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BACKGROUND: Neoantigens can serve as targets for T cell-mediated antitumor immunity via personalized neopeptide vaccines. Interim data from our clinical study NCT03715985 showed that the personalized peptide-based neoantigen vaccine EVX-01, formulated in the liposomal adjuvant, CAF09b, was safe and able to elicit EVX-01-specific T cell responses in patients with metastatic melanoma. Here, we present results from the dose-escalation part of the study, evaluating the feasibility, safety, efficacy, and immunogenicity of EVX-01 in addition to anti-PD-1 therapy. METHODS: Patients with metastatic melanoma on anti-PD-1 therapy were treated in three cohorts with increasing vaccine dosages (twofold and fourfold). Tumor-derived neoantigens were selected by the AI platform PIONEER and used in personalized therapeutic cancer peptide vaccines EVX-01. Vaccines were administered at 2-week intervals for a total of three intraperitoneal and three intramuscular injections. The study's primary endpoint was safety and tolerability. Additional endpoints were immunological responses, survival, and objective response rates. RESULTS: Compared with the base dose level previously reported, no new vaccine-related serious adverse events were observed during dose escalation of EVX-01 in combination with an anti-PD-1 agent given according to local guidelines. Two patients at the third dose level (fourfold dose) developed grade 3 toxicity, most likely related to pembrolizumab. Overall, 8 out of the 12 patients had objective clinical responses (6 partial response (PR) and 2 CR), with all 4 patients at the highest dose level having a CR (1 CR, 3 PR). EVX-01 induced peptide-specific CD4+ and/or CD8+T cell responses in all treated patients, with CD4+T cells as the dominating responses. The magnitude of immune responses measured by IFN-γ ELISpot assay correlated with individual peptide doses. A significant correlation between the PIONEER quality score and induced T cell immunogenicity was detected, while better CRs correlated with both the number of immunogenic EVX-01 peptides and the PIONEER quality score. CONCLUSION: Immunization with EVX-01-CAF09b in addition to anti-PD-1 therapy was shown to be safe and well tolerated and elicit vaccine neoantigen-specific CD4+and CD8+ T cell responses at all dose levels. In addition, objective tumor responses were observed in 67% of patients. The results encourage further assessment of the antitumor efficacy of EVX-01 in combination with anti-PD-1 therapy.
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Antígenos de Neoplasias , Vacunas contra el Cáncer , Melanoma , Medicina de Precisión , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/uso terapéutico , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Metástasis de la Neoplasia , Medicina de Precisión/métodos , Vacunas de Subunidad/uso terapéutico , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/administración & dosificaciónRESUMEN
In this study, we describe continuing bonds and grief reactions and assess their association in 980 parents bereaved in pregnancy, at or shortly after birth. We found that most parents experienced continuing bonds. However, they differed by type of loss. Parents losing their child due to termination of pregnancy or miscarriage experienced bonds less frequently and had the least intense grief reaction. Parents losing their child postpartum experienced bonds most frequently and had the most intense grief reaction. Continuing bonds were associated with intensified grief in parents losing their child after termination or miscarriage, while this relationship was less obvious after stillbirth or postpartum death.
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Pesar , Apego a Objetos , Padres , Mortinato , Humanos , Femenino , Embarazo , Adulto , Mortinato/psicología , Padres/psicología , Masculino , Aborto Espontáneo/psicología , AflicciónRESUMEN
Distinguishing patterns of grief over time in parents with a loss in pregnancy or during the neonatal period is important for identification of parents with severe grief symptoms, who may need additional support. Our aim was to describe grief in this population and to examine variations by type of loss in a large prospective cohort. We used questionnaire data from the Danish longitudinal cohort, Life After the Loss, which contains information on parents with a loss in pregnancy (from 14 weeks) or during the neonatal period. Parents completed the Prolonged Grief-13 scale at 1, 7, and 13 months after their loss. We applied Latent Growth Mixture Modelling to identify prolonged grief trajectories and used multinomial regression models to assess factors associated with class membership. Three distinct trajectories were identified in 676 parents: resilience (73.1%), recovery (16.9%), and chronic (10%). The distribution varied by type of loss, and the chronic group were overrepresented by parents with stillbirths (16.2%) and neonatal deaths (16.1%) in contrast to parents with spontaneous abortions (8.2%) and termination of pregnancy due to fetal anomalies (6.2%). Furthermore, not having a living child or being a woman was associated with following the chronic trajectory. These results underline that, while most bereaved parents are resilient, 10% experience consistently high levels of grief symptoms during the first year after the loss. Information on type of loss, gender, and whether the parent has living children are meaningful indicators of grief class membership.
