RESUMEN
Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors (n = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUVmax of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUVmax was associated with longer progression-free survival in our clinical trial (n = 26). We saw no such trends with pretreatment FDG PET SUVmax. Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid.
Asunto(s)
Melanoma , Triptófano , Humanos , Triptófano/metabolismo , Triptófano/farmacología , Fluorodesoxiglucosa F18 , Estudios Prospectivos , Quinurenina/metabolismo , Melanoma/diagnóstico por imagen , Melanoma/tratamiento farmacológico , Glucosa , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Oncolytic viruses are genetically engineered or naturally occurring viruses that selectively replicate in cancer cells without harming normal cells. Talimogene laherparepvec (Imlygic®), the first oncolytic viral therapy approved for treatment of cancer, was approved for treatment of locally advanced melanoma in October 2015. PURPOSE: As a biologic product, use of T. laherparepvec in the clinical setting requires pretreatment planning and a unique systematic approach to deliver the therapy. The processes we describe herein could be adopted by other centers that choose to prescribe T. laherparepvec. METHODS: We studied our clinical trial experience with T. laherparepvec before we embarked on using commercially available T. laherparepvec. We created a standard operating procedure (SOP) with multidisciplinary buy-in and oversight from leadership in Infection Control at our institution. We reflected on clinical cases and the actual procedures of administering T. laherparepvec to create the SOP. RESULTS: The preimplementation planning, patient selection, identification of lesions to treat, the actual procedure, and ongoing assessment of patients are described. Tumoral-related factors that lead to unique challenges are described. CONCLUSIONS: A process to ensure safe and responsible implementation of a program to administer T. laherparepvec for treatment of melanoma may improve the quality of treatment for patients who suffer from advanced melanoma.