First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆.

BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

The alpha-Gpdh polymorphism in the tick Ixodes ricinus: similar diurnal trends in genotypic composition in Irish and Swedish population samples.

Analysis of the alpha-Gpdh locus, coding for the enzyme alpha-glycerophosphate dehydrogenase (glycerol-3-phosphate dehydrogenase), was conducted using starch-gel electrophoresis on samples from one Irish and one Swedish population of the tick Ixodes ricinus. Morning ('AM') and late afternoon ('PM') samples of unfed adults were collected in each case. The results show a higher frequency of homozygotes in females in the AM than in the PM sub-samples in both populations. No such diurnal differentiation was found in the case of male ticks. The results are discussed in relation to previous studies on the polymorphism in Ireland and in the context of the known metabolic role of alpha-glycerophosphate dehydrogenase in insect muscle. The possible selective influence of climatological factors is considered.

Reflex venomotor responses to lower body negative pressure following endurance training.

The effect of endurance training on reflex venomotor control during an orthostatic challenge was investigated in 11 sedentary male volunteers. An exercise (E) group (n = 6) underwent 12 weeks of endurance exercise training, whereas a control (C) group (n = 5) remained sedentary. Training significantly increased VO2max values in E (pre-training: 37.0 +/- 2.5 ml.kg-1.min-1; post training: 44.6 +/- 2.5 ml.kg-1.min-1), while C showed no significant change. During exposures to two levels of lower body negative pressure (-10 and -40 mm Hg), both C and E groups showed similar graded decreases in forearm venous volume (FVV). The magnitude of the FVV decreases did not differ between groups or when comparing pre-training and post-training values. We conclude that the reflex venoconstrictor response to LBNP was not affected by endurance training.

Cardiovascular response to lower body negative pressure (LBNP) following endurance training.

Eleven sedentary male volunteers were assigned to either an exercise (E) group (n = 6; endurance exercise for 12 weeks) or a control (C) group (n = 5; no exercise). After training, E significantly increased (p less than 0.01) their VO2max (pretraining: 37.0 +/- 2.3; posttraining: 44.6 +/- 2.5), whereas C showed no significant change. Heart rate (HR), arterial blood pressure (BP) and forearm blood flow (FBF) were measured both pre- and posttraining at rest and during 2 levels of LBNP: -10 mm Hg and -40 mm Hg. Both C and E had similar decreases in systolic BP and similar increases in HR and diastolic BP during LBNP when comparing the pre- and posttraining periods. In both groups, FBF significantly decreased during -40 mm Hg of LBNP in the pretraining period. However, after training, E had a significantly attenuated (p less than 0.05) decrease in FBF at -40 mm Hg (pretraining: -45.0 +/- 3.7%; posttraining: -29.8 +/- 3.1%). In C, there was no difference in the response of FBF to -40 mm Hg of LBNP comparing pretraining and posttraining. These findings indicate that endurance exercise training decreases the forearm vasoconstrictor response to high levels of LBNP.

Phosphoglucomutase polymorphism in the tick Ixodes ricinus.

Ten variants of phosphoglucomutase were detected by starch-gel electrophoresis in extracts of the tick Ixodes ricinus. Agreement of phenotype frequencies with those predicted by the Hardy-Weinberg model indicated that the enzyme is coded by a single gene locus (Pgm) at which 10 alleles are segregating. Allelic proportions in 5 Irish tick samples indicated that both spatial and temporal genetic differentiation exist. It is suggested that this polymorphism may be of use as a marker for studying the relationships of I. ricinus populations in Europe, as well as in taxonomic studies. A hypothesis is advanced which offers a possible adaptive explanation of the very high Pgm heterozygosity in tick populations. It is suggested that if kinetic differences exist between the various enzyme variants, the polymorphism may act to maintain an array of individuals in each population with varying developmental rates and longevities. Such a genetic strategy could be one factor which determines that the host-infesting seasons are spread over several months, thus ensuring maximum feeding and reproductive rates in each population.

Polymorphic tetrameric superoxide dismutase in the pike Esox lucius L. (Pisces; Esocidae).

1. Heart muscle extracts of northern pike from Lake Malaren in Sweden exhibited two electophoretic types of superoxide dismutase, one of which was identified as the cytoplasmic enzyme (s-SOD) and the other as the mitochondrial form (m-SOD). 2. Individual analysis of 51 pike indicated that s-SOD was invariant while m-SOD displayed a pattern of variation which was explicable by a single-locus polymorphism. 3. The observed m-SOD phenotype patterns suggested that the enzyme is a tetramer. This interpretation is supported by in vitro molecular hybridization studies.