RESUMEN
The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Magnesio/metabolismo , Animales , Infecciones Bacterianas/inmunología , Restricción Calórica , Línea Celular Tumoral , Citotoxicidad Inmunológica , Células HEK293 , Humanos , Memoria Inmunológica , Sinapsis Inmunológicas/metabolismo , Inmunoterapia , Activación de Linfocitos/inmunología , Sistema de Señalización de MAP Quinasas , Magnesio/administración & dosificación , Masculino , Ratones Endogámicos C57BL , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Fenotipo , Fosforilación , Proteínas Proto-Oncogénicas c-jun/metabolismoRESUMEN
OBJECTIVE: To report on the surgical safety and quality of pelvic lymph node dissection (PLND) in patients treated with radical cystectomy (RC) and PLND for muscle-invasive bladder cancer (MIBC) after neoadjuvant chemo-immunotherapy. PATIENTS AND METHODS: The Swiss Group for Clinical Cancer Research (SAKK) 06/17 was an open-label single-arm phase II trial including 61 cisplatin-fit patients with clinical stage (c)T2-T4a cN0-1 operable urothelial MIBC or upper urinary tract cancer. Patients received neoadjuvant cisplatin/gemcitabine and durvalumab followed by surgery. Prospective quality assessment of surgeries was performed via central review of intraoperative photographs. Postoperative complications were assessed using the Clavien-Dindo Classification. Data were analysed descriptively. RESULTS: A total of 50 patients received RC and PLND. All patients received neoadjuvant chemo-immunotherapy. The median (interquartile range) number of lymph nodes removed was 29 (23-38). No intraoperative complications were registered. Grade ≥III postoperative complications were reported in 12 patients (24%). Complete nodal dissection (100%) was performed at the level of the obturator fossa (bilaterally) and of the left external iliac region; in 49 patients (98%) at the internal iliac region and at the right external iliac region; in 39 (78%) and 38 (76%) patients at the right and left presacral level, respectively. CONCLUSION: This study supports the surgical safety of RC and PLND following neoadjuvant chemo-immunotherapy in patients with MIBC. The extent and completeness of protocol-defined PLND varies between patients, highlighting the need to communicate and monitor the surgical template.
RESUMEN
EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.
Asunto(s)
Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Pirimidinas , Masculino , Humanos , Femenino , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , ExonesRESUMEN
Immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape of various cancers. While ICI treatments result in improved survival, quality of life and are cost-effective, the majority of patients experience at least one immune-related adverse event (irAE). Many of these side effects cause little discomfort or are asymptomatic; however, irAEs can affect any organ and are potentially life-threatening. Consequently, early diagnosis and appropriate treatment of irAEs are critical for optimizing long-term outcomes and quality of life in affected patients. Some irAEs are diagnosed according to typical symptoms, others by abnormal findings from diagnostic tests. While there are various guidelines addressing the management of irAEs, recommendations for the early recognition of irAEs as well as the optimal extent and frequency of laboratory tests are mostly lacking. In clinical practice, blood sampling is usually performed before each ICI administration (i.e., every 2-3 weeks), often for several months, representing a burden for patients as well as health care systems. In this report, we propose essential laboratory and functional tests to improve the early detection and management of irAEs and in cancer patients treated with ICIs. These multidisciplinary expert recommendations regarding essential laboratory and functional tests can be used to identify possible irAEs at an early time point, initiate appropriate interventions to improve patient outcomes, and reduce the burden of blood sampling during ICI treatment.
Asunto(s)
Antineoplásicos Inmunológicos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias , Humanos , Calidad de Vida , Antineoplásicos Inmunológicos/uso terapéutico , Detección Precoz del Cáncer , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
INTRODUCTION: Since the development of the first immune checkpoint inhibitor, a new era in tumour immunotherapy has been initiated and response and survival rates have improved in many tumour entities. Despite this encouraging progress, the number of patients who achieve a durable response is limited by resistance mechanisms, and immune-related adverse events (irAEs) complicate treatment. The mechanism of irAE is not understood in all details. In this review, we summarise the mechanisms of action of immune checkpoint inhibitors, the different forms of irAE and their possible mechanisms of development, and describe possible prevention strategies and treatment options. strategies for prevention and treatment options.
