Regulation of Immune Cells by microRNAs and microRNA-Based Cancer Immunotherapy.

MicroRNAs (miRNAs) are small (~21 nucleotides) endogenous noncoding RNA molecules involved in the posttranscriptional regulation of gene expression. Modulation of gene expression by miRNAs occurs via base-pairing of the specific miRNA primary sequence to its corresponding target messenger RNA, which can be located either in the 3' untranslated region or within the coding sequence. This pairing can lead to either translational repression or cleavage of the mRNA, resulting in reduced levels of the target protein. MiRNAs are involved in mediating and controlling several interactions between immune and cancer cells and are also important regulators of immune responses. Increasing interest has focused on elucidating the role of miRNAs in the regulation of anticancer immune responses and how this could affect the efficacy of different cancer therapeutics. Indeed, immune responses have both pro- and anti-oncogenic effects, and functional interactions between immune and cancer cells in the tumor microenvironment are crucial in determining the course of cancer progression. Thus, understanding the role of miRNAs in controlling cancer immunity is important for revealing mechanisms that could be modulated to enhance the success of immunotherapy for patients with cancer. In this chapter, we discuss the involvement of miRNAs in the regulation of immune cells and potential therapeutic approaches in which miRNAs are used for cancer immunotherapy.

Five-year overall survival with ipilimumab and stereotactic ablative radiotherapy for metastatic disease.

PURPOSE: Ipilimumab plus stereotactic ablative radiotherapy (SABR) demonstrate satisfactory short-term clinical benefit and low toxicities in metastatic cancers. Here, we report the 5-year overall survival (OS) rates for patients with metastatic disease treated with this combined-modality therapy in a phase II trial (NCT02239900). METHODS AND MATERIALS: SABR was delivered to patients with metastatic lesions in the liver and lung either during the first dose (concurrent) or 1 week after the second dose (sequential) of ipilimumab (every 3 weeks for 4 cycles). SABR was administered to liver or lung metastases as 50 Gy in 4 fractions or 60 Gy in 10 fractions, considering the tumor location. The OS rates at 12, 36, and 60 months were estimated by the Kaplan-Meier method; subgroup analyses of progression-free survival (PFS) and OS by SABR-targeted lesions (liver/lung) were performed by log-rank tests. RESULTS: A total of 106 patients were enrolled in this long-term follow-up analysis. At the median follow-up time of 15.32 months (range, 0.97-82.13 months), the median PFS was 6.52 months (95% CI, 5.86-7.14) and the median OS was 15.32 months (95% CI,13.03-17.23). The 12-, 36-, and 60-month OS rates were 61%, 23%, and 15%, respectively. There was a significant difference in OS between cohorts (P = 0.039), with a stronger response observed in lung-treated subgroups. Patients who had received sequential fractions (50 Gy/4f) to the lung had improved OS compared to those who had received sequential fractions (18.29 vs 8.9 months, P = 0.043) to the liver. Subgroup analysis of SABR-targeted lesions showed that lung-targeted groups had significantly longer PFS (6.87 months vs. 5.63 months, P = 0.034) and OS (18.67 months vs. 13.63 months, P = 0.013) compared to liver-targeted groups. The sequence did not affect the outcomes of PFS and OS. Exploratory analyses showed that SABR-targeted lesions and smoking history comprised an independent risk factor for OS. CONCLUSIONS: Updated 5-year OS data from the phase II trial demonstrate the long-term clinical benefit of ipilimumab and SABR, which warrants further research and cumulative data.

Evaluating Primary Care Providers' Readiness for Delivering Genetic and Genomic Services to Underserved Populations.

INTRODUCTION: Increased genomics knowledge and access are advancing precision medicine and care delivery. With the translation of precision medicine across health care, genetics and genomics will play a greater role in primary care services. Health disparities and inadequate representation of racial and ethnically diverse groups threaten equitable access for those historically underserved. Health provider awareness, knowledge, and perceived importance are important determinants of the utilization of genomic applications. METHODS: We evaluated the readiness of primary care providers at a Federally Qualified Health Center, the Community Health Center, Inc. (CHCI) for delivering genetic and genomic testing to underserved populations. Online survey questions focused on providers' education and training in basic and clinical genetics, familiarity with current genetic tests, and needs for incorporating genetics and genomics into their current practice. RESULTS: Fifty of 77 (65%) primary care providers responded to the survey. Less than half received any training in basic or clinical genetics (40%), were familiar with specific genetic tests (36%), or felt confident with collecting family health history (44%), and 70% believed patients would benefit from genetic testing. CONCLUSION: Despite knowledge gaps, respondents recognized the value and need to bring these services to their patients, though would like more education on applying genetics and genomics into their practice, and more training about discussing risk factors associated with race or ethnicity. We provide further evidence of the need for educational resources and standardized guidelines for providers caring for underserved populations to optimize appropriate use and referral of genetic and genomic services and to reduce disparities in care.