RESUMO
Background Treatment of recurrent, unresectable granulosa cell tumor (GCT) of the ovary can be challenging. Given the rarity of the tumor, alternative therapies have been difficult to evaluate in large prospective clinical trials. Currently, to our knowledge, there are no reports of the use of immune checkpoint inhibitors in GCT patients. Here, we present a case series of GCT patients treated with pembrolizumab who were enrolled in a phase II basket trial in advanced, rare solid tumors (ClinicalTrials.gov: NCT02721732). Cases We identified 5 patients with recurrent GCT (4 adult and 1 juvenile type); they had an extensive history of systemic therapy at study enrollment (range, 3-10), with most regimens resulting in less than 12 months of disease control. Pembrolizumab was administered in these patients, as per trial protocol. Although there were no objective responses according to the irRECIST guidelines, 2 patients with adult-type GCT experienced disease control for ≥ 12 months (565 and 453 days). In one, pembrolizumab represented the longest duration of disease control compared to prior lines of systemic therapy (565 days vs. 13 months). In the other, pembrolizumab was the second longest systemic therapy associated with disease control (453 days vs. 22 months) compared to prior lines of therapy. In this patient, pembrolizumab was discontinued following withdrawal of consent. PD-L1 expression was not observed in any baseline tumor samples. Pembrolizumab was well tolerated, with no grade 3 or 4 treatment-related adverse events. Conclusions Although our results do not support the routine use of pembrolizumab monotherapy in unselected GCT patients, some patients with adult-type GCT may derive a clinical benefit, with a low risk of toxicity. Future studies should investigate the role of immunotherapy and predictors of clinical benefit in this patient population.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Tumor de Células da Granulosa/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Feminino , Proteína Forkhead Box L2/genética , Tumor de Células da Granulosa/genética , Tumor de Células da Granulosa/imunologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Neurofibromina 1/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
Axonal Kv1 channels regulate action potential propagation-an evolutionarily conserved function important for the control of motor behavior as evidenced from the linkage of human Kv1 channel mutations to myokymia/episodic ataxia type 1 (EA1) and the Shaker mutant phenotype in Drosophila. To search for the machinery that mediates axonal targeting of Kv1 channels composed of both alpha and beta subunits, we first demonstrate that Kvbeta2 is responsible for targeting Kv1 channels to the axon. Next, we show that Kvbeta2 axonal targeting depends on its ability to associate with the microtubule (MT) plus-end tracking protein (+TIP) EB1. Not only do Kvbeta2 and EB1 move in unison down the axon, Brefeldin A-sensitive Kv1-containing vesicles can also be found at microtubule ends near the cell membrane. In addition, we found that Kvbeta2 associates with KIF3/kinesin II as well. Indeed, Kv1 channels rely on both KIF3/kinesin II and EB1 for their axonal targeting.