Asunto(s)
Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Inmunoterapia/efectos adversosRESUMEN
Tumour neoantigens arising from cancer-specific mutations generate a molecular fingerprint that has a definite specificity for cancer. Although this fingerprint perfectly discriminates cancer from healthy somatic and germline cells, and is therefore therapeutically exploitable using immune checkpoint blockade, gut and extra-gut microbial species can independently produce epitopes that resemble tumour neoantigens as part of their natural gene expression programmes. Such tumour molecular mimicry is likely not only to influence the quality and strength of the body's anti-cancer immune response, but could also explain why certain patients show favourable long-term responses to immune checkpoint blockade while others do not benefit at all from this treatment. This article outlines the requirement for tumour neoantigens in successful cancer immunotherapy and draws attention to the emerging role of microbiome-mediated tumour neoantigen mimicry in determining checkpoint immunotherapy outcome, with far-reaching implications for the future of cancer immunotherapy.
Asunto(s)
Antígenos de Neoplasias/genética , Epítopos/farmacología , Neoplasias/tratamiento farmacológico , Epítopos/uso terapéutico , Microbioma Gastrointestinal , Humanos , Inmunoterapia , Imitación Molecular , Mutación , Neoplasias/genética , Neoplasias/inmunologíaRESUMEN
INTRODUCTION: The safety of first-line (1L) durvalumab in patients with advanced nonsmall-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (PS2) is unknown. This is an interim unplanned safety analysis of the study SAKK 19/17 for patients with metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression in ≥ 25% of tumor cells and an ECOG PS2 treated with 1L durvalumab. This safety analysis was triggered by the SAKK data and safety monitoring board due to a high mortality rate observed after the recruitment of the first 21 patients. METHODS: This single-arm phase II study recruited patients with metastatic NSCLC with PD-L1 in ≥ 25% and ECOG PS2. Patients received durvalumab 1500 mg every four weeks. The trial aims to recruit 48 patients in total. This report includes safety analyses only. Adverse events (AEs) were assessed using National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 5.0. Efficacy data including the primary endpoint overall survival at 6 months and secondary endpoints (objective response rate, progression-free survival, and quality of life) will be reported at a later time point. RESULTS: The data from 21 patients were available at this interim safety analysis. Among these, 13 deaths (13/21; 62%) were reported, including one treatment-related fatal colonic perforation at 9 months after treatment initiation (1/13; 8%). Twelve deaths were not treatment-related (12/13; 92%), and mostly attributed to tumor progression (10/13; 77%). Of note, seven deaths (7/13; 54%) occurred during the first 5 weeks (range 0.6-4.7 weeks) after treatment initiation. Four (4/7; 57%) were respiratory failures attributed to tumor progression. One of these patients (25%) had pre-existing COPD, and three (75%) had baseline dyspnea grade 2-3 related to the tumor. Grade ≥ 3 treatment-related AEs (TRAEs) included colonic perforation (grade 5), abdominal pain, and colitis (grade 3 each) in one patient, and fatigue (grade 3) in another. Other Grade ≥ 3 AEs unrelated to treatment were all of pulmonary origin: lung infections (19%), dyspnea (24%), cough (5%), and bronchial obstruction (5%). CONCLUSIONS: 1L durvalumab in patients with ECOG PS2 and metastatic NSCLC with PD-L1 expression ≥ 25% resulted in an unexpectedly high number of fatal early events due to rapid tumor progression. We recommend to avoid treatment with 1 L durvalumab of patients who are highly symptomatic from the tumor, particularly those with respiratory symptoms. The study is continuing its accrual after an amendment excluding these patients.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Antígeno B7-H1/metabolismo , Carcinogénesis , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Perforación Intestinal/etiología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/mortalidad , Masculino , Metástasis de la Neoplasia , Estadificación de Neoplasias , Insuficiencia Respiratoria/etiología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
