High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance.

Sipuleucel-T (sip-T) is the only FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report high-dimensional analyses of sip-T using cytometry by time of flight (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ∼60%) of sip-T, followed by B cells, and natural killer (NK) and NKT cells. We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate tumors. Of the cytokines tested, IL15 was the most effective at enhancing activation and proliferation of effector lymphocytes, as well as augmenting tumor cytotoxicity in vitro. Co-culture of sip-T with IL15 and control or prostate-relevant antigens showed substantial activation and expansion of CD8+ T cells and NKT cells in an antigen-specific manner. Adoptive transfer of IL15-treated sip-T into NSG mice resulted in more potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2- to 14-fold higher influx of sip-T and a significant increase in IFNγ producing CD8+ T cells and NKT cells within the tumor microenvironment in the IL15 group. In conclusion, we put forward evidence that IL15 treatment can enhance the functional antitumor immunity of sip-T, providing rationale for combining IL15 or IL15 agonists with sip-T to treat patients with mCRPC.

The Mental Health of Frontline Health Care Providers During Pandemics: A Rapid Review of the Literature.

OBJECTIVE: This rapid review addresses two key questions posed by the COVID-19 pandemic: What are the anticipated mental health sequelae for frontline health workers? and What are best practices during health emergencies to address the mental health needs of these workers? METHODS: This review synthesized the literature on the mental health sequelae for health workers during major pandemics and epidemics that occurred in the 21st century (severe acute respiratory syndrome, Middle East respiratory syndrome, Ebola virus disease, and swine flu) and interventions used to address related mental health sequelae. PubMed, MEDLINE, and PsycINFO were searched with terms related to these epidemics/pandemics. RESULTS: Of 3,876 articles retrieved, 94 were included in this review. Across these studies, most health workers exhibited some adverse psychological experiences during outbreaks, with stress and anxiety being most common. Psychological distress decreased over time. Some studies reported insomnia, burnout, and posttraumatic stress for a subset of individuals up to 3 years after the disease outbreak. Few interventions have been implemented to address providers' mental health needs, and these strategies have not been evaluated systematically. CONCLUSIONS: Systems-level interventions may alleviate distress for most providers without the need for specialized mental health intervention. Psychotherapeutic support and referral to specialty care should be available to health workers with severe and intense adverse psychological outcomes during and beyond the COVID-19 pandemic. Evidence-based interventions are urgently needed to better serve health workers both during and following epidemics/pandemics.