Chimeric antigen receptor (CAR) T cells, T cells that have been genetically engineered to express a receptor that recognizes a specific antigen, have given rise to breakthroughs in treating hematological malignancies. However, their success in treating solid tumors has been limited. The unique challenges posed to CAR T cell therapy by solid tumors can be described in three steps: finding, entering, and surviving in the tumor. The use of dual CAR designs that recognize multiple antigens at once and local administration of CAR T cells are both strategies that have been used to overcome the hurdle of localization to the tumor. Additionally, the immunosuppressive tumor microenvironment has implications for T cell function in terms of differentiation and exhaustion, and combining CARs with checkpoint blockade or depletion of other suppressive factors in the microenvironment has shown very promising results to mitigate the phenomenon of T cell exhaustion. Finally, identifying and overcoming mechanisms associated with dysfunction in CAR T cells is of vital importance to generating CAR T cells that can proliferate and successfully eliminate tumor cells. The structure and costimulatory domains chosen for the CAR may play an important role in the overall function of CAR T cells in the TME, and “armored” CARs that secrete cytokines and third- and fourth-generation CARs with multiple costimulatory domains offer ways to enhance CAR T cell function.

Background:Dignity therapy is psychotherapy to relieve psychological and existential distress in patients at the end of life. Little is known about its effect.Aim:To analyse the outcomes of dignity therapy in patients with advanced life-threatening diseases.Design:Systematic review was conducted. Three authors extracted data of the articles and evaluated quality using Critical Appraisal Skills Programme. Data were synthesized, considering study objectives.Data sources:PubMed, CINAHL, Cochrane Library and PsycINFO. The years searched were 2002 (year of dignity therapy development) to January 2016. ‘Dignity therapy’ was used as search term. Studies with patients with advanced life-threatening diseases were included.Results:Of 121 studies, 28 were included. Quality of studies is high. Results were grouped into effectiveness, satisfaction, suitability and feasibility, and adaptability to different diseases and cultures. Two of five randomized control trials applied dignity therapy to patients with high levels of baseline psychological distress. One showed statistically significant decrease on patients’ anxiety and depression scores over time. The other showed statistical decrease on anxiety scores pre–post dignity therapy, not on depression. Nonrandomized studies suggested statistically significant improvements in existential and psychosocial measurements. Patients, relatives and professionals perceived it improved end-of-life experience.Conclusion:Evidence suggests that dignity therapy is beneficial. One randomized controlled trial with patients with high levels of psychological distress shows DT efficacy in anxiety and depression scores. Other design studies report beneficial outcomes in terms of end-of-life experience. Further research should understand how dignity therapy functions to establish a means for measuring its impact and assessing whether high level of distress patients can benefit most from this therapy.

Cancer progression is marked by dysfunctional tumorinfiltrating lymphocytes (TIL) with high inhibitory receptor (IR) expression. Because IR blockade has led to clinical responses in some patients with non-small cell lung cancer (NSCLC), we investigated how IRs influenced CD8 þ TIL function from freshly digested early-stage NSCLC tissues using a killing assay and intracellular cytokine staining after in vitro T-cell restimulation. Early-stage lung cancer TIL function was heterogeneous with only about one third of patients showing decrements in cytokine production and lytic function. TIL hypofunction did not correlate with clinical factors, coexisting immune cells (macrophages, neutrophils, or CD4 þ T regulatory cells), nor with PD-1, TIGIT, TIM-3, CD39, or CTLA-4 expression. Instead, we found that the presence of the integrin a e b 7 (CD103), characteristic of tissue-resident memory cells (T RM), was positively associated with cytokine production, whereas expression of the transcription factor Eomesodermin (Eomes) was negatively associated with TIL function. These data suggest that the functionality of CD8 þ TILs from early-stage NSCLCs may be influenced by competition between an antitumor CD103 þ T RM program and an exhaustion program marked by Eomes expression. Understanding the mechanisms of T-cell function in the progression of lung cancer may have clinical implications for immunotherapy.

The Spanish version of the PDI showed adequate psychometric properties when tested with advanced cancer patients. This research provides a three-factor alternative in Spanish to the PDI.

Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations. MCLA-145 potently activates T cells at sub-nanomolar concentrations, even under suppressive conditions, and enhances T cell priming, differentiation and memory recall responses. In vivo, MCLA-145 anti-tumor activity is superior to immune checkpoint inhibitor comparators and linked to recruitment and intra-tumor expansion of CD8 + T cells. No graft-versus-host-disease is observed in contrast to other antibodies inhibiting the PD-1 and PD-L1 pathway. Non-human primates treated with 100 mg/kg/week of MCLA-145 show no adverse effects. The conditional activation of CD137 signaling by MCLA-145, triggered by neighboring cells expressing >5000 copies of PD-L1, may provide both safety and potency advantages.

