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Objectives: Autologous chimeric antigen receptor (CAR) αβ T-cell therapies have demonstrated remarkable antitumor efficacy in patients with haematological malignancies; however, not all eligible cancer patients receive clinical benefit. Emerging strategies to improve patient access and clinical responses include using premanufactured products from healthy donors and alternative cytotoxic effectors possessing intrinsic tumoricidal activity as sources of CAR cell therapies. γδ T cells, which combine innate and adaptive mechanisms to recognise and kill malignant cells, are an attractive candidate platform for allogeneic CAR T-cell therapy. Here, we evaluated the manufacturability and functionality of allogeneic peripheral blood-derived CAR + Vδ1 γδ T cells expressing a second-generation CAR targeting the B-cell-restricted CD20 antigen., Methods: Donor-derived Vδ1 γδ T cells from peripheral blood were ex vivo -activated, expanded and engineered to express a novel anti-CD20 CAR. In vitro and in vivo assays were used to evaluate CAR-dependent and CAR-independent antitumor activities of CD20 CAR + Vδ1 γδ T cells against B-cell tumors., Results: Anti-CD20 CAR + Vδ1 γδ T cells exhibited innate and adaptive antitumor activities, such as in vitro tumor cell killing and proinflammatory cytokine production, in addition to in vivo tumor growth inhibition of B-cell lymphoma xenografts in immunodeficient mice. Furthermore, CD20 CAR + Vδ1 γδ T cells did not induce xenogeneic graft-versus-host disease in immunodeficient mice., Conclusion: These preclinical data support the clinical evaluation of ADI-001, an allogeneic CD20 CAR + Vδ1 γδ T cell, and a phase 1 study has been initiated in patients with B-cell malignancies (NCT04735471)., Competing Interests: KPN, TB, AA, AM, JMR, LB, MMB, JK‐W, HS, SP, AD, CM, NTH, HT, VDR, AG‐R, M Hoopes, DS, RS, M Herrman, SEA, BTA, ZA, SP and SMH are, or were, employees of Adicet Bio, Inc., and FD, KS and KB are employees of Regeneron Pharmaceuticals, Inc., (© 2022 Adicet Bio Inc. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: Glypican-3 (GPC-3) is an oncofetal protein that is highly expressed in various solid tumors, but rarely expressed in healthy adult tissues and represents a rational target of particular relevance in hepatocellular carcinoma (HCC). Autologous chimeric antigen receptor (CAR) αβ T cell therapies have established significant clinical benefit in hematologic malignancies, although efficacy in solid tumors has been limited due to several challenges including T cell homing, target antigen heterogeneity, and immunosuppressive tumor microenvironments. Gamma delta (γδ) T cells are highly cytolytic effectors that can recognize and kill tumor cells through major histocompatibility complex (MHC)-independent antigens upregulated under stress. The Vδ1 subset is preferentially localized in peripheral tissue and engineering with CARs to further enhance intrinsic antitumor activity represents an attractive approach to overcome challenges for conventional T cell therapies in solid tumors. Allogeneic Vδ1 CAR T cell therapy may also overcome other hurdles faced by allogeneic αβ T cell therapy, including graft-versus-host disease (GvHD)., Methods: We developed the first example of allogeneic CAR Vδ1 T cells that have been expanded from peripheral blood mononuclear cells (PBMCs) and genetically modified to express a 4-1BB/CD3z CAR against GPC-3. The CAR construct (GPC-3.CAR/secreted interleukin-15 (sIL)-15) additionally encodes a constitutively-secreted form of IL-15, which we hypothesized could sustain proliferation and antitumor activity of intratumoral Vδ1 T cells expressing GPC-3.CAR., Results: GPC-3.CAR/sIL-15 Vδ1 T cells expanded from PBMCs on average 20,000-fold and routinely reached >80% purity. Expanded Vδ1 T cells showed a primarily naïve-like memory phenotype with limited exhaustion marker expression and displayed robust in vitro proliferation, cytokine production, and cytotoxic activity against HCC cell lines expressing low (PLC/PRF/5) and high (HepG2) GPC-3 levels. In a subcutaneous HepG2 mouse model in immunodeficient NSG mice, GPC-3.CAR/sIL-15 Vδ1 T cells primarily accumulated and proliferated in the tumor, and a single dose efficiently controlled tumor growth without evidence of xenogeneic GvHD. Importantly, compared with GPC-3.CAR Vδ1 T cells lacking sIL-15, GPC-3.CAR/sIL-15 Vδ1 T cells displayed greater proliferation and resulted in enhanced therapeutic activity., Conclusions: Expanded Vδ1 T cells engineered with a GPC-3 CAR and sIL-15 represent a promising platform