Salem, Aliasger K.

Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8 + T cell infiltration and functionality in established tumors, identification of neoantigens support emerging immunopreventative tactics against brain cancer. Functionally potent tissue-resident memory CD8 + T cells (T RM ) can be generated in the brain following peripheral infection or vaccination. However, the ability of brain T RM to prevent intracranial malignancy remains unknown. Here, mice were seeded with tumor-specific or bystander brain T RM via peripheral infection prior to depletion of circulating memory T cells (T CIRCM ) and subsequent brain tumor challenge. Tumor-specific brain T RM durably protected mice against intracranial malignancy even in the absence T CIRCM . These brain T RM persisted in tumor-surviving mice and protected against a second antigen-matched challenge. Importantly, a translationally-relevant mRNA-lipid nanoparticle (LNP) vaccine phenocopied peripheral infection-induced outcomes, generating functional brain T RM that controlled tumor growth. Altogether, this work points to the utility of brain T RM in cancer immunoprevention, supporting the development of antitumor mRNA-LNP vaccines to bolster brain immunity.

Abstract Purpose: Data on clear-cell renal cell carcinoma (ccRCC) xenografts defined the seleno-L-methionine (SLM) dose and the plasma selenium concentrations associated with the enhancement of hypoxia-inducible factor-1α/2α degradation, stabilization of tumor vasculature, enhanced drug delivery, and efficacy of axitinib. The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC. Patients and Methods: Patients were ≥18 years with histologically and radiologically confirmed advanced or metastatic ccRCC who had received at least one prior systemic therapy, which could include axitinib (last dose ≥6 months prior to enrollment). Escalating dose levels of SLM (2,500, 3,000, and 4,000 μg) were administered orally twice daily for 14 days and then once daily concurrently with axitinib 5 mg twice daily using a 3 + 3 design in phase I. Patients were treated at the 4,000 μg dose level in the expansion cohort to obtain preliminary estimates of efficacy. Results: No dose-limiting toxicities occurred at the 4,000 μg SLM dose level. Among the 27 patients treated with 4,000 μg of SLM, the overall response rate was 55.6%, median duration of response was 18.4 months, median progression-free survival was 14.8 months, and median overall survival was 19.6 months. Preliminary results have shown that plasma selenium concentrations, inhibition of TGF-β1, and stabilization of tumor vasculature by SLM are time dependent. Conclusions: SLM (4,000 μg) in sequential combination with axitinib is well tolerated with encouraging efficacy.

This study was carried out to quantitate the expression levels of microRNA-17, -19a, -34a, -155, and -210 (miRs) expressed in nine clear cell renal cell carcinoma (ccRCC) and one chromophobe renal cell carcinoma cell line with and without sarcomatoid differentiation, and in six primary kidney tumors with matching normal kidney tissues. The data in the five non-sarcomatoid ccRCC cell lines—RC2, CAKI-1, 786-0, RCC4, and RCC4/VHL—and in the four ccRCC with sarcomatoid differentiation—RCJ41T1, RCJ41T2, RCJ41M, and UOK-127—indicated that miR-17 and -19a were expressed at lower levels relative to miR-34a, -155, and -210. Compared with RPTEC normal epithelial cells, miR-34a, miR-155, and miR-210 were expressed at higher levels, independent of the sarcomatoid differentiation status and hypoxia-inducible factors 1α and 2α (HIFs) isoform expression. In the one chromophobe renal cell carcinoma cell line, namely, UOK-276 with sarcomatoid differentiation, and expressing tumor suppressor gene TP53, miR-34a, which is a tumor suppressor gene, was expressed at higher levels than miR-210, -155, -17, and -19a. The pilot results generated in six tumor biopsies with matching normal kidney tissues indicated that while the expression of miR-17 and -19a were similar to the normal tissue expression profile, miR-210, -155, -and 34a were expressed at a higher level. To confirm that differences in the expression levels of the five miRs in the six tumor biopsies were statistically significant, the acquisition of a larger sample size is required. Data previously generated in ccRCC cell lines demonstrating that miR-210, miR-155, and HIFs are druggable targets using a defined dose and schedule of selenium-containing molecules support the concept that simultaneous and concurrent downregulation of miR-210, miR-155, and HIFs, which regulate target genes associated with increased tumor angiogenesis and drug resistance, may offer the potential for the development of a novel mechanism-based strategy for the treatment of patients with advanced ccRCC.