In non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here, we evaluated the predictive power of TMB measured by the Oncomine™ Tumor Mutational Load targeted sequencing assay in 76 NSCLC patients treated with ICIs. TMB was assessed retrospectively in 76 NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were classified as having either durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD-L1 expression were assessed and compared with TMB and response rate. TMB was significantly higher in patients with DCB than in patients with NDB (median TMB = 8.5 versus 6.0 mutations/Mb, Mann-Whitney p = 0.0244). 64% of patients with high TMB (cut-off = third tertile, TMB ≥ 9) were responders (DCB) compared to 33% and 29% of patients with intermediate and low TMB, respectively (cut-off = second and first tertile, TMB = 5-9 and TMB ≤ 4, respectively). TMB-high patients showed significantly longer progression-free survival (PFS) and OS (log-rank test p = 0.0014 for PFS and 0.0197 for OS). While identifying different subgroups of patients, combining PD-L1 expression and TMB increased the predictive power (from AUC 0.63 to AUC 0.65). Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. A combination of biomarkers might maximize the predictive precision for patient stratification. Our study supports TMB evaluation through targeted NGS in NSCLC patient samples as a tool to predict response to ICI therapy. We offer recommendations for a reliable and cost-effective assessment of TMB in a routine diagnostic setting. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Análisis Mutacional de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Toma de Decisiones Clínicas , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Selección de Paciente , Fenotipo , Medicina de Precisión , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , SuizaRESUMEN
OBJECTIVES: Early clinical trials showed promising outcomes with immune-checkpoint inhibitors (ICI) in a subset of patients with relapsed small-cell lung carcinoma (SCLC). The aim of this retrospective analysis was to assess the efficacy and safety of ICI for relapsed SCLC in a real-world patient population. METHODS: Nine cancer centres in Switzerland contributed data to this cohort. Responses were assessed by the local investigators using standard RECIST v1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were analysed by the Kaplan-Meier method. Associations between potential predictive markers and survival endpoints were probed by Cox proportional hazards. RESULTS: Forty-five patients were included in the analysis. Median age was 63 years, 73% were males and 18% had an ECOG performance status (PS) ≥ 2. ICIs were given as second-line treatment in 60%. Twenty-four patients (53%) received ipilimumab with nivolumab. Twenty-eight patients (62%) had undergone irradiation (RT) prior to or during ICI. Overall response rate (ORR) was 29% and median PFS and OS were 2.3 and 6.5 months, respectively. Median duration of response was 9 months (95% CI 2.8-NA). Five patients maintained their response for > 6 months, all of them receiving combination treatment. There were no new safety signals. CONCLUSION: This is the first report of "real-world" data on ICI in relapsed SCLC also including patients with poor PS. Promising durable responses were observed. No biological prognostic marker could be identified.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia/mortalidad , Neoplasias Pulmonares/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Biomarcadores de Tumor/análisis , Femenino , Estudios de Seguimiento , Humanos , Ipilimumab/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Nivolumab/administración & dosificación , Pronóstico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/inmunología , Carcinoma Pulmonar de Células Pequeñas/patología , Tasa de Supervivencia , SuizaRESUMEN
OBJECTIVE: Highly distressed cancer patients often do not use psycho-oncological services (POS). Research on predictors of POS uptake has mainly focused on patient-related variables and less on communication variables, so we examined the link between patient-oncologist communication (ie, talking about psychosocial distress, providing detailed information, and recommending POS) and POS uptake. METHODS: We conducted a prospective, observational study in an Oncology Outpatient Clinic in Switzerland. Predictors (ie, patient-related variables and patient's reports of the patient-oncologist communication) were assessed via semistructured interviews, and information on outpatient POS uptake was assessed after 4 months. For statistical analysis, a multivariate logistic regression was performed. RESULTS: Of 333 participants (mean age 61 years; 55% male; 54% distress thermometer ≥5), 77 (23%) had used POS during a 4-month period. Patients who reported an oncologist-recommended POS (odds ratio [OR] = 6.27, 95% confidence interval [CI] = 3.14-12.85) and those who were not sure if they had received a recommendation (OR = 4.64, 95% CI = 1.83-11.97) were more likely to attend POS than those who reported receiving no recommendation. Talking about psychosocial distress (OR = 0.74, 95% CI = 0.38-1.46) and providing detailed information about POS did not predict POS uptake (OR = 1.06, 95% CI = 0.46-2.38). CONCLUSIONS: Oncologists' expert recommendations to attend POS were strongly associated with patients' uptake of POS. The central role played by oncologists should be accounted for in stepped psycho-oncological care when POS referral pathways are defined.
