PVRIG is Expressed on Stem-Like T Cells in Dendritic Cell-Rich Niches in Tumors and Its Blockade May Induce Immune Infiltration in Non-Inflamed Tumors.

Cancers that are poorly immune infiltrated pose a substantial challenge, with current immunotherapies yielding limited clinical success. Stem-like memory T cells (TSCM) have been identified as a subgroup of T cells that possess strong proliferative capacity and that can expand and differentiate following interactions with dendritic cells (DCs). In this study, we explored the pattern of expression of a recently discovered inhibitory receptor poliovirus receptor-related immunoglobulin domain protein (PVRIG) and its ligand, poliovirus receptor-related ligand 2 (PVRL2), in the human tumor microenvironment. Using spatial and single-cell RNA transcriptomics data across diverse cancer indications, we found that among the T-cell checkpoints, PVRIG is uniquely expressed on TSCM and PVRL2 is expressed on DCs in immune aggregate niches in tumors. PVRIG blockade could therefore enhance TSCM-DC interactions and efficiently drive T-cell infiltration to tumors. Consistent with these data, following PVRIG blockade in patients with poorly infiltrated tumors, we observed immune modulation including increased tumor T-cell infiltration, T-cell receptor (TCR) clonality, and intratumoral T-cell expansion, all of which were associated with clinical benefit. These data suggest PVRIG blockade as a promising strategy to induce potent antitumor T-cell responses, providing a novel approach to overcome resistance to immunotherapy in immune-excluded tumors.

A phase 1b study of trebananib in combination with pegylated liposomal doxorubicin or topotecan in women with recurrent platinum-resistant or partially platinum-sensitive ovarian cancer.

OBJECTIVE: To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. METHODS: In this open-label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m(2) (cohorts A1 and A3, respectively) or topotecan 4 mg/m(2) (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary). RESULTS: 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug-drug interactions were apparent. CONCLUSIONS: Trebananib 10mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts.

Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study.

BACKGROUND: Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. METHODS: Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m(2) on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681. FINDINGS: ORRs for the motesanib group and the placebo group did not differ significantly (49%vs 41%; absolute difference 8% [95% CI -6 to 22]; p=0.31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature. INTERPRETATION: Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population. FUNDING: Amgen.