PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non–small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.
We report the enhanced inhibitory potency of methotrexate (MTX) polyglutamates and dihydrofolate pentaglutamate on the catalytic activity of phosphoribosylaminoimidazolecarboxamide (AICAR) transformylase purified from MCF-7 human breast cancer cells. In the present work, MTX (4-amino-10-methylpteroylglutamic acid) and dihydrofolate, both monoglutamates, were found to be weak competitive inhibitors of AICAR transformylase with Kis of 143 and 63 ,uM, respectively, and their inhibitory capacity was largely unaffected by the glutamated state of the folate cosubstrate. In contrast, MTX polyglutamates were found to be potent competitive inhibitors, with an =10-fold increase in inhibitory potency with the addition of each glutamate group up to four (i.e., the pentaglutamate derivative). MTX (2), and the polyglutamated forms of MTX have been detected in a number of neoplastic and, to a lesser extent, normal tissues following MTX exposure (3-9). While retaining a potent inhibitory effect on H2PteGlu reductase, the polyglutamated forms of MTX differ from parent MTX in that they possess a more prolonged intracellular half-life resulting from a slower efflux rate from cells (10). The selective retention of the MTX polyglutamates results in prolonged antimetabolic effects after the removal of extracellular drug.We have investigated the possibility that polyglutamation of MTX may increase its ability to inhibit other folatedependent enzymes, particularly those that have a higher affinity for polyglutamated folate substrates. This report describes the 2500-fold enhanced capacity of MTX polyglutamate to inhibit 10-formyltetrahydrofolate:5'-phosphoribosyl-5-amino-4-imidazolecarboxamide formyltransferase [5-amino-4-imidazolecarboxamide ribotide (AICAR) transformylase, EC 2.1.2.3; AICAR TFase], a folate-requiring enzyme that catalyzes the reaction: 10-formyl-tetrahydrofolate (10-formyl-H4PteGlu) + AICAR, yielding 5'-phosphoribosyl-5-formamido-4-imidazole-carboxamide (formyl-AICAR), an intermediate in the de novo purine biosynthetic pathway, and tetrahydrofolic acid (H4PteGlu). We also report that H2PteGlu5, which increases in the cell following inhibition of H2PteGlu reductase (11) (Glu-Glu), and H2PteGlu were purchased from Sigma, and H2PteGlu5 was reduced from PteGlu5 as described (13,14) and purified by recrystallization. Affi-Gel Blue was purchased from Bio-Rad. All other chemicals were of reagent grade and purchased from Sigma.Preparation of Reduced Folates. Pure, biologically active l-L-10-formyl-H4PteGlu and -Glu5 were prepared by enzymatic reduction of H2PteGlu or -Glu5 to H4PteGlu or -Glu5 (15). For the enzymatic reduction, H2PteGlu or -Glu5 (50 mg) and NADPH (125 mg) in 20 ml 0.05 M Tris HCl buffer (pH 7.4) were incubated at 370C with partially purified Lactobacterium casei H2PteGlu reductase (New England Enzyme Center, Boston). The reaction was followed spectrophotometrically at 340 nm until no additional NADPH was metabolized. The H4PteGlu and -Glu5 thus formed were purified by elution from a DEAE-cel...
The metabolic role of 5-formyltetrahydrofolate is not known; however, it is an inhibitor of several folate-dependent enzymes including serine hydroxymethyltransferase. Methenyltetrahydrofolate synthetase (MTHFS) is the only enzyme known to metabolize 5-formyltetrahydrofolate and catalyzes the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate. In order to address the function of 5-formyltetrahydrofolate in mammalian cells, intracellular 5-formyltetrahydrofolate levels were depleted in human 5Y neuroblastoma by overexpressing the human cDNA encoding MTHFS (5YMTHFS cells). When cultured with 2 mM exogenous glycine, the intracellular serine and glycine concentrations in 5YMTHFS cells are elevated approximately 3-fold relative to 5Y cells; 5YMTHFS cells do not contain measurable levels of free methionine and display a 30 -40% decrease in cell proliferation rates compared with 5Y cells. Medium supplemented with pharmacological levels of exogenous folinate or methionine ameliorated the glycine induced growth inhibition. Analysis of the folate derivatives demonstrated that 5-methyltetrahydrofolate accounts for 30% of total cellular folate in 5Y cells when cultured with 5 mM exogenous glycine. 5YMTHFS cells do not contain detectable levels of 5-methyltetrahydrofolate under the same culture conditions. These results suggest that 5-formyltetrahydrofolate inhibits serine hydroxymethyltransferase activity in vivo and that serine synthesis and homocysteine remethylation compete for one-carbon units in the cytoplasm.
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