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Aflicción , Niño , Femenino , Embarazo , Recién Nacido , Humanos , Estudios Prospectivos , Pesar , Padres , Encuestas y CuestionariosRESUMEN
Background: The B-cell lymphoma-extra-large (Bcl-XL) protein plays an important role in cancer cells' resistance to apoptosis. Pre-clinical studies have shown that vaccination with Bcl-XL-derived peptides can induce tumor-specific T cell responses that may lead to the elimination of cancer cells. Furthermore, pre-clinical studies of the novel adjuvant CAF®09b have shown that intraperitoneal (IP) injections of this adjuvant can improve the activation of the immune system. In this study, patients with hormone-sensitive prostate cancer (PC) received a vaccine consisting of Bcl-XL-peptide with CAF®09b as an adjuvant. The primary aim was to evaluate the tolerability and safety of IP and intramuscular (IM) administration, determine the optimal route of administration, and characterize vaccine immunogenicity. Patients and methods: Twenty patients were included. A total of six vaccinations were scheduled: in Group A (IM to IP injections), ten patients received three vaccines IM biweekly; after a three-week pause, patients then received three vaccines IP biweekly. In Group B (IP to IM injections), ten patients received IP vaccines first, followed by IM under a similar vaccination schedule. Safety was assessed by logging and evaluating adverse events (AE) according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.0). Vaccines-induced immune responses were analyzed by Enzyme-Linked Immunospot and flow cytometry. Results: No serious AEs were reported. Although an increase in T cell response against the Bcl-XL-peptide was found in all patients, a larger proportion of patients in group B demonstrated earlier and stronger immune responses to the vaccine compared to patients in group A. Further, we demonstrated vaccine-induced immunity towards patient-specific CD4, and CD8 T cell epitopes embedded in Bcl-XL-peptide and an increase in CD4 and CD8 T cell activation markers CD107a and CD137 following vaccination. At a median follow-up of 21 months, no patients had experienced clinically significant disease progression. Conclusion: The Bcl-XL-peptide-CAF®09b vaccination was feasible and safe in patients with l hormone-sensitive PC. In addition, the vaccine was immunogenic and able to elicit CD4 and CD8 T cell responses with initial IP administration eliciting early and high levels of vaccine-specific responses in a higher number og patients. Clinical trial registration: https://clinicaltrials.gov, identifier NCT03412786.
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Neoplasias de la Próstata , Vacunas , Masculino , Humanos , Linfocitos T CD8-positivos , Vacunación , Neoplasias de la Próstata/terapia , HormonasRESUMEN
Background: Arginase-1-producing cells inhibit T cell-mediated anti-tumor responses by reducing L-arginine levels in the tumor microenvironment. T cell-facilitated elimination of arginase-1-expressing cells could potentially restore L-arginine levels and improve anti-tumor responses. The activation of arginase-1-specific T cells may convert the immunosuppressive tumor microenvironment and induce or strengthen local Th1 inflammation. In the current clinical study, we examined the safety and immunogenicity of arginase-1-based peptide vaccination. Methods: In this clinical phase I trial, ten patients with treatment-refractory progressive solid tumors were treated. The patients received an arginase-1 peptide vaccine comprising three 20-mer peptides from the ARG1 immunological "hot spot" region in combination with the adjuvant Montanide ISA-51. The vaccines were administered subcutaneously every third week (maximum 16 vaccines). The primary endpoint was to evaluate safety assessed by Common Terminology Criteria for Adverse Events 4.0 and laboratory monitoring. Vaccine-specific immune responses were evaluated using enzyme-linked immune absorbent spot assays and intracellular cytokine staining on peripheral blood mononuclear cells. Clinical responses were evaluated using Response Evaluation Criteria in Solid Tumors 1.1. Results: The vaccination was feasible, and no vaccine-related grade 3-4 adverse events were registered. Nine (90%) of ten patients exhibited peptide-specific immune responses in peripheral blood mononuclear cells. Six (86%) of the seven evaluable patients developed a reactive T cell response against at least one of the ARG1 peptides during treatment. A phenotypic classification revealed that arginase-1 vaccine-specific T cells were both CD4+ T cells and CD8+ T cells. Two (20%) of ten patients obtained stable disease for respectively four- and seven months on vaccination treatment. Conclusion: The peptide vaccine against arginase-1 was safe. Nine (90%) of ten patients had measurable peptide-specific responses in the periphery blood, and two (20%) of ten patients attained stable disease on protocol treatment. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03689192, identifier NCT03689192.
