CAR T Cells in Solid Tumors: Blueprints for Building Effective Therapies

Genetic redirection of T lymphocytes with chimeric antigen receptors (CARs) has soared from treating cancers preclinically to FDA approval for hematologic malignancies and commercial-grade production scale in under 30 years. To date, solid tumors are less susceptible to CAR therapies and instead have been treated more successfully with immune checkpoint blockade or tumor-infiltrating lymphocyte therapy. Here, we discuss the current challenges in treating solid tumors with CAR T cells, and the obstacles within the host and tumor microenvironment hindering their efficacy. We present a novel three-pronged approach for enhancing the efficacy of CAR T cells whereby a single infusion product can synergize the power of an optimal CAR construct, a highly potent T cell subset, and rejuvenate the endogenous immune response to conquer therapeutically-resistant solid tumors

Fueling Cancer Immunotherapy With Common Gamma Chain Cytokines

Adoptive T cell transfer therapy (ACT) using tumor infiltrating lymphocytes or lymphocytes redirected with antigen receptors (CAR or TCR) has revolutionized the field of cancer immunotherapy. Although CAR T cell therapy mediates robust responses in patients with hematological malignancies, this approach has been less effective for treating patients with solid tumors. Additionally, toxicities post T cell infusion highlight the need for safer ACT protocols. Current protocols traditionally expand T lymphocytes isolated from patient tumors or from peripheral blood to large magnitudes in the presence of high dose IL-2 prior to infusion. Unfortunately, this expansion protocol differentiates T cells to a full effector or terminal phenotype in vitro, consequently reducing their long-term survival and antitumor effectiveness in vivo. Post-infusion, T cells face further obstacles limiting their persistence and function within the suppressive tumor microenvironment. Therapeutic manipulation of T cells with common γ chain cytokines, which are critical growth factors for T cells, may be the key to bypass such immunological hurdles. Herein, we discuss the primary functions of the common γ chain cytokines impacting T cell survival and memory and then elaborate on how these distinct cytokines have been used to augment T cell-based cancer immunotherapy

Rapid review and meta-meta-analysis of self-guided interventions to address anxiety, depression, and stress during COVID-19 social distancing

We conducted a rapid review and quantitative summary of meta-analyses that have examined interventions which can be used by individuals during quarantine and social distancing to manage anxiety, depression, stress, and subjective well-being. A literature search yielded 34 meta-analyses (total number of studies k = 1,390, n = 145,744) that were summarized. Overall, self-guided interventions showed small to medium effects in comparison to control groups. In particular, self-guided therapeutic approaches (including cognitive-behavioral, mindfulness, and acceptance-based interventions), selected positive psychology interventions, and multi-component and activity-based interventions (music, physical exercise) showed promising evidence for effectiveness. Overall, self-guided interventions on average did not show the same degree of effectiveness as traditional guided individual or group therapies. There was no consistent evidence of dose effects, baseline differences, and differential effectiveness of eHealth interventions. More research on the effectiveness of interventions in diverse cultural settings is needed

Identification of human CD4+ T cell populations with distinct antitumor activity

How naturally arising human CD4+ T helper subsets affect cancer immunotherapy is unclear. We reported that human CD4+CD26high T cells elicit potent immunity against solid tumors. As CD26high T cells are often categorized as TH17 cells for their IL-17 production and high CD26 expression, we posited these populations would have similar molecular properties. Here, we reveal that CD26high T cells are epigenetically and transcriptionally distinct from TH17 cells. Of clinical importance, CD26high and TH17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched TH1 or TH2 cells. Only human CD26high T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8+ CAR T cells. CD26high T cells cosecreted effector cytokines, produced cytotoxic molecules, and persisted long term. Collectively, our work underscores the promise of CD4+ T cell populations to improve durability of solid tumor therapies

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

The Consequences of not Acting on Personally and Socially Important Value-Expressive Behaviours on Hedonic and Eudaimonic Wellbeing

Wellbeing is thought to decrease when one’s actions do not align with one’s values. This study refined a previous experimental method to investigate how perceived failure to live up to expectations of value-expressive behaviours may affect eudaimonic and hedonic wellbeing. One hundred and ninety-nine students considered their own past value-expressive behaviours in a survey designed to induce a discrepancy or “gap” between reported and ideal behaviour. We tested whether the importance of value-expressive behaviours—and whether this importance was based on personal or social ideals—would affect the perception of behavioural discrepancies and wellbeing. Results showed that being asked about more important behaviours predicted a greater perceived behavioural gap and less hedonic wellbeing. Whether this importance was based on personal values or social desirability did not differentially predict perceived behavioural gap or wellbeing, challenging the focus that some therapy models place on personal value expression to improve wellbeing. The perceived behavioural gap did not mediate a relationship between experimental condition and wellbeing, suggesting that other variables may play a role in the relationship between values, behaviour, and wellbeing. Further exploratory tests, limitations, and theoretical implications are discussed

The complexities of “minding the gap”: perceived discrepancies between Values and behavior affect well-being

Research on self-determination theory and clinical models such as acceptance and commitment therapy has shown that behaving in line with our values is a key to maintaining healthy well-being. Combining work on values and experimental studies on moral hypocrisy and well-being, we experimentally tested how behaving incongruently with values affects well-being. We hypothesized that discrepancies between how one thinks one should have behaved and how one reported one did behave would be more detrimental to well-being when the behaviors were value-expressive and motivationally coherent compared to a control condition; greater perceived gaps between how participants feel they should have acted and how they report they did act would be associated with more negative well-being outcomes; the relationship between value manipulation and well-being would be mediated by perceived behavioral gap; and that personal values would interact with value manipulation to produce differential effects on well-being. One-hundred and fifty-eight first-year psychology students participated in an experiment designed to highlight discrepancies between how participants have behaved in accordance with a certain value and how they think they should have behaved, before reporting their well-being. As hypothesized, greater discrepancies between reported past behavior and how participants thought they should have behaved was associated with negative affect and decreased reports of positive well-being. We found no evidence for differential effects of manipulated value-expressive behaviors on well-being, or for our hypothesis that personal values and manipulated value-expressive behaviors interact. Nevertheless, value content mattered in terms of inducing perceived behavioral gaps. Our study suggests that perceived discrepancies between any value and reported past behavior can have a negative impact on some aspects of well-being. We discuss how the application of our methodology can be used in further studies to disentangle the value-behavior nexus

PI3Kδ Inhibition Enhances the Antitumor Fitness of Adoptively Transferred CD8+ T Cells

Phosphatidylinositol-3-kinase p110δ (PI3Kδ) inhibition by Idelalisib (CAL-101) in hematological malignancies directly induces apoptosis in cancer cells and disrupts immunological tolerance by depleting regulatory T cells. Yet, little is known about the direct impact of PI3Kδ blockade on effector T cells from CAL-101 therapy. Herein, we demonstrate a direct effect of p110δ inactivation via CAL-101 on murine and human CD8+ T cells that promotes a strong undifferentiated phenotype (elevated CD62L/CCR7, CD127, and Tcf7). These CAL-101 T cells also persisted longer after transfer into tumor bearing mice in both the murine syngeneic and human xenograft mouse models. The less differentiated phenotype and improved engraftment of CAL-101 T cells resulted in stronger antitumor immunity compared to traditionally expanded CD8+ T cells in both tumor models. Thus, this report describes a novel direct enhancement of CD8+ T cells by a p110δ inhibitor that leads to markedly improved tumor regression. This finding has significant implications to improve outcomes from next generation cancer immunotherapies

Rapid review and meta-meta-analysis of self-guided interventions to address anxiety, depression and stress during COVID-19 social distancing

We conducted a rapid review and quantitative summary of meta-analyses that have examined interventions which can be used by individuals during quarantine and social distancing to manage anxiety, depression, stress and subjective well-being. A literature search yielded 34 meta-analyses (total number of studies k = 1,390, n = 145,744) that were summarized. Overall, self-guided interventions showed small to medium effects in comparison to control groups demonstrating their effectiveness. In particular, therapeutic approaches (including cognitive-behavioral, mindfulness, and acceptance-based interventions), selected positive psychology interventions, and multi-component and activity based interventions (music, physical exercise) showed promising evidence for effectiveness. Many of these interventions are available in online or smartphone app form. At the same time, self-guided interventions on average did not show the same degree of effectiveness as traditional guided individual or group therapies. The review points to activities and practices that can be adapted by individuals as a first step to manage their mental health during social distancing and quarantines. Further research is clearly needed on activities helping individuals to interact and live in constrained living conditions (e.g, improving social interactions during quarantine) and the relative effectiveness of self-guided interventions across cultural boundaries