Asunto(s)
Comunicación , Neoplasias/psicología , Pacientes Ambulatorios , Aceptación de la Atención de Salud , Relaciones Médico-Paciente , Psicooncología , Derivación y Consulta , Estrés Psicológico/terapia , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Aceptación de la Atención de Salud/estadística & datos numéricos , Estudios Prospectivos , Psicooncología/estadística & datos numéricos , Derivación y Consulta/estadística & datos numéricos , SuizaRESUMEN
BACKGROUND: Molecular precision oncology is an emerging practice to improve cancer therapy by decreasing the risk of choosing treatments that lack efficacy or cause adverse events. However, the challenges of integrating molecular profiling into routine clinical care are manifold. From a computational perspective these include the importance of a short analysis turnaround time, the interpretation of complex drug-gene and gene-gene interactions, and the necessity of standardized high-quality workflows. In addition, difficulties faced when integrating molecular diagnostics into clinical practice are ethical concerns, legal requirements, and limited availability of treatment options beyond standard of care as well as the overall lack of awareness of their existence. METHODS: To the best of our knowledge, we are the first group in Switzerland that established a workflow for personalized diagnostics based on comprehensive high-throughput sequencing of tumors at the clinic. Our workflow, named SwissMTB (Swiss Molecular Tumor Board), links genetic tumor alterations and gene expression to therapeutic options and clinical trial opportunities. The resulting treatment recommendations are summarized in a clinical report and discussed in a molecular tumor board at the clinic to support therapy decisions. RESULTS: Here we present results from an observational pilot study including 22 late-stage cancer patients. In this study we were able to identify actionable variants and corresponding therapies for 19 patients. Half of the patients were analyzed retrospectively. In two patients we identified resistance-associated variants explaining lack of therapy response. For five out of eleven patients analyzed before treatment the SwissMTB diagnostic influenced treatment decision. CONCLUSIONS: SwissMTB enables the analysis and clinical interpretation of large numbers of potentially actionable molecular targets. Thus, our workflow paves the way towards a more frequent use of comprehensive molecular diagnostics in Swiss hospitals.
