Nivolumab plus relatlimab in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study.

BACKGROUND: Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma. Here, we present the results from patients with MSI-H/dMMR metastatic CRC treated with nivolumab plus relatlimab in the CheckMate 142 study. METHODS: In this open-label, phase II study, previously treated patients with MSI-H/dMMR metastatic CRC received nivolumab 240 mg plus relatlimab 160 mg intravenously every 2 weeks. The primary end point was investigator-assessed objective response rate (ORR). RESULTS: A total of 50 previously treated patients received nivolumab plus relatlimab. With median follow-up of 47.4 (range 43.9-49.2) months, investigator-assessed ORR was 50% (95% CI 36% to 65%) and disease control rate was 70% (95% CI 55% to 82%). The median time to response per investigator was 2.8 (range 1.3-33.1) months, and median duration of response was 42.7 (range 2.8-47.0+) months. The median progression-free survival per investigator was 27.5 (95% CI 5.3 to 43.7) months with a progression-free survival rate at 3 years of 38%, and median overall survival was not reached (95% CI 17.2 months to not estimable), with a 56% overall survival rate at 3 years. The most common any-grade treatment-related adverse events (TRAEs) were diarrhea (24%), asthenia (16%), and hypothyroidism (12%). Grade 3 or 4 TRAEs were reported in 14% of patients, and TRAEs of any grade leading to discontinuation were observed in 8% of patients. No treatment-related deaths were reported. CONCLUSIONS: Nivolumab plus relatlimab provided durable clinical benefit and was well tolerated in previously treated patients with MSI-H/dMMR metastatic CRC. TRIAL REGISTRATION NUMBER: NCT02060188.

The spatial organization of lipid synthesis in the yeast Saccharomyces cerevisiae derived from large scale green fluorescent protein tagging and high resolution microscopy.

The localization pattern of proteins involved in lipid metabolism in the yeast Saccharomyces cerevisiae was determined using C-terminal green fluorescent protein tagging and high resolution confocal laser scanning microscopy. A list of 493 candidate proteins ( approximately 9% of the yeast proteome) was assembled based on proteins of known function in lipid metabolism, their interacting proteins, proteins defined by genetic interactions, and regulatory factors acting on selected genes or proteins. Overall 400 (81%) transformants yielded a positive green fluorescent protein signal, and of these, 248 (62% of the 400) displayed a localization pattern that was not cytosolic. Observations for many proteins with known localization patterns were consistent with published data derived from cell fractionation or large scale localization approaches. However, in many cases, high resolution microscopy provided additional information that indicated that proteins distributed to multiple subcellular locations. The majority of tagged enzymes localized to the endoplasmic reticulum (91), but others localized to mitochondria (27), peroxisomes (17), lipid droplets (23), and vesicles (53). We assembled enzyme localization patterns for phospholipid, sterol, and sphingolipid biosynthetic pathways and propose a model, based on enzyme localization, for concerted regulation of sterol and sphingolipid metabolism that involves shuttling of key enzymes between endoplasmic reticulum, lipid droplets, vesicles, and Golgi.