RESUMEN
Metastatic small cell lung cancer (SCLC) is not curable. While SCLC is initially sensitive to chemotherapy, remissions are short-lived. The relapse is induced by chemotherapy-selected tumor stem cells, which express the AC133 epitope of the CD133 stem cell marker. We studied the effectiveness of AC133-specific CAR T cells post-chemotherapy using human primary SCLC and an orthotopic xenograft mouse model. AC133-specific CAR T cells migrated to SCLC tumor lesions, reduced the tumor burden, and prolonged survival in a humanized orthotopic SCLC model, but were not able to entirely eliminate tumors. We identified CD73 and PD-L1 as immune-escape mechanisms and combined PD-1-inhibition and CD73-inhibition with CAR T cell treatment. This triple-immunotherapy induced cures in 25% of the mice, without signs of graft-versus-host disease or bone marrow failure. AC133+ cancer stem cells and PD-L1+CD73+ myeloid cells were detectable in primary human SCLC tissues, suggesting that patients may benefit from the triple-immunotherapy. We conclude that the combination of AC133-specific CAR T cells, anti-PD-1-antibody and CD73-inhibitor specifically eliminates chemo-resistant tumor stem cells, overcomes SCLC-mediated T cell inhibition, and might induce long-term complete remission in an otherwise incurable disease.
Asunto(s)
Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Animales , Antígeno B7-H1 , Línea Celular Tumoral , Humanos , Inmunoterapia Adoptiva , Neoplasias Pulmonares/patología , Ratones , Recurrencia Local de Neoplasia , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/terapiaRESUMEN
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Following the publication of the above article, the Editor was notified that an error occurred in which all images were published with incorrect versions. The Editor has taken the decision that the manuscript is no longer acceptable in its current form, nor with a corrigendum, as the extensive changes to the figures and publication would lead to ambiguity for our readers. We have therefore made the decision to retract this manuscript from Cancer Letters with the possibility of resubmission and republication of the manuscript in its corrected form after peer review.
RESUMEN
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Following the publication of the above article, the Editor was notified that an error occurred in which all images were published with incorrect versions. The Editor has taken the decision that the manuscript is no longer acceptable in its current form, nor with a corrigendum, as the extensive changes to the figures and publication would lead to ambiguity for our readers. We have therefore made the decision to retract this manuscript from Cancer Letters with the possibility of resubmission and republication of the manuscript in its corrected form after peer review.
Asunto(s)
5'-Nucleotidasa/genética , Antígeno AC133/genética , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células Pequeñas/terapia , 5'-Nucleotidasa/antagonistas & inhibidores , Antígeno AC133/inmunología , Animales , Anticuerpos Antiidiotipos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Inmunoterapia Adoptiva/tendencias , Masculino , Ratones , Metástasis de la Neoplasia , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/inmunología , Carcinoma Pulmonar de Células Pequeñas/patología , Linfocitos T/inmunología , Carga TumoralRESUMEN
Treatment decisions for aggressive non-Hodgkin lymphoma in elderly and frail patients still remain challenging. The heterogeneity of elderly patients consists of various physical and psychological states, coexisting comorbidities as well as frailty and socioeconomic status. Comprehensive geriatric assessment in elderly patients is efficient and necessary for risk stratification to identify fit patients without cardiac comorbidities who can tolerate curative treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) and those who are not suitable for a standard regimen. If anthracycline-containing therapy is not feasible, alternative treatment options have to be carefully evaluated and individual risk factors have to be considered.