Asunto(s)
Neoplasias/diagnóstico , Neoplasias/genética , Patología Molecular , Medicina de Precisión , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Neoplasias/terapia , Proyectos Piloto , Estudios Retrospectivos , SuizaRESUMEN
BACKGROUND: International standards prioritize introducing routine emotional distress screening in cancer care to accurately identify patients who most need psycho-oncological treatment, and ensure that patients can access appropriate supportive care. However, only a moderate proportion of distressed patients accepts referrals to or uses psycho-oncological support services. Predictors and barriers to psycho-oncological support service utilization are under-studied. We know little about how patients and oncologists perceive the discussions when oncologists assess psychosocial distress with a screening instrument. We aim to 1) assess the barriers and predictors of uptake of in-house psycho-oncological support along the distress screening pathway in cancer patients treated at a University Oncology Outpatient Clinic and, 2) determine how patients and clinicians perceive communication about psychosocial distress after screening with the Distress Thermometer. METHODS: This is a quantitative prospective observational study with qualitative aspects. We will examine medical and demographic variables, cancer patient self-reports of various psychological measures, and aspects of the patient-clinician communication as variables that potentially predict uptake of psycho-oncological support service. We will also assess the patients' reasons for accepting or refusing psycho-oncological support services. We assess at three points in time, based on paper-and-pencil questionnaires and two patient interviews during the study period. We will monitor outcomes (psycho-oncology service uptake) four months after study entry. DISCUSSION: The study will improve our understanding of characteristics of patients who accept or refuse psycho-oncological support, and help us understand how patients' and oncologists perceive communication about psychosocial distress, and referral to a psycho-oncologist. We believe this is the first study to focus on factors that affect uptake or rejection of psycho-oncological support services along the screening and referral pathway. The study 1) combines standard assessment with qualitative data collection, 2) embraces patient and oncologist perspectives, and, 3) focuses on patient-clinician communication about psychosocial issues raised by a standard screening instrument. Our results may improve routine practices and eliminate barriers to adequate health care, and make it easier to recognize patients with high distress levels who underuse the service.
Asunto(s)
Neoplasias/psicología , Pacientes/psicología , Estrés Psicológico/psicología , Anciano , Composición Familiar , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Neoplasias/patología , Médicos/psicología , Derivación y Consulta , Estrés Psicológico/epidemiología , Estrés Psicológico/patología , Encuestas y CuestionariosRESUMEN
Tumor-infiltrating lymphocytes play an important role in cell-mediated immune destruction of cancer cells and tumor growth control. We investigated the heterogeneity of immune cell infiltrates between primary non-small cell lung carcinomas (NSCLC) and corresponding metastases. Formalin-fixed, paraffin-embedded primary tumors and corresponding metastases from 34 NSCLC patients were analyzed by immunohistochemistry for CD4, CD8, CD11c, CD68, CD163 and PD-L1. The percentage of positively stained cells within the stroma and tumor cell clusters was recorded and compared between primary tumors and metastases. We found significantly fewer CD4(+) and CD8(+) T cells within tumor cell clusters as compared with the stromal compartment, both in primary tumors and corresponding metastases. CD8(+) T cell counts were significantly lower in metastatic lesions than in the corresponding primary tumors, both in the stroma and the tumor cell islets. Of note, the CD8/CD4 ratio was significantly reduced in metastatic lesions compared with the corresponding primary tumors in tumor cell islets, but not in the stroma. We noted significantly fewer CD11c(+) cells and CD68(+) as well as CD163(+) macrophages in tumor cell islets compared with the tumor stroma, but no difference between primary and metastatic lesions. Furthermore, the CD8/CD68 ratio was higher in primary tumors than in the corresponding metastases. We demonstrate a differential pattern of immune cell infiltration in matched primary and metastatic NSCLC lesions, with a significantly lower density of CD8(+) T cells in metastatic lesions compared with the primary tumors. The lower CD8/CD4 and CD8/CD68 ratios observed in metastases indicate a rather tolerogenic and tumor-promoting microenvironment at the metastatic site.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/patología , Masculino , Metástasis de la Neoplasia , Pronóstico , Microambiente TumoralRESUMEN
AIMS: ID1 is an important component of the MET-SRC signaling pathway, which is a regulator of cell migration and invasion. We hypothesized that the ALK/MET inhibitor crizotinib inhibits migration via MET-SRC-ID1, rather than ALK. MATERIALS & METHODS: We used ALK fusion-positive and -negative lung cancer cell lines; crizotinib, PHA-665752, and saracatinib, and stable transfection with shMET. We performed western blotting for p-ALK, ALK, p-MET, MET, p-SRC, SRC and ID1, and quantitative real-time PCR for ID1. RESULTS: Crizotinib decreased p-MET, p-SRC and ID1 levels in ALK- and or MET-positive cell lines and inhibited cell migration. Knockdown of MET was comparable with the effect of crizotinib. CONCLUSION: The effects of crizotinib on ID1 expression and cancer cell migration were associated with the presence of activated MET, rather than ALK fusion.
Asunto(s)
Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Proteína 1 Inhibidora de la Diferenciación/metabolismo , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirazoles/farmacología , Piridinas/farmacología , Línea Celular Tumoral , Crizotinib , Humanos , Proteína 1 Inhibidora de la Diferenciación/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Terapia Molecular Dirigida , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Proto-Oncogénicas c-met/genéticaRESUMEN
INTRODUCTION: The safety and efficacy of first-line durvalumab in PS2 patients with advanced NSCLC is unknown. Here, we present the primary analysis of first-line durvalumab in PS2 patients, unsuitable for combination chemotherapy. METHODS: In this single-arm, multicenter, phase II trial patients with PD-L1 positive (tumor proportional score ≥25%), advanced NSCLC with PS2, received four-weekly durvalumab 1500 mg. The primary endpoint was overall survival (OS) at 6 months. RESULTS: Forty-eight patients were included. Median follow-up was 23.3 months (95% CI: 14.3-28.6). OS at 6 months was 60% (95% CI: 45-74%). Median OS was 8.5 months (95%CI: 4.4-16.7). Objective response rate and median progression free survival were 17% (95% CI: 8-30%) and 2.5 months (95% CI: 1.8-7.1), respectively. Thirty-three deaths were observed at the time point of the analysis. Seven early fatal events considered not treatment-related occurred during the first 5 weeks of treatment. Four out of the first 7 early fatal events (4/7; 57%) were respiratory failure in patients with advanced symptomatic primary lung tumors. Three more early fatal events occurred after exclusion of patients with grade ≥ 3 dyspnea. Treatment-related AEs ≥G3 were reported in 9 patients (19%) and included colonic perforation in one patient (grade 5), colitis in 4 patients (8%), increased lipase in 3 patients (6%), and hepatitis in 2 patients (4%). CONCLUSIONS: First-line durvalumab in PS2 patients with advanced PD-L1 positive NSCLC results in a high number of early fatal events. When patients with grade ≥ 3 dyspnea are excluded a promising 6-month OS with an acceptable toxicity profile can be observed. Durvalumab could be an option instead of single agent chemotherapy for PS2 patients who are not candidates for platinum doublet chemotherapy provided they are well selected.
Asunto(s)
Anticuerpos Monoclonales , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Antígeno B7-H1/metabolismo , Disnea , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Introduction: On the basis of the landmark trial KEYNOTE-189 (KN-189), pembrolizumab plus chemotherapy has become the standard-of-care first-line treatment for patients with advanced nonsquamous NSCLC without oncogenic driver alterations.KN-189 included a selected patient population and lacks external validity. In clinical practice, many patients do not meet the inclusion criteria of KN-189, although they are treated accordingly. It is unknown whether these patients benefit equally as the trial population. Methods: We retrospectively analyzed all patients with advanced nonsquamous NSCLC without targetable oncogenic alterations who received the KN-189 treatment regimen between April 2018 and May 2021 at the University Hospital Basel, Switzerland. Patients were grouped into those who retrospectively met the inclusion criteria of KN-189 (group A) and those who did not (group B). Outcome parameters included progression-free survival (PFS), overall survival (OS), and objective response rate. Multivariate subgroup analyses were performed. Results: We identified 75 patients, including 29 patients in group A and 46 patients in group B. Median PFS was 9.2 and 4.6 months in group A and B, respectively (p = 0.12). Median OS was 16.5 and 6.5 months in group A and B, respectively (p = 0.11). Objective response rate was 59% in group A and 33% in group B (p = 0.03). Eastern Cooperative Oncology Group performance status greater than or equal to 2 and active infections were significantly associated with shorter PFS and OS. Conclusions: We report real-world data for patients treated according to the KN-189 regimen with inferior outcomes in patients who did not meet the KN-189 inclusion criteria. Better treatment options for this vulnerable patient population are needed.
