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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.

Background: The timely and early diagnosis of ectopic pregnancy has made medical management of ectopic pregnancy the preferred treatment. Methotrexate is used in various regimens to treat ectopic pregnancy. A study was carried out to compare the effectiveness of double-dose and single-dose methotrexate regimen in medical management of unruptured ectopic pregnancy. Materials and Methods: The study included 80 hemodynamically stable patients with unruptured ectopic pregnancy. They were randomly assigned in to two groups. Group A patients received two doses of methotrexate 50 mg/m² on day 1 and day 4 whereas group B patients received single dose 50 mg/m² methotrexate on the day 1. Serum β human chorionic gonadotropin (β-hCG) and blood parameters were measured in both the groups on day 4 and day 7 followed by serial serum β-hCG weekly till negative value was obtained. Outcome measures were success rate of treatment, need for extra dose of methotrexate, need of laparotomy, and side effects of methotrexate. Results: The two groups were comparable in demographic parameters, baseline serum β-hCG, and blood parameters. The treatment success rate was slightly more in group A (70%) than group B (65%); however, it was statistically insignificant. Need of extra dose of methotrexate was 5% in group A and 17.5% in group B, respectively. Ten patients in group A and seven patients in group B underwent laparotomy for rupture of the ectopic mass. The reported side effects of methotrexate was comparable in both the groups. Conclusion: Study shows that double-dose methotrexate is as effective as single dose in the medical management of ectopic pregnancy. It has slightly better success rate though statistically insignificant, with less need for extra dose and less duration of follow-up. [ABSTRACT FROM AUTHOR]