The programmed death-1 (PD-1) receptor serves as an immunologic checkpoint, limiting bystander tissue damage and preventing the development of autoimmunity during inflammatory responses. PD-1 is expressed by activated T cells and downmodulates T-cell effector functions upon binding to its ligands, PD-L1 and PD-L2, on antigen-presenting cells. In patients with cancer, the expression of PD-1 on tumor-infiltrating lymphocytes and its interaction with the ligands on tumor and immune cells in the tumor microenvironment undermine antitumor immunity and support its rationale for PD-1 blockade in cancer immunotherapy. This report details the development and characterization of nivolumab, a fully human IgG4 (S228P) anti-PD-1 receptor-blocking monoclonal antibody. Nivolumab binds to PD-1 with high affinity and specificity, and effectively inhibits the interaction between PD-1 and its ligands. In vitro assays demonstrated the ability of nivolumab to potently enhance T-cell responses and cytokine production in the mixed lymphocyte reaction and superantigen or cytomegalovirus stimulation assays. No in vitro antibody-dependent cell-mediated or complement-dependent cytotoxicity was observed with the use of nivolumab and activated T cells as targets. Nivolumab treatment did not induce adverse immune-related events when given to cynomolgus macaques at high concentrations, independent of circulating anti-nivolumab antibodies where observed. These data provide a comprehensive preclinical characterization of nivolumab, for which antitumor activity and safety have been demonstrated in human clinical trials in various solid tumors. Cancer Immunol Res; 2(9); 846-56. Ó2014 AACR.

The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies.

This longitudinal study examined the intergenerational gap in acculturation, subsequent conflict, and their mental health consequences in Southeast Asian American adolescents. It was hypothesized that perceived intergenerational discrepancy in acculturation during early adolescence would predict intergenerational conflict in late adolescence, which, in turn, would increase depressive symptomatology in late adolescence. Using data from the Children of Immigrants Longitudinal Study (A. Portes & R. G. Rumbaut, 2001; R. G. Rumbaut, 1994), 490 Southeast Asian American adolescents in 8th and 9th grades completed surveys and again 3 years later. The results supported the hypothesis and showed that intergenerational/intercultural conflict fully mediated the longitudinal effect of perceived intergenerational discrepancy in acculturation on depressive symptomatology. Recommendations for community-based interventions for both parents and youth are offered.

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According to the 2008