Prognostic capacity of peripheral blood-derived biomarkers in NSCLC patients treated with PD-1/PD-L1 blockade immunotherapy

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Prognostic capacity of peripheral blood-derived biomarkers in NSCLC patients treated with PD-1/PD-L1 blockade immunotherapy

El cáncer de pulmón genera una importante carga de morbimortalidad a nivel mundial. Durante la última década ha existido un importante desarrollo terapéutico por la aprobación de fármacos de inmunoterapia, especialmente en el bloqueo de PD-1 y PD-L1 en pacientes sin dianas terapéuticas. Pese a la propuesta de numerosos biomarcadores, resulta difícil identificar aquellos pacientes que se benefician del tratamiento y obtienen respuestas prolongadas. En este estudio observacional retrospectivo, se recogieron variables clínicas junto con la composición corporal medida por TC, así como extracción muestras de sangre periférica tras el inicio de tratamiento en una cohorte de pacientes con carcinoma no microcítico pulmonar avanzado en tratamiento con inmunoterapia. Se realizó una citometría de flujo multidimensional para la detección e inmunofenotipado de diferentes poblaciones mieloides. Además se analizó la concentración de 45 proteínas circulantes solubles en plasma, agrupados como puntos de control inmunes y quimiocinas mediante Luminex®. En contraste con bibliografía previa, no encontramos diferencias respecto a tasas de respuesta según la composición corporal. Respecto a variables clínicas, observamos un incremento de neutrófilos en sangre periférica en los pacientes no respondedores, así como una aceleración de este fenómeno previamente al deterioro clínico y fallecimiento del paciente, y un descenso paralelo de las cifras absolutas de linfocitos. No observamos diferencias respecto a las cifras de monocitos y plaquetas. Un inmunofenotipado preciso de estas poblaciones mediante citometría de flujo permitió detectar una predominancia de monocitos en respondedores y su correlación con la respuesta al tratamiento. Los niveles de expresión de PD-L1 en estas poblaciones mieloides se puede asociar con las respuestas al tratamiento de inmunoterapia. Las concentraciones de varias proteínas circulantes entre las que se encuentran TIM-3, HVEM, IFN-gamma y VEGF se asociaron con la actividad del tratamiento y el pronóstico de la enfermedad, con impacto en supervivencia global. Además, la histopatología del tumor primario fue un factor diferencial importante en el perfil de acti-vidad de estos tratamientos. Finalmente, se realizó un análisis multivariante de la cohorte. El número previo de líneas de tratamiento, un estatus funcional medido por ECOG > 2, el número de localizaciones metastásicas incluyendo las lesiones hepáticas, el incremento de neutrófilos circulantes medidos por citometría de flujo, y las concentraciones plasmáticas de MCP1 e IL-17alfa se establecieron como predictores independientes de supervivencia

Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics

Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation

Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics

Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation