CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes.

A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial.

Fluctuation in red cell distribution width predicts disseminated intravascular coagulation morbidity and mortality in sepsis: a retrospective single-center study.

BACKGROUND: Red cell distribution width (RDW) values increase in many diseases and conditions, including sepsis. However, the relationship between RDW fluctuation and prognosis in patients with sepsis or the likely morbidity associated with sepsis-induced disseminated intravascular coagulation (DIC) has not been previously investigated. This study examined the association between dynamic changes to RDW and DIC occurrence in sepsis, as well as the prognostic significance of changes to RDW during hospital stay in patients with sepsis. METHODS: We collected baseline emergency department admissions' data. All RDW values recorded during hospitalization of patients with sepsis were combined to calculate RDW standard deviation (RDW-SD) and the increase rate of RDW; we also collected data on coagulation indicators. The endpoints were 28-day mortality and sepsis-related DIC morbidity. RESULTS: Of 232 patients included in our analysis, 66 were diagnosed with DIC (28.4%), and 86 (37.1%) died within 28 days. The RDW-SD and the increase rate of RDW were independent risk factors for 28-day mortality and sepsis-associated DIC morbidity, respectively. The DIC occurrence and mortality rate increased continually with an increasing rate of RDW of at least 6%. CONCLUSIONS: The RDW-SD and RDW increase rate shown in the study as the indicators of RDW fluctuation can help predict sepsis-related DIC morbidity and prognosis in patients with sepsis.

Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction.

Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community.

HLA-B27 and its subtypes in 4 Taiwanese Aborigine tribes: a comparison to Han Chinese patients with ankylosing spondylitis.

OBJECTIVE: We surveyed B27 and its subtypes in 5 ethnic groups in Taiwan. METHODS: Blood was obtained from 281 Aborigine people of the Atayal tribe (I-Lan), 141 Paiwan (Ping-Ton), 38 Rukai (Ping-Ton), and 40 Yami (Orchid Island), and also 47 B27+ healthy Han Chinese subjects and 82 B27+ Han patients with ankylosing spondylitis (AS). HLA-B27 and its subtypes were determined by standard methods. RESULTS: A much higher prevalence of B27 was found among the Atayal Aborigines (9.2%), which was significantly different from a lower prevalence in the Paiwan (2.1%; p = 0.004) and even higher than that of Han Chinese (5.59%; p = 0.04). No blood sample from the 38 Rukai Aborigines showed any B27. B2704 was the only subtype (100%) found in the 28 healthy Aborigines and 2 Aborigine patients with AS. However, in Chinese subjects, 40 of 47 (85%) B27+ healthy subjects were B2704, and 7 of 47 (15%) were B2705. In Chinese B27+ AS patients, 77 of 82 (94%) were B2704 and 5 of 82 (6%) were B2705. No other subtypes were found. Only the Aborigines without AS carrying B2704 showed a significant difference from the Chinese without AS carrying B2704 (p = 0.041). CONCLUSION: The different prevalence of B27, but similar frequency of the B2704 subtype, between Aborigines and Han Chinese suggests Aborigines are a unique population and may originate from an Asian country, possibly mainland China.