Therapeutic modalities that engage the immune system to recognize and eliminate cancer, known as cancer immunotherapy, has emerged as a distinct pillar of cancer therapy. Among the most promising treatment approaches are therapeutic vaccines, immune checkpoint blockade, bispecific T-cell engagers (BiTEs) and adoptive cell therapies. These approaches share a common mechanism of action, which is elicitation of a T-cell-based immune response, either endogenous or engineered, against tumor antigens, but interactions between the innate immune system, particularly antigen-presenting cells, and immune effectors also underlie the efficacy of cancer immunotherapies and approaches engaging these cells are also under development. To view this SnapShot, open or download the PDF.

Forks in the road for CAR T and CAR NK cell cancer therapies.

The advent of chimeric antigen receptor (CAR) T cell therapy has resulted in unprecedented long-term clearance of relapse/refractory hematological malignancies in both pediatric and adult patients. However, severe toxicities, such as cytokine release syndrome and neurotoxicity, associated with CAR T cells affect therapeutic utility; and treatment efficacies for solid tumors are still not impressive. As a result, engineering strategies that modify other immune cell types, especially natural killer (NK) cells have arisen. Owing to both CAR-dependent and CAR-independent (innate immune-mediated) antitumor killing capacity, major histocompatibility complex-independent cytotoxicity, reduced risk of alloreactivity and lack of major CAR T cell toxicities, CAR NK cells constitute one of the promising next-generation CAR immune cells that are also amenable as 'off-the-shelf' therapeutics. In this Review, we compare CAR T and CAR NK cell therapies, with particular focus on immunological synapses, engineering strategies and challenges.

Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies.

CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies.

Distinguishing Truncated and Normal MUC1 Glycoform Targeting from Tn-MUC1-Specific CAR T Cells: Specificity Is the Key to Safety.

Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate potent clinical antitumor effects in a variety of blood cancers. However, clinical activity in solid tumors has been disappointing and toxicity has been a serious concern (Lamers et al., 2013; Morgan et al., 2010). We recently found that a CAR composed of a scFv antibody fragment specific for the Tn-glycoform of MUC1 had potent activity in preclinical models of blood cancer and adenocarcinoma (Posey et al., 2016).

Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.

Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.

Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells.

Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. Despite extensive clinical use, the attributes of CAR co-stimulatory domains that impact persistence and resistance to exhaustion of CAR-T cells remain largely undefined. Here, we report the influence of signaling domains of coreceptors CD28 and 4-1BB on the metabolic characteristics of human CAR T cells. Inclusion of 4-1BB in the CAR architecture promoted the outgrowth of CD8(+) central memory T cells that had significantly enhanced respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis. In contrast, CAR T cells with CD28 domains yielded effector memory cells with a genetic signature consistent with enhanced glycolysis. These results provide, at least in part, a mechanistic insight into the differential persistence of CAR-T cells expressing 4-1BB or CD28 signaling domains in clinical trials and inform the design of future CAR T cell therapies.

Sweet Immune Checkpoint Targets to Enhance T Cell Therapy.

Despite tremendous success against hematological malignancies, the performance of chimeric Ag receptor T cells against solid tumors remains poor. In such settings, the lack of success of this groundbreaking immunotherapy is in part mediated by ligand engagement of immune checkpoint molecules on the surface of T cells in the tumor microenvironment. Although CTLA-4 and programmed death-1 (PD-1) are well-established checkpoints that inhibit T cell activity, the engagement of glycans and glycan-binding proteins are a growing area of interest due to their immunomodulatory effects. This review discusses exemplary strategies to neutralize checkpoint molecules through an in-depth overview of genetic engineering approaches aimed at overcoming the inhibitory programmed death ligand-1 (PD-L1)/PD-1 axis in T cell therapies and summarizes current knowledge on glycoimmune interactions that mediate T cell immunosuppression.

Meeting muscle-strengthening recommendation is associated with lower adiposity, higher physical fitness and healthier lifestyle in adolescents: The EHDLA study.