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Vacunas contra el Cáncer , Neoplasias , Humanos , Vacunas contra el Cáncer/efectos adversos , Vacunas de Subunidad/efectos adversos , Arginasa , Leucocitos Mononucleares , Neoplasias/tratamiento farmacológico , Péptidos/uso terapéutico , Arginina , Microambiente TumoralRESUMEN
The majority of neoantigens arise from unique mutations that are not shared between individual patients, making neoantigen-directed immunotherapy a fully personalized treatment approach. Novel technical advances in next-generation sequencing of tumor samples and artificial intelligence (AI) allow fast and systematic prediction of tumor neoantigens. This study investigates feasibility, safety, immunity, and anti-tumor potential of the personalized peptide-based neoantigen vaccine, EVX-01, including the novel CD8+ T-cell inducing adjuvant, CAF®09b, in patients with metastatic melanoma (NTC03715985). The AI platform PIONEERTM was used for identification of tumor-derived neoantigens to be included in a peptide-based personalized therapeutic cancer vaccine. EVX-01 immunotherapy consisted of 6 administrations with 5-10 PIONEERTM-predicted neoantigens as synthetic peptides combined with the novel liposome-based Cationic Adjuvant Formulation 09b (CAF®09b) to strengthen T-cell responses. EVX-01 was combined with immune checkpoint inhibitors to augment the activity of EVX-01-induced immune responses. The primary endpoint was safety, exploratory endpoints included feasibility, immunologic and objective responses. This interim analysis reports the results from the first dose-level cohort of five patients. We documented a short vaccine manufacturing time of 48-55 days which enabled the initiation of EVX-01 treatment within 60 days from baseline biopsy. No severe adverse events were observed. EVX-01 elicited long-lasting EVX-01-specific T-cell responses in all patients. Competitive manufacturing time was demonstrated. EVX-01 was shown to be safe and able to elicit immune responses targeting tumor neoantigens with encouraging early indications of a clinical and meaningful antitumor efficacy, warranting further study.
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Vacunas contra el Cáncer , Melanoma , Antígenos de Neoplasias/genética , Inteligencia Artificial , Humanos , Melanoma/tratamiento farmacológico , PéptidosRESUMEN
This study describes religious/spiritual beliefs, practices, changes, and needs among parents bereaved by pregnancy or neonatal loss, and assess gender differences in religiosity/spirituality, in this population. A cross-sectional study using data from the Danish cohort Life After the Loss was conducted. Data were gathered from a questionnaire survey collected between January 2016 and December 2019. Among 713 respondents, several answered in the affirmative to items related to religious/spiritual beliefs and practices. Some experienced changes in religious/spiritual beliefs and practices, and some wished to talk to someone about these questions. Women reported higher levels of religiosity/spirituality than men.
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Religión , Espiritualidad , Estudios Transversales , Dinamarca , Femenino , Humanos , Recién Nacido , Masculino , Padres , Embarazo , Encuestas y CuestionariosRESUMEN
BACKGROUND: Many parents bereaved of a stillborn baby spend time with the child. In this time frame, different acts with the child in focus may occur. Some parents invite others to see the child too. Parents who suffer the loss of a newborn are vulnerable, and understanding acts and practices surrounding the dead newborn is important knowledge for caretakers. AIMS: This article aims to enlighten the amount of time Danish parents spend with their stillborn in hospital settings that encourage this practice. Furthermore, it aims to transcend the mere quantitative numbers through a theoretical approach that frames the analysis and discussion of possible layers of meaning imbedded in time spent with a dead newborn. STUDY DESIGN: Data from a Danish cohort of bereaved parents were collected using web-based questionnaires. These numbers were successively interpreted through an anthropological lens within the perspective of transition and ritualisation. Knowledge from existing empirical literature was also fused. RESULTS FROM THE COHORT: Danish parents spend hours or days with their stillborn child. They feel supported in this by healthcare professionals. Mainly close relatives join the parents while admitted to the hospital to see the stillborn child, followed by other family members and friends. CONCLUSION: Danish parents engage to a very high degree in contact with their dead baby. The analysis points out that 'Time' and 'Others' are needed to create a socially comprehensible status for parents and child when birth brings death. In liminal space during the transition, healthcare professionals act as ritual experts, supporting parents and their relatives to ascribe social status to the dead body of the child through ritualised acts. Instead of only thinking of this period as 'memory-making', we suggest regarding it as a time of ontological clarification as well.