warranting further clinical evaluation as an off-the-shelf treatment of HCC and potentially other GPC-3-expressing solid tumors., Competing Interests: Competing interests: AM, XY, TB, AL, KPN, MMB, JTSW, SRYG, MTa, LB, AB, ZA, SA, BTA and MH are employees of Adicet Therapeutics. MTu is currently an employee of Allogene. DS is currently an employee of Astellas Pharma., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mental health problems start early in life. However, the majority of adolescents fulfilling the criteria for mental health disorders do not receive treatment, and half of those who do get treatment drop out. This begs the question of what differentiates helpful from unhelpful treatment processes from the perspective of young clients. In this study, we interviewed 12 young people who entered mental health care reluctantly at the initiative of others before the age of 18. Their journeys through mental health care varied significantly despite sharing the same starting point. Our analyses resulted in a model of three trajectories. We describe relational and structural facilitators and obstacles within each trajectory and have formulated narratives highlighting core experiences differentiating them. Trajectory 1 ( I never saw the point - Being met as a case ) was characterized by a rapid loss of hope, leading the adolescents to conclude that mental health care was not worth the investment. Trajectory 2 ( I gave it a go, but nothing came of it - Being met by a therapist representing a rigid and unhelpful system ) was characterized by a lingering hope that never materialized into a constructive therapeutic process despite prevailing efforts by both therapists and adolescents. Trajectory 3 ( Something good came of it - Being met by a therapist who cares and wants to help ) was characterized by genuine meetings, allowing the therapist to transform from an unsafe stranger into a safe, competent, and benevolent adult. We discuss how our results have implications for understanding agency displayed by adolescent clients in therapy, therapist flexibility and authenticity, service organization, and attributional processes influencing clinical judgment and therapeutic processes when adolescent psychotherapy has a difficult starting point (i.e., initiated by adults)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Stige, Barca, Lavik and Moltu.)

Introduction and Objectives: drug use is associated with multiple complications with an increase in morbidity, with death by acute drugs reactions (ADR) being the most serious. A large percentage of the prison population has problems associated with drug additions, and substance abuse is also a common internal problem of penal institutions, despite their control measures. The goal of this study is to analyse the prevalence of ADR in penitentiaries, deceased sociodemographic characteristics as well as the circumstances in which they are produced., Material and Methods: All deaths by ADR between 2001-2010 in Galicia are studied, in particular, those deaths that took place inside prisons., Results: In the whole sample (n=510) male (90.6%), single (46.1%) with an average age of 35.8 and with a prevalent factor of long experience in drug abuse. Thirty seven of them died in Penal/Correctional Institutions, representing 7.3% of the total sample. The characteristics of this population subtype were similar to the total sample (average age: 34.7 years; 89.2% were males) but we found significant differences regarding the substances detected., Discussion: ADR is the most frequent cause of death among drug addict convicts in prisons. The pattern of the detected substances in the toxicological analysis as well as the socio-demographic characteristics can help to establish a higher risk profile and preventive measures.

Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV strains. ZKA190 is highly effective in vivo in preventing morbidity and mortality of ZIKV-infected mice. NMR and cryo-electron microscopy show its binding to an exposed epitope on DIII of the E protein. ZKA190 Fab binds all 180 E protein copies, altering the virus quaternary arrangement and surface curvature. However, ZIKV escape mutants emerged in vitro and in vivo in the presence of ZKA190, as well as of other neutralizing mAbs. To counter this problem, we developed a bispecific antibody (FIT-1) comprising ZKA190 and a second mAb specific for DII of E protein. In addition to retaining high in vitro and in vivo potencies, FIT-1 robustly prevented viral escape, warranting its development as a ZIKV immunotherapy., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)