AIM: To determine the prevalence of adolescents who meet muscle-strengthening activities (MSA) recommendation and their associations with anthropometric variables, physical fitness, and lifestyle behaviours in a sample of Spanish adolescents aged 12-17 years. METHODS: This was a cross-sectional study using data from The Eating Healthy and Daily Life Activities (EHDLA) Study. Participants reported the days on which they engaged in MSA (≥3 days per week were considered to meet World Health Organization recommendation). Physical fitness was assessed with the ALPHA fitness battery. Additionally, body mass index, waist circumference, skinfolds and body fat percentage were assessed. Lifestyle variables were recreational screen time, sleep time and adherence to the Mediterranean diet. The associations between MSA and outcome variables were tested with linear and logistic regressions. RESULTS: Of the 852 participants, 48% met MSA recommendation. Meeting MSA recommendation was associated with lower adiposity and higher performance in the shuttle run test, maximal oxygen consumption, standing long jump, speed-agility, flexibility, lower screen time (in weekdays) and higher adherence to the Mediterranean diet. CONCLUSION: Engaging in MSA once or twice a week was linked with more desirable health outcomes than not engaging in such activities. However, meet with MSA recommendation (i.e., at least 3 days per week) reinforced these benefits.

Utilizing the Frailty Index to Predict Long-term Mortality in Patients Undergoing Major Lower Extremity Amputation.

The 5-factor modified Frailty Index (mFI-5) is a risk-stratification tool utilized to predict complications and mortality following major lower extremity (LE) amputation. However, its prognostic value for long-term mortality is unknown. The study aim was to assess whether a high mFI-5 score relates to long-term mortality following major LE amputation for chronic wounds. Patients ≥60 years who underwent major LE amputation from 2017 to 2021 were retrospectively reviewed. Data regarding demographics, comorbidities, perioperative factors, amputation type, and postoperative complications was collected and mFI-5 was calculated. Survival analysis was performed with Kaplan-Meier curves and differences were assessed with Log-Rank test. A total of 172 patients were identified. Mean age was 70.7 ± 8.0 years. Median time to ambulation was 3.7 months (IQR 4.0). By final follow-up of 17.5 ± 15.9 months, ambulatory rate was 51.7% (n = 89), overall mortality 36.0% (n = 62), 1-year mortality 14.0% (n = 24), and 3-year mortality 27.9% (n = 48). Patients with an mFI-5 of ≥4 (26.7%, n = 46) compared with patients with mFI-5 <4 (73.3%, n = 126) had a higher rate of prolonged postoperative LOS (34.8% vs 19.8%, p = .042), overall mortality (52.2% vs 30.2%, p = .008), 1-year mortality (23.9% vs 10.3%, p = .023), and 3-year mortality (45.7% vs 21.4%, p = .002). Multivariate analysis demonstrated mFI-5 was an independent predictor of 3-year mortality (OR 2.35, p = .043). At a threshold ≥4, the mFI-5 demonstrated utility in predicting long-term mortality. The value of this prognostic indicator is in its preoperative application of assessing risk of mortality, which should be utilized in conjunction with other measures.

Heterosynaptic long-term potentiation of non-nociceptive synapses requires endocannabinoids, NMDARs, CamKII, and PKCζ.

