RESUMEN
INTRODUCTION: In October 2020, the French Health Authority granted early access outside of the clinical trial setting for dostarlimab, a programmed death-1 inhibitor. Dostarlimab was approved by the European Medicines Agency (in April 2021) as monotherapy for patients with post-platinum mismatch repair deficient/microsatellite instability-high advanced/recurrent endometrial cancer, based on the results of the GARNET trial (NCT02715284). METHODS: This was a real-world descriptive analysis of patients granted cohort temporary authorization of use to receive dostarlimab between November 2020 and June 2021. Physicians could complete follow-up forms at each treatment cycle to provide clinical information, safety, and efficacy data. Safety and disease progression data were also captured through pharmacovigilance reports. RESULTS: Of 95 temporary authorization of use requests made by 80 oncologists in 59 French hospitals, 87 patients were eligible, and 80 received≥1 dose of dostarlimab. Based on treatment response assessments received (n=43), the mean (standard deviation) time from treatment initiation to response evaluation was 11 (6) weeks. The disease control rate (complete plus partial responses plus stable disease rates) was 56% (n=24/43), and the overall response rate was 35% (n=15/43); both consistent with those reported in the GARNET trial. No new safety signals were reported. DISCUSSION: The enrolment of 80 patients in an 8-month period highlights the need for access to novel treatment regimens in France for these patients post-platinum. Prospective randomized studies are ongoing to assess the efficacy and safety of dostarlimab and other checkpoint inhibitors as first-line treatment in patients with endometrial cancer.
Asunto(s)
Neoplasias Endometriales , Platino (Metal) , Femenino , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad Crónica , Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales/tratamiento farmacológico , Inestabilidad de Microsatélites , Estudios Prospectivos , Ensayos Clínicos como AsuntoRESUMEN
CD8+/CD103+ tissue-resident memory T cells (TRM cells) accumulate in several human solid tumors, where they have been associated with a favorable prognosis. However, the role of CD103, the α subunit of the integrin αEß7 (also known as CD103), in the retention and functions of these TRM is undefined. In this report, we investigated the role of CD103 cytoplasmic domain and the focal adhesion-associated protein paxillin (Pxn) in downstream signaling and functional activities triggered through αE/CD103 chain. Binding to immobilized recombinant (r)E-cadherin-Fc of CD103 integrin expressed on tumor-specific CTL clones promotes phosphorylation of Pxn and Pyk2 and binding of Pxn to the αE/CD103 subunit tail. Inhibition of Pxn phosphorylation by the Src inhibitor saracatinib or its knockdown via shRNA dramatically altered adhesion and spreading of freshly isolated CD8+/CD103+ lung tumor-infiltrating lymphocytes and CD103+ tumor-specific CTL clones. Inhibition of Pxn phosphorylation with saracatinib in these CTL clones also severely compromised their functional activities toward autologous tumor cells. Using Jurkat T cells as a model to study CD103 integrin activation, we demonstrated a key role of serine residue S1163 of the αE chain intracellular domain in polarization of CD103 and recruitment of lysosomes and Pxn at the contact zone of T lymphocytes with rE-cadherin-Fc-coated beads. Overall, our results show how Pxn binding to the CD103 cytoplasmic tail triggers αEß7 integrin outside-in signaling that promotes CD8+ T-cell migratory behavior and effector functions. These results also explain the more favorable prognosis associated with retention of TRM cells in the tumor microenvironment. Cancer Res; 77(24); 7072-82. ©2017 AACR.
Asunto(s)
Antígenos CD/metabolismo , Linfocitos T CD8-positivos , Adhesión Celular , Citotoxicidad Inmunológica/fisiología , Cadenas alfa de Integrinas/metabolismo , Linfocitos Infiltrantes de Tumor , Paxillin/metabolismo , Antígenos CD/química , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Citoplasma/metabolismo , Células HEK293 , Humanos , Memoria Inmunológica/fisiología , Cadenas alfa de Integrinas/química , Células Jurkat , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Microambiente Tumoral/inmunologíaRESUMEN
Homing of CD8(+) T lymphocytes to the tumor microenvironment is an important step for mounting a robust antitumor immune response. TGFß is responsible for CD103 (αEß7) integrin induction in activated intraepithelial CD8(+) T lymphocytes. However, the interplay between TGFß and CD103 and their contribution to T-cell infiltration and antitumor activity remain unknown. Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Moreover, TGFß enhanced CD103-dependent T-cell adhesion and signaling, whereas it inhibited leukocyte function-associated antigen (LFA)-1 (αLß2) integrin expression and LFA-1-mediated T-lymphocyte functions. Mechanistic investigations revealed that TGFß bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrin-linked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation, thereby initiating integrin inside-out signaling. Collectively, our findings suggest that the abundance of TGFß in the tumor microenvironment may in fact engage with integrin signaling pathways to promote T-lymphocyte antitumor functions, with potential implications for T-cell-based immunotherapies for cancer. Cancer Res; 76(7); 1757-69. ©2016 AACR.
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Antígenos CD/metabolismo , Complejo CD3/metabolismo , Cadenas alfa de Integrinas/metabolismo , Neoplasias Pulmonares/metabolismo , Linfocitos T/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Microscopía Confocal , Transducción de Señal , Microambiente TumoralRESUMEN
The lytic function of CTL relies on the polarized release of cytotoxic granules (CG) at the immune synapse (IS) with target cells. CTL also contain CCL5 in cytoplasmic storage vesicles (CCL5V) distinct from CG, the role of which, in regulating T cell effector functions, is not understood. Using human CD8(+) T cells specific to a lung tumor-associated Ag, we show in this article that CTL release both secretory compartments into the immune synapse with autologous tumor cells. Moreover, we demonstrate that disorganization of the T cell microtubule cytoskeleton and defects in hMunc13-4 or Rab27a abrogate CG exocytosis and synaptic secretion of the chemokine. Mechanistically, synaptic release of CCL5 cytoplasmic storage vesicles likely occurs upon their coalescence with the Rab27a-hMunc13-4 compartment and results in autocrine, CCR5-dependent induction of CXCR4 cell surface expression, thereby promoting T cell migration in response to CXCL12. We propose that CCL5 polarized delivery represents a mechanism by which CTL control immune synapse duration.