RESUMEN
INTRODUCTION: The combination of checkpoint inhibition and cisplatin-based chemotherapy is investigated in muscle invasive bladder cancer (MIBC) and results from phase 2 trials have been presented. Intravesical BCG has been used for non-MIBC (NMIBC) in patients with carcinoma in situ and high-grade Ta/T1 tumours. BCG induces innate and adapted immune response and upregulation of PD-L1 in preclinical models. The proposed trial is intended to implement a new immuno-immuno-chemotherapy induction therapy for MIBC. The combination of BCG and checkpoint inhibition with chemotherapy aims at higher intravesical responses and better local and systemic control of disease. METHODS AND ANALYSIS: SAKK 06/19 is an open-label single-arm phase II trial for patients with resectable MIBC T2-T4a cN0-1. Intravesical recombinant BCG (rBCG: VPM1002BC) is applied weekly for three instillations followed by four cycles of neoadjuvant cisplatin/gemcitabine every 3 weeks. Atezolizumab 1200 mg every 3 weeks is started together with rBCG and given for four cycles. All patients then undergo restaging and radical cystectomy and pelvic lymphadenectomy. Atezolizumab is continued as maintenance therapy after surgery every 3 weeks for 13 cycles. Pathological complete remission is the primary endpoint. Secondary endpoints include pathological response rate (Asunto(s)
Cisplatino
, Neoplasias de la Vejiga Urinaria
, Humanos
, Cisplatino/uso terapéutico
, Vacuna BCG/uso terapéutico
, Cistectomía
, Terapia Neoadyuvante
, Neoplasias de la Vejiga Urinaria/tratamiento farmacológico
, Neoplasias de la Vejiga Urinaria/patología
, Inmunoterapia
, Administración Intravesical
, Músculos/patología
, Escisión del Ganglio Linfático
, Estudios Multicéntricos como Asunto
, Ensayos Clínicos Fase II como Asunto
RESUMEN
BACKGROUND: An increasing number of clinical trials are being conducted exploring the efficacy of neoadjuvant immune checkpoint inhibitors. Surrogate end-points for overall survival (OS) are urgently needed. METHODS: Phase II or III trials of neoadjuvant immunotherapy that reported data on OS and surrogate end-points were identified from January 1, 2000, to November 25, 2022. Individual patient data, and trial-level data were requested from corresponding authors or extracted from eligible trials. At the individual level, correlations between radiological and pathological response and OS were measured by the Cox model and quantified by hazard ratio (HR). C-statistic was used to quantify the predictive performance of radiological and pathological response for OS. The coefficient of determination (R2) between RFS and OS was evaluated by a bivariate survival model. RESULTS: A total of 29 trials reporting 2901 patients were included. ORR correlated with improved OS (3-year OS: 87.0% versus 70.4% for ORR versus non-ORR, respectively; HR, 0.34, 95% confidence interval [CI], 0.17-0.68). The HRs for OS in patients achieving MPR and pCR were 0.24 (95% CI, 0.12-0.46) and 0.13 (95% CI, 0.05-0.36). The survival benefit maintained after adjusting tumour type. C-statistics of ORR, MPR and pCR were 0.63, 0.63 and 0.65, respectively. The strength of association between RFS and OS was strong (R2 = 0.88, 95% CI, 0.79-0.94). CONCLUSIONS: These findings suggest that ORR, MPR, pCR and RFS are valid predictors for OS when using neoadjuvant immune checkpoint inhibitors. Moreover, MPR, pCR and RFS may be the most optimal surrogates for OS.