Noxious stimuli or injury can trigger long-lasting sensitization to non-nociceptive stimuli (referred to as allodynia in mammals). Long-term potentiation (LTP) of nociceptive synapses has been shown to contribute to nociceptive sensitization (hyperalgesia) and there is even evidence of heterosynaptic spread of LTP contributing to this type of sensitization. This study will focus on how activation of nociceptors elicits heterosynaptic LTP (hetLTP) in non-nociceptive synapses. Previous studies in the medicinal leech (Hirudo verbana) have demonstrated that high-frequency stimulation (HFS) of nociceptors produces both homosynaptic LTP as well as hetLTP in non-nociceptive afferent synapses. This hetLTP involves endocannabinoid-mediated disinhibition of non-nociceptive synapses at the presynaptic level, but it is not clear if there are additional processes contributing to this synaptic potentiation. In this study, we found evidence for the involvement of postsynaptic level change and observed that postsynaptic N-methyl-d-aspartate (NMDA) receptors (NMDARs) were required for this potentiation. Next, Hirudo orthologs for known LTP signaling proteins, CamKII and PKCζ, were identified based on sequences from humans, mice, and the marine mollusk Aplysia. In electrophysiological experiments, inhibitors of CamKII (AIP) and PKCζ (ZIP) were found to interfere with hetLTP. Interestingly, CamKII was found to be necessary for both induction and maintenance of hetLTP, whereas PKCζ was only necessary for maintenance. These findings show that activation of nociceptors can elicit a potentiation of non-nociceptive synapses through a process that involves both endocannabinoid-mediated disinhibition and NMDAR-initiated signaling pathways.NEW & NOTEWORTHY Pain-related sensitization involves increases in signaling by non-nociceptive sensory neurons. This can allow non-nociceptive afferents to have access to nociceptive circuitry. In this study, we examine a form of synaptic potentiation in which nociceptor activity elicits increases in non-nociceptive synapses. This process involves endocannabinoids, "gating" the activation of NMDA receptors, which in turn activate CamKII and PKCζ. This study provides an important link in how nociceptive stimuli can enhance non-nociceptive signaling related to pain.

Repetitive nociceptive stimulation elicits complex behavioral changes in Hirudo: evidence of arousal and motivational adaptations.

Appropriate responses to real or potential damaging stimuli to the body (nociception) are critical to an animal's short- and long-term survival. The initial goal of this study was to examine habituation of withdrawal reflexes (whole-body and local shortening) to repeated mechanical nociceptive stimuli (needle pokes) in the medicinal leech, Hirudo verbana, and assess whether injury altered habituation to these nociceptive stimuli. While repeated needle pokes did reduce shortening in H. verbana, a second set of behavior changes was observed. Specifically, animals began to evade subsequent stimuli by either hiding their posterior sucker underneath adjacent body segments or engaging in locomotion (crawling). Animals differed in terms of how quickly they adopted evasion behaviors during repeated stimulation, exhibiting a multi-modal distribution for early, intermediate and late evaders. Prior injury had a profound effect on this transition, decreasing the time frame in which animals began to carry out evasion and increasing the magnitude of these evasion behaviors (more locomotory evasion). The data indicate the presence in Hirudo of a complex and adaptive defensive arousal process to avoid noxious stimuli that is influenced by differences in internal states, prior experience with injury of the stimulated areas, and possibly learning-based processes.

Time-of-Day Effects of Exercise on Cardiorespiratory Responses and Endurance Performance-A Systematic Review and Meta-Analysis.

ABSTRACT: Kang, J, Ratamess, NA, Faigenbaum, AD, Bush, JA, Finnerty, C, DiFiore, M, Garcia, A, and Beller, N. Time-of-day effects of exercise on cardiorespiratory responses and endurance performance-A systematic review and meta-analysis. J Strength Cond Res 37(10): 2080-2090, 2023-The time-of-day effect of exercise on human function remains largely equivocal. Hence, this study aimed to further analyze the existing evidence concerning diurnal variations in cardiorespiratory responses and endurance performance using a meta-analytic approach. Literature search was conducted through databases, including PubMed, CINAHL, and Google Scholar. Article selection was made based on inclusion criteria concerning subjects' characteristics, exercise protocols, times of testing, and targeted dependent variables. Results on oxygen uptake (V̇ o2 ), heart rate (HR), respiratory exchange ratio, and endurance performance in the morning (AM) and late afternoon or evening (PM) were extracted from the chosen studies. Meta-analysis was conducted with the random-effects model. Thirty-one original research studies that met the inclusion criteria were selected. Meta-analysis revealed higher resting V̇ o2 (Hedges' g = -0.574; p = 0.040) and resting HR (Hedges' g = -1.058; p = 0.002) in PM than in AM. During exercise, although V̇ o2 remained indifferent between AM and PM, HR was higher in PM at submaximal (Hedges' g = -0.199; p = 0.046) and maximal (Hedges' g = -0.298; p = 0.001) levels. Endurance performance as measured by time-to-exhaustion or the total work accomplished was higher in PM than in AM (Hedges' g = -0.654; p = 0.001). Diurnal variations in V̇ o2 appear less detectable during aerobic exercise. The finding that exercising HR and endurance performance were greater in PM than in AM emphasizes the need to consider the effect of circadian rhythm when evaluating athletic performance or using HR as a criterion to assess fitness or monitor training.

