Deletion of the inhibitory co-receptor CTLA-4 enhances and invigorates chimeric antigen receptor T cells.

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has achieved tremendous success treating B cell malignancies; however, some patients fail to respond due to poor autologous T cell fitness. To improve response rates, we investigated whether disruption of the co-inhibitory receptors CTLA4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion of CTLA4 in preclinical models of leukemia and myeloma improved CAR T cell proliferation and anti-tumor efficacy. Importantly, this effect was specific to CTLA4 and not seen upon deletion of CTLA4 and/or PDCD1 in CAR T cells. Mechanistically, CTLA4 deficiency permitted unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under conditions of high antigen load. In clinical studies, deletion of CTLA4 rescued the function of T cells from patients with leukemia that previously failed CAR T cell treatment. Thus, selective deletion of CTLA4 reinvigorates dysfunctional chronic lymphocytic leukemia (CLL) patient T cells, providing a strategy for increasing patient responses to CAR T cell therapy.

Decade-long leukaemia remissions with persistence of CD4+ CAR T cells.

The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers1-7. However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1-4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.

Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells.

Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these products are generally safe, efficacy is limited. Therefore, we generated and characterized a potent, fully human anti-MSLN CAR. In a phase 1 dose-escalation study of patients with solid tumors, we observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1-3 × 108 T cells per m2). Both patients demonstrated progressive hypoxemia within 48 h of infusion with clinical and laboratory findings consistent with cytokine release syndrome. One patient ultimately progressed to grade 5 respiratory failure. An autopsy revealed acute lung injury, extensive T cell infiltration, and accumulation of CAR T cells in the lungs. RNA and protein detection techniques confirmed low levels of MSLN expression by benign pulmonary epithelial cells in affected lung and lung samples obtained from other inflammatory or fibrotic conditions, indicating that pulmonary pneumocyte and not pleural expression of mesothelin may lead to dose-limiting toxicity. We suggest patient enrollment criteria and dosing regimens of MSLN-directed therapies consider the possibility of dynamic expression of mesothelin in benign lung with a special concern for patients with underlying inflammatory or fibrotic conditions.

Neural Sensitivity to Peer Feedback and Depressive Symptoms: Moderation by Executive Function.

Theories of adolescent development suggest that elevated neural sensitivity to social evaluation confers tradeoffs for adolescents' wellbeing, promoting adaptation to changing social contexts but increasing risk for emotional distress and depression. This study investigated whether the association between neural processing of peer feedback and depressive symptoms depends on teacher-reported executive function (EF) ability in adolescent girls. Girls showed activation to negative and positive peer feedback in regions implicated in social-emotional processing that interacted with EF to predict depressive symptoms. Specifically, activation predicted more depression in youth with poorer EF but less depression in youth with better EF, suggesting that the impact of increased social sensitivity may depend on youths' ability to regulate this sensitivity in adaptive ways.

Need for approval and antisocial behavior moderate the effect of socioemotional cues on adolescent girls' cognitive control.

To examine whether need for approval (NFA) and antisocial behavior (ASB) moderate the effects of socioemotional stimuli on cognitive control, 88 girls (Mage  = 16.31 years; SD = 0.84; 65.9% White) completed a socioemotional Go/No-go and questionnaires. At high approach NFA, girls responded more slowly during appetitive than control (b = -8.80, p < .01) and aversive (b = -5.58, p = .01) trials. At high ASB, girls responded more slowly (b = -6.12, p = .02) and less accurately (OR = 1.11, p = .03) during appetitive than aversive trials; at low ASB, girls responded more slowly during aversive than control trials (b = -4.42, p = .04). Thus, both context and individual differences influence adolescents' cognitive control.

Early life adversity and psychopathology in preschoolers: mechanisms and moderators.