ObjectivesPalliative care (PC) services and patients differ across countries. Data on PC delivery paired with medical and self-reported data are seldom reported. Aims were to describe (1) PC organisation and services in participating centres and (2) characteristics of patients in PC programmes.MethodsThis was an international prospective multicentre study with a single web-based survey on PC organisation, services and academics and patients' self-reported symptoms collected at baseline and monthly thereafter, with concurrent registrations of medical data by healthcare providers. Participants were patients ≥18 enrolled in a PC programme.Results30 centres in 12 countries participated; 24 hospitals, 4 hospices, 1 nursing home, 1 home-care service. 22 centres (73%) had PC in-house teams and inpatient and outpatient services. 20 centres (67%) had integral chemotherapy/radiotherapy services, and most (28/30) had access to general medical or oncology inpatient units. Physicians or nurses were present 24 hours/7 days in 50% and 60% of centres, respectively. 50 centres (50%) had professorships, and 12 centres (40%) had full-time/part-time research staff. Data were available on 1698 patients: 50% females; median age 66 (range 21–97); median Karnofsky score 70 (10–100); 1409 patients (83%) had metastatic/disseminated disease; tiredness and pain in the past 24 hours were most prominent. During follow-up, 1060 patients (62%) died; 450 (44%) <3 months from inclusion and 701 (68%) within 6 months. ANOVA and χ2 tests showed that hospice/nursing home patients were significantly older, had poorer performance status and had shorter survival compared with hospital-patients (p<.0.001).ConclusionsThere is a wide variation in PC services and patients across Europe. Detailed characterisation is the first step in improving PC services and research.Trial registration numberClinicalTrials.gov Identifier: NCT01362816.

Context. Demoralization is a state of existential distress in patients with advanced illness, typically with coping difficulties, feelings of loss of sense, and purpose in life and despair, among other things. The New Demoralization Scale (DS-II) is an evaluation tool for this syndrome, which has recently been reformulated on a shorter scale.Objectives. The objective of this study was to obtain a Spanish version of the DS-II and to assess its psychometric properties in advanced cancer patients in Spain and a number of Latin American countries.Methods. Following a translationeback translation process, a validation study and a confirmatory analysis using structural equation models with their corresponding latent constructs were undertaken. Patients completed the DS-II in Spanish (DS-II (es)), the Hospital Anxiety and Depression Scale, and the Edmonton Symptom Assessment Systemerevised. Reliability was studied according to internal consistency; construct validity and concurrent validity with the Hospital Anxiety and Depression Scale and the Edmonton Symptom Assessment Systemerevised; discriminant validity using the Karnofsky Performance Status scale; and feasibility, with response ratio and required time. Cutoff points were established, and sensitivity and specificity were studied.Results. The DS-II (es) was obtained. One hundred fifty patients completed the validation study. The confirmatory analysis showed coherence, and all items correlated positively with their subscales and with the overall scale. Cronbach's alpha for the DS-II (es) was 0.88, for the sense and purpose subscale 0.83, and for the coping ability 0.79. Demoralization correlated significantly with emotional distress (rho ¼ 0.73, P < 0.001). The tool distinguished between patients with diverse functional levels (rho ¼ À0.319, P ¼ 0.001). Cutoff points at 10 and 20 out of 32 were established. The scale showed high sensitivity (81.97%) and specificity (80.90%). The prevalence of demoralization was 33% in our sample.Conclusion. The Spanish version of the new Kissane DS-II demoralization scale has shown to be valid, reliable, and feasible with adequate psychometric properties.

Given the growing interest and promising preliminary results of immunotherapy in malignant pleural mesothelioma (MPM), it has become important to more fully understand the immune landscape in this tumor. This may be especially relevant in deciding who might benefit most from checkpoint blockade or agonist antibody therapy. Since the phenotype of tumor infiltrating lymphocytes (TILs) in MPM has not been fully described and their function has not been carefully assessed, we collected fresh tumor and blood from 22 patients undergoing surgical resection and analysed single cell suspensions by flow cytometry. The functionality of TILs was assessed by measurement of cytokine expression (IFN-γ) following overnight stimulation ex vivo. Results showed low numbers of CD8+ TILs whose function was either moderately or severely suppressed. The degree of TIL hypofunction did not correlate with the presence of co-existing macrophages or neutrophils, nor with expression of the inhibitory receptors PD-1, CD39 and CTLA-4. Hypofunction was associated with higher numbers of CD4 regulatory T cells (Tregs) and with expression of the inhibitory receptor TIGIT. On the other hand, presence of tissue-resident memory (Trm) cells and expression of TIM-3 on CD8+ cells were positively associated with cytokine production. However, Trm function was partially suppressed when the transcription factor Eomesodermin (Eomes) was coexpressed. Understanding the function of TILs in malignant mesothelioma may have clinical implications for immunotherapy, especially in choosing the best immunotherapy targets. Our data suggests that Treg cell blocking agents or TIGIT inhibitor antibodies might be especially valuable in these patients.