Sociodemographic Disparities in Craniosynostosis: A Systematic Review.

OBJECTIVE: Given the consequences of delayed treatment and diagnosis of craniosynostosis, this study reviews the literature on sociodemographic risk factors and disparities associated with delayed craniosynostosis treatment. DESIGN: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search of PubMed/Medline and Embase was performed by two independent reviewers. Included studies discussed craniosynostosis health disparities. Demographic characteristics and outcomes were analyzed. SETTING: Not applicable. PATIENTS: Patients with craniosynostosis. INTERVENTIONS: Standard surgical intervention for craniosynostosis. RESULTS: Our literature search yielded 273 studies, of which 18 were included for analysis. Included studies represented data from 31 256 U.S. patients with craniosynostosis. Sixty percent of patients (n = 16 510) were White, 13.8% were Hispanic/Latino, 6.2% were Black/African American, 1.3% were Asian, 0.3% were American Indian or Alaska Native, and 0.1% were Native Hawaiian or Pacific Islander. Average age at surgery was 6.36 months for White patients, 10.63 months for Black patients, and 9.18 months for Hispanic patients. Minority racial and/or ethnic status was a risk factor for delayed presentation, and increased incidence of open surgery, complication rates, hospital charges, operative time, anesthesia duration, and hospital length of stay. Government-funded health insurance was associated with delayed intervention and increased complications. CONCLUSIONS: Minority craniosynostosis patients experience delays in intervention and increased complication rates. Our findings highlight the importance of expedited and equitable referrals, screenings, and treatment, and the need for a standardized approach to investigating longitudinal demographic and outcomes data in this population.

May the Force Be with Youth: Foundational Strength for Lifelong Development.

ABSTRACT: Today's youth are weaker than previous generations, and measurable reductions in physical fitness are beginning to emerge. Without targeted initiatives that recognize the foundational importance of resistance training, weaker children and adolescents may be more likely to experience the inevitable consequences of neuromuscular dysfunction and less likely to experience the pleiotropic benefits of exercise and sport. Early exposure to strength-building activities is needed to prepare today's youth for ongoing participation in varied physical activities throughout this developmental phase of life. The novel iceberg of physical development is a metaphoric image that illustrates the sequential and cumulative influence of muscular strength on motor skills and physical abilities. Efforts to enhance the physical capacity of youth should include resistive skills that improve basic movement patterns and enhance motoric competence. A shift in our conceptual thinking about youth resistance training is needed to alter the current trajectory toward physical inactivity and related comorbidities.

A cellular antidote to specifically deplete anti-CD19 chimeric antigen receptor-positive cells.

Unintentional transduction of B-cell acute lymphoblastic leukemia blasts during CART19 manufacturing can lead to CAR19+ leukemic cells (CARB19) that are resistant to CART19 killing. We developed an anti-CAR19 idiotype chimeric antigen receptor (αCAR19) to specifically recognize CAR19+ cells. αCAR19 CAR T cells efficiently lysed CARB19 cells in vitro and in a primary leukemia-derived xenograft model. We further showed that αCAR19-CART cells could be used as an "antidote" to deplete CART19 cells to reduce long-term side effects, such as B-cell aplasia.

Effects of Integrative Neuromuscular Training on Motor Performance in Prepubertal Soccer Players.