Developmental theories suggest that exposure to early life adversity (ELA) alters developing emotional response systems, predicting risk for psychopathology across the life span. The present study examines whether negative emotionality (NE), a trait-like measure of emotionality that develops during early childhood, mediates the association between ELA and psychopathology in a representative sample of 917 preschoolers (Mage = 3.84). Additionally, we explored whether cognitive control, which supports attentional focusing and inhibition and has been identified as a transdiagnostic protective factor, moderates the impact of heightened emotionality following adversity on psychopathology risk. We utilized parent report of adversity, psychopathology, and NE and parent report and task-based measures of cognitive control. Structural equation modeling of cross-sectional data revealed that NE partially mediated the link between ELA and psychopathology symptoms. Moreover, parent-reported cognitive control buffered this link such that the effect of ELA on psychopathology through NE was stronger in children with low versus high cognitive control. These results identify elevated NE as one mechanism linking ELA and psychopathology, specifically among children with poorer top-down control, informing our understanding of key risk and protective factors among adversity-exposed children.

Risk for Depressive Symptoms Among Adolescents with a History of Adversity: Unique Role of Stress Appraisals.

Lifetime social adversity predicts elevated depressive symptoms in adolescence. However, most adversity-exposed youth do not develop depression, highlighting the importance of examining risk and protective factors. The present study leveraged a multi-method approach, incorporating self-report, interview, and independent coding to examine whether appraisals of recent stressors moderate the effect of social adversity on depressive symptoms in 81 adolescent girls (Mage = 16.30 years, SD = .85). We utilized semi-structured interviews of lifetime adversity and recent stressors and semi-structured interviews and self-reports of depressive symptoms. Stress appraisals were calculated by regressing youths' subjective estimations of event stressfulness and dependence on estimations of independent coders. Lifetime social adversity predicted elevated depressive symptoms more strongly in girls who appraised interpersonal events as more stressful and dependent on their actions, providing insight into individual differences in depressive symptoms in adversity-exposed adolescents.

How does peer adversity "Get inside the Brain?" Adolescent girls' differential susceptibility to neural dysregulation of emotion following victimization.

Exposure to peer victimization is a traumatic stressor, with adverse consequences for mental and physical health. This prospective, multi-method, multi-informant study investigated how victimization "gets into the brain," as reflected in neural dysregulation of emotion during adolescence. Moreover, we examined whether certain youth are particularly vulnerable to compromised neural function (i.e., a pattern of positive amygdala-right ventrolateral prefrontal cortex [rVLPFC] connectivity linked to poor emotion regulation [ER] and emotional distress) following victimization. In all, 43 adolescent girls completed an implicit ER task during a functional brain scan, and reported on rejection sensitivity. In 6th-9th grades, teachers and adolescents reported annually on victimization. Results revealed that a history of elevated victimization predicted less effective neural regulation of emotion (more positive amygdala-rVLPFC connectivity) in girls with high but not low rejection sensitivity. Consistent with a differential susceptibility model, high rejection sensitivity was associated with particularly effective neural regulation of emotion (more negative amygdala-rVLPFC connectivity) in girls with low-victimization histories. A parallel pattern emerged for a behavioral index of ER. This research provides insight into one pathway through which peer adversity undermines emotional development in ways that forecast compromised future health, and identifies youth who are at particularly high risk following peer adversity.

Hungry for inclusion: Exposure to peer victimization and heightened social monitoring in adolescent girls.

Belonging to a social group is one of the most important factors contributing to well-being. The Belonging Regulation model proposes that humans possess a social monitoring system (SMS) that evaluates social inclusion and monitors belonging needs. Here, we used a prospective longitudinal design to examine links between peer victimization experienced across 7 years and social monitoring at the behavioral and neural level in adolescent girls (n = 38, Mage = 15.43 years, SD = .33). Participants completed a social evaluation task during a functional magnetic resonance imaging (fMRI) scan. More severe peer victimization was associated with increased activation to in-group versus out-group peers in the amygdala, ventral striatum, fusiform gyrus, and temporoparietal junction. Moreover, participants who displayed increased activation in these regions reported lower social self esteem and higher levels of internalizing and externalizing symptoms. These results suggest that exposure to peer victimization across the school years is associated with heightened social monitoring at the neural level during adolescence, which has potential adverse implications for girls' adjustment and well-being.

Maternal Antecedents to Adolescent Girls' Neural Regulation of Emotion.