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Conducta Ceremonial , Mortinato , Niño , Dinamarca , Femenino , Humanos , Lactante , Recién Nacido , Padres , Parto , EmbarazoRESUMEN
BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has shown remarkable results in malignant melanoma (MM), while studies on the potential in other cancer diagnoses are sparse. Further, the prospect of using checkpoint inhibitors (CPIs) to support TIL production and therapy remains to be explored. STUDY DESIGN: TIL-based ACT with CPIs was evaluated in a clinical phase I/II trial. Ipilimumab (3 mg/kg) was administered prior to tumor resection and nivolumab (3 mg/kg, every 2 weeks ×4) in relation to TIL infusion. Preconditioning chemotherapy was given before TIL infusion and followed by low-dose (2 10e6 international units (UI) ×1 subcutaneous for 14 days) interleukin-2 stimulation. RESULTS: Twenty-five patients covering 10 different cancer diagnoses were treated with in vitro expanded TILs. Expansion of TILs was successful in 97% of recruited patients. Five patients had sizeable tumor regressions of 30%-63%, including two confirmed partial responses in patients with head-and-neck cancer and cholangiocarcinoma. Safety and feasibility were comparable to MM trials of ACT with the addition of expected CPI toxicity. In an exploratory analysis, tumor mutational burden and expression of the alpha-integrin CD103 (p=0.025) were associated with increased disease control. In vitro tumor reactivity was seen in both patients with an objective response and was associated with regressions in tumor size (p=0.028). CONCLUSION: High success rates of TIL expansion were demonstrated across multiple solid cancers. TIL ACTs were found feasible, independent of previous therapy. Tumor regressions after ACT combined with CPIs were demonstrated in several cancer types supported by in vitro antitumor reactivity of the TILs. TRIAL REGISTRATION NUMBERS: NCT03296137, and EudraCT No. 2017-002323-25.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia Adoptiva/métodos , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias/tratamiento farmacológico , Anciano , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To describe the clinical characteristics of women admitted to a specialized unit for bereaved parents and to identify the characteristics of women who stayed more than 2 days. DESIGN: A population-based descriptive study. SETTING: A midwifery-led specialized unit for bereaved parents at Aarhus University Hospital, Denmark. PARTICIPANTS: Women with miscarriage (>14 weeks), missed abortion (>14 weeks), termination of pregnancy (>14 weeks), stillbirth, or death of their neonate during the first 48 hours after birth. METHODS: We collected information from the electronic health care records for women admitted to the unit from January 2012 through December 2018, including parity, type of loss, gestational age, mode and duration of birth, pain relief, and duration of stay. RESULTS: From January 1, 2012. to December 31, 2018, 579 women were admitted to the unit. Hospitalization varied from 1 day to 1 week. More women with a loss after 22 gestational weeks stayed for more than 2 days. In multivariate analyses, the hazard ratio (HR) of staying longer than 2 days was 1.3 times greater for primiparous women than for multiparous women (HR = 1.3, 95% confidence interval [1.0, 1.7]) and 2.4 times greater for women with near-term loss compared to women with perinatal loss before gestational week 22 (HR = 2.4, 95% confidence interval [1.7, 3.6]). CONCLUSION: Providing unlimited stay at a specialized unit for perinatal loss resulted in variation in length of stay. Primiparous women and women who lost neonates or fetuses closer to term gestation were more likely to stay in the unit for up to 8 days. This may indicate a need for individual support not available in standard care.
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Partería , Dinamarca , Femenino , Humanos , Recién Nacido , Tiempo de Internación , Padres , Paridad , EmbarazoRESUMEN
OBJECTIVE: To describe the prevalence of spondyloarthritis (SpA) and subtypes diagnosed prior to delivery in a nationwide population of pregnant women, and to estimate how SpA was associated with adverse pregnancy-related outcomes. METHODS: Using the Danish Medical Birth Register, we identified 1,199,610 singleton pregnancies (1997-2016). Information on SpA and related subtypes (ankylosing spondylitis, psoriatic arthritis, reactive arthritis, arthritis associated with inflammatory bowel diseases, and undifferentiated SpA) was derived from the Danish National Patient Registry. Odds ratios were calculated using logistic regression models. The analyses were performed with overall SpA as exposure and stratified by subtype. RESULTS: The overall prevalence of SpA diagnosed prior to delivery was 0.31%, increasing from 0.1% in 1997 to 0.6% in 2016. Comparing women without SpA to women with SpA, the adjusted odds ratios were increased for moderately preterm birth (ORadj 1.56 [95% confidence interval (95% CI) 1.33-1.83]), very preterm birth (ORadj 1.47 [95% CI 1.04-2.08]), elective cesarean section (ORadj 1.44 [95% CI 1.26-1.64]), emergency cesarean section (ORadj 1.17 [95% CI 1.04-1.33]), and use of epidural (ORadj 1.11 [95% CI 1.02-1.20]). The odds ratios for small for gestational age birth and preeclampsia were not increased for women with SpA compared to controls. Results were comparable for the subtypes of SpA. CONCLUSION: Pregnancies in women with SpA were more often complicated by adverse pregnancy outcomes than pregnancies in women without SpA. Clinicians should be aware of this when advising women with SpA in their childbearing years. Future research should focus on investigating causal relations and possible interventions aimed at preventing these outcomes.