ABSTRACT: Menezes, GB, Alexandre, DR, Pinto, JC, Assis, TV, Faigenbaum, AD, and Mortatti, AL. Effects of integrative neuromuscular training on motor performance in prepubertal soccer players. J Strength Cond Res 36(6): 1667-1674, 2022-The present study examined the effects of integrative neuromuscular training (INT) on motor performance in prepubertal soccer players. Subjects were randomly assigned to the experimental group (INT; n = 20, age: 8.2 ± 1.2 years; body mass: 28.4 ± 6.4 kg; height: 1.3 ± 0.1 m) or the control group (CON; n = 18, age: 8.5 ± 1.3 years; body mass: 32.8 ± 8.9 kg; height: 1.3 ± 0.1 m). Integrative neuromuscular training program was performed twice per week during the 12-week training intervention. Balance, flexibility, countermovement vertical jump height (CVJH), sprint speed, and change of direction speed (CODS) were assessed in both groups at baseline, sixth week and 12th week. A mixed model repeated measures analysis of variance was used to examine the group changes in performance for each variable. There was a time effect for balance in the INT from pre to 12th weeks (p < 0.001, g = 0.72), and from 6th to 12th weeks (p = 0.005, g = 0.34). An interaction effect for balance was also observed between INT and CON after the 12th week. A time effect in flexibility was observed in INT from baseline to 6th and 12th weeks (p = 0.02; g = 0.45 and p < 0.001; g = 0.71) and from 6 to 12th weeks (p = 0.003; g = 0.24). There was a time effect in CVJH, from baseline to 12th week and from 6th to 12th weeks (p < 0.05; g = 0.34 and g = 0.53, respectively). There was no significant between-group speed performance change. A time effect was found in CODS in INT, but only from baseline to 12th week (p = 0.02; g = 0.31). There were significant improvements in the percent change (Δ%) from baseline to 12 weeks (p < 0.05) for balance, flexibility, and CVJH in INT. These findings indicate that the addition of an INT program to soccer practice can improve selected motor performance skills in prepubertal soccer players.

Effects of Integrative Neuromuscular Training and Detraining on Countermovement Jump Performance in Youth Volleyball Players.

ABSTRACT: Nunes, ACCA, Cattuzzo, MT, Faigenbaum, AD, and Mortatti, AL. Effects of integrative neuromuscular training and detraining on countermovement jump performance in youth volleyball players. J Strength Cond Res 35(8): 2242-2247, 2021-The purpose of this study was to analyze the effect of integrative neuromuscular training (INT) on countermovement vertical jump height (CVJH) performance in youth volleyball players before and after a detraining period. Thirty-two novice volleyball players were cluster randomized into 2 groups: intervention group-INT (age: 13.1 ± 0.4 years; body mass: 55.3 ± 12.1 kg; and height: 161.1 ± 6.4 cm) and control group-CON (age: 12.8 ± 0.7 years; body mass: 51.8 ± 13.6 kg; and height: 160.1 ± 10.7 cm). The subjects were evaluated for somatic maturation (years from peak height velocity) and for CVJH performance at 4 time points during the 20-week study period: baseline, 6 weeks of INT, 12 weeks of INT, and 8 weeks after INT (detraining). The analysis used repeated-measures analysis of variance and Bonferroni post hoc test to identify possible differences in the CVJH delta in both groups. Spearman correlation was performed to verify the association between the values of the vertical jump tests and maturational levels found. The INT showed a significant improvement in the CVJH from baseline to 12 weeks and maintained training-induced gains after detraining period (p > 0.001). Significant increase in CVJH was found in the percentage of change (Δ%) from baseline to 6 weeks (p < 0.005), 12 weeks (p < 0.001), and detraining (p < 0.001) in INT compared with the CON. The results of this study indicate that INT was able to improve CVJH performance in novice youth volleyball players and these gains were sustained during the detraining period. These findings indicate that regular participation in supervised INT can enhance jumping performance in young volleyball players, and that this type of neuromuscular program may be particularly beneficial for youth with limited fundamental motor skill performance.

Squat and Bench Press Force-Velocity Profiling in Male and Female Adolescent Rugby Players.