The purpose of this study was to investigate contributions of maternal emotional resources to individual differences in adolescents' functional connectivity during emotion regulation. Participants included 35 adolescent girls who completed an implicit emotion regulation task during fMRI. Mothers reported on the quality of their adult attachment and emotional awareness when youth were in elementary school. Higher anxious attachment and lower emotional awareness were significantly correlated with more positive amygdala-right ventrolateral prefrontal cortex connectivity, a pattern linked in prior research with ineffective emotion regulation and emotional difficulties. Further, there was an indirect effect of anxious attachment on adolescent connectivity through emotional awareness. These results suggest that compromised maternal emotional resources in childhood may be linked to atypical neural processing of emotions.

Differential Susceptibility to Parenting in Adolescent Girls: Moderation by Neural Sensitivity to Social Cues.

This research examined whether heightened neural activation to social cues confers adjustment advantages in supportive social contexts but adjustment disadvantages in stressful social contexts. Forty-five adolescent girls were exposed to social exclusion during an fMRI scan and reported on parent-child relationship quality and depressive symptoms. Stressful parent-child relationships predicted subsequent depressive symptoms in girls with high and moderate but not low dorsal anterior cingulate cortex, subgenual anterior cingulate cortex, and anterior insula activation during exclusion. In the context of supportive parent-child relationships, however, neural activation to exclusion predicted particularly low levels of depressive symptoms. This support for a biological sensitivity to context model suggests the possibility of redirecting adolescent girls' neural sensitivity to social cues toward more positive adaptation.

How do i participate in T-cell immunotherapy?

T cells play a key role in the adaptive immune response, and the ability to manipulate T cells for therapeutic uses has advanced in the past decade. Infusion of expanded or engineered T cells can potentially be used to treat cancer, viral infections, graft-versus-host disease, and organ transplant rejection. The role that blood banks play in the manufacture and distribution of T-cell therapeutics is still being defined. Given the regulatory framework of blood banks, they are well positioned to collect raw material for manufacture of T-cell therapies and to distribute finished product to hospitals in support of clinical trials or eventually for licensed products. A deeper level of involvement in manufacture of T-cell therapeutics is also possible, although that requires more substantial investment in physical facilities and personnel with the regulatory and scientific expertise to prepare and produce cellular therapy products. Examples of physical infrastructure needed would be a laboratory with a clean room for culture of T cells, specialized equipment for expansion of the cells, and adequate administrative and storage support space. Processes that would need to be developed to produce T-cell therapeutics would include development of standard operating procedures and an appropriate quality assurance program. As blood banks consider supporting this novel class of therapies, they will need to weigh capital and expertise requirements with the benefits of providing a novel therapy and the potential of growth for their operations.

Early-Childhood Social Reticence Predicts Brain Function in Preadolescent Youths During Distinct Forms of Peer Evaluation.

Social reticence is expressed as shy, anxiously avoidant behavior in early childhood. With development, overt signs of social reticence may diminish but could still manifest themselves in neural responses to peers. We obtained measures of social reticence across 2 to 7 years of age. At age 11, preadolescents previously characterized as high (n = 30) or low (n = 23) in social reticence completed a novel functional-MRI-based peer-interaction task that quantifies neural responses to the anticipation and receipt of distinct forms of social evaluation. High (but not low) social reticence in early childhood predicted greater activity in dorsal anterior cingulate cortex and left and right insula, brain regions implicated in processing salience and distress, when participants anticipated unpredictable compared with predictable feedback. High social reticence was also associated with negative functional connectivity between insula and ventromedial prefrontal cortex, a region commonly implicated in affect regulation. Finally, among participants with high social reticence, negative evaluation was associated with increased amygdala activity, but only during feedback from unpredictable peers.

Thumbs up or thumbs down: neural processing of social feedback and links to social motivation in adolescent girls.