ABSTRACT: Alonso-Aubin, DA, Chulvi-Medrano, I, Cortell-Tormo, JM, Picón-Martínez, M, Rial-Rebullido, T, and Faigenbaum, AD. Squat and bench press force-velocity profiling in male and female adolescent rugby players. J Strength Cond Res 35(2S): S44-S50, 2021-Power development is critical for enhancing rugby performance because there is a close relationship between power and sport-specific skills. The aim of this study was to examine the force-velocity profiling generated by adolescent rugby players in the squat and bench press exercises and to compare sex-related differences. Subjects were 46 men (age: 14.48 ± 1.31 years; body height: 1.65 ± 0.09 m; and body mass: 58.07 ± 13.01 kg) and 41 women (age: 14.93 ± 2.76 years; body height: 1.63 ± 0.12 m; and body mass: 59.23 ± 12.66 kg) who were recruited from a national amateur rugby league team. Maximal strength, power, and velocity were assessed on the squat and bench press exercises using a Smith Machine and a linear power transducer with intensities ranging from 40 to 80% 1 repetition maximum (1RM) on the squat and 50-80% 1RM on the bench press. 1 repetition maximum squat and bench press performance were 104.26 ± 30.83 and 46.97 ± 13.59 kg, respectively, for men and 115.17 ± 41.42 and 45.85 ± 16.71 kg, respectively, for women. The maximum squat power results for men and women were 521.91 ± 298.75 and 591.26 ± 352.69 W, respectively, and the maximum bench press power results for men and women were 190.26 ± 150.54 and 326.16 ± 195.57 W, respectively. Significant sex-related differences (p < 0.001) were found on the squat exercise for maximum (40%), mean (40-50%), and time to maximum velocities (40-80%) as well as time to maximum power (80%). On the bench press exercise, significant sex-related differences (p < 0.001) were found for power and time to maximum velocity (40%-60%-70%-80%). These results may aid in the design of strength and conditioning programs for adolescent rugby players by targeting training prescriptions toward enhancing strength or velocity.

Integrative Neuromuscular Training Enhances Physical Fitness in 6- to 14-Year-Old Rugby Players.

ABSTRACT: Alonso-Aubin, DA, Picón-Martínez, M, Rebullido, TR, Faigenbaum, AD, Cortell-Tormo, JM, and Chulvi-Medrano, I. Integrative neuromuscular training enhances physical fitness in 6- to 14-year-old rugby players. J Strength Cond Res 35(8): 2263-2271, 2021-The purpose of this study was to assess the effects of an 8-week integrative neuromuscular training (INT) program on physical fitness measures in young rugby players. A sample of 138 male rugby players (age range, 6-14 years) was divided into 5 age-related groups: group 1 (G1) (n = 20; age, 7.05 ± 0.58), group 2 (G2) (n = 27; age, 8.57 ± 0.49), group 3 (G3) (n = 31; age, 11.02 ± 0.56), group 4 (G4) (n = 33; age, 13.12 ± 0.58, and group 5 (G5) (n = 27; age, 14.85 ± 1.53 and additionally into 2 game position groups: forwards (FOR) (n = 69) and backs (BAC) (n = 69). Physical fitness measures included the Functional Movement Screen (FMS), dominant and nondominant hand-to-eye coordination, sprint capacity, core muscular endurance, and lower- and upper-body power. Integrative neuromuscular training (INT) included progressive strength, coordination, and speed exercises performed twice per week for 20 minutes. Following INT, significant improvements in selected age-related groups (p < 0.01) were found in total FMS score G3 (effect size [ES] = 0.47), G4 (ES = 0.88), and G5 (ES = 0.58); dominant hand-to-eye coordination G1 (ES = 1.48), G2 (ES = 0.71), G3 (ES = 0.55), G4 (ES = 1.47), and G5 (ES = 1.15), nondominant hand-to-eye coordination G2 (ES = 0.74), G4 (ES = 1.34), and G5 (ES = 1.09); lower-body power G2 (ES = 0.44), G4 (ES = 0.39), and G5 (ES = 0.43); core muscular endurance G1 (ES = 0.82), G3 (ES = 0.68), and G4 (ES = 1.04); upper-body power G2 (ES = 0.53); and sprint capacity G4 (ES = 0.69). Significant improvements were also found between player's positions for all tests. These findings indicate that a progressive INT program can enhance functional movement abilities and selected physical fitness measures in young rugby players regardless of game position and age.