Adolescence is a period of rapid biological and psychological development, characterized by increasing emotional reactivity and risk-taking, especially in peer contexts. Theories of adolescent neural development suggest that the balance in sensitivity across neural threat, reward and regulatory systems contributes to these changes. Building on previous research, this study used a novel social feedback task to explore activation and functional connectivity in the context of social threat and reward in a sample of mid-adolescent girls (n = 86, Mage = 16.32). When receiving negative peer feedback, adolescents showed elevated activation in, and amygdala connectivity with, social processing regions [e.g. medial prefrontal cortex (mPFC) and temporoparietal junction (TPJ)]. When receiving positive feedback, adolescents showed elevated activation in social and reward (e.g. mPFC and ventromedial prefrontal cortex) processing regions and less striatum-cerebellum connectivity. To understand the psychological implications of neural activation and co-activation, we examined associations between neural processing of threat and reward and self-reported social goals. Avoidance goals predicted elevated amygdala and striatum connectivity with social processing regions [e.g. medial temporal gyrus (MTG)], whereas approach goals predicted deactivation in social processing regions (e.g. MTG/TPJ and precuneus), highlighting the importance of considering individual differences in sensitivity to social threat and reward in adolescence.

Emotion mindsets and depressive symptoms in adolescence: The role of emotion regulation competence.

Recent theories posit that emotion mindsets (i.e., the extent to which individuals believe emotions are malleable or fixed) play a crucial role in experiences of emotion and influence emotion regulation (ER) processes. Drawing from mindset theory, this study examined the hypothesis that fixed emotion mindsets (FEMs) would predict depressive symptoms via compromised ER competence in adolescence, a period when many first episodes of depression occur. Results supported these hypotheses across two studies assessing participants in midadolescence (ages 14-18; M age = 16.17) and late adolescence (ages 18-21; M age = 18.52). Using a comprehensive approach to assessing ER, results demonstrated that FEMs were associated with less voluntary engagement and more disengagement and emotion dysregulation. In turn, higher voluntary engagement was associated with lower depressive symptoms, whereas higher disengagement and emotion dysregulation were associated with higher depressive symptoms. These findings highlight that one understudied pathway from FEMs to depressive symptoms may be the manner in which individuals respond to their emotions, implicating emotion mindsets as one target for efforts to improve clinical outcomes during adolescence. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Neighborhood Disadvantage Associated With Blunted Amygdala Reactivity to Predictable and Unpredictable Threat in a Community Sample of Youth.

BACKGROUND: Childhood socioeconomic disadvantage is a form of adversity associated with alterations in critical frontolimbic circuits involved in the pathophysiology of psychiatric disorders. Most work has focused on individual-level socioeconomic position, yet individuals living in deprived communities typically encounter additional environmental stressors that have unique effects on the brain and health outcomes. Notably, chronic and unpredictable stressors experienced in the everyday lives of youth living in disadvantaged neighborhoods may impact neural responsivity to uncertain threat. METHODS: A community sample of children (N = 254) ages 8 to 15 years (mean = 12.15) completed a picture anticipation task during a functional magnetic resonance imaging scan, during which neutral and negatively valenced photos were presented in a temporally predictable or unpredictable manner. Area Deprivation Index (ADI) scores were derived from participants' home addresses as an index of relative neighborhood disadvantage. Voxelwise analyses examined interactions of ADI, valence, and predictability on neural response to picture presentation. RESULTS: There was a significant ADI × valence interaction in the middle temporal gyrus, anterior cingulate cortex, hippocampus, and amygdala. Higher ADI was associated with less amygdala activation to negatively valenced images. ADI also interacted with predictability. Higher ADI was associated with greater activation of lingual and calcarine gyri for unpredictably presented stimuli. There was no three-way interaction of ADI, valence, and predictability. CONCLUSIONS: Neighborhood disadvantage may impact how the brain perceives and responds to potential threats. Future longitudinal work is critical for delineating how such effects may persist across the life span and how health outcomes may be modifiable with community-based interventions and policies.

BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion.

Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of PRDM1, encoding the BLIMP1 transcription factor, defined highly potent TCF7 [encoding T cell factor 1 (TCF1)]-expressing CD8+ CAR T cells, whereas enrichment of HAVCR2 [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]-expressing CD8+ T cells with elevated PRDM1 was associated with poor outcomes. PRDM1 knockout promoted TCF7-dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)-driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of NR4A3 and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of PRDM1 and NR4A3 skewed CAR T cell phenotypes away from TIM-3+CD8+ and toward TCF1+CD8+ to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with PRDM1 and NR4A3 single knockout alone. These data underscore dual targeting of PRDM1 and NR4A3 as a promising approach to advance adoptive cell immuno-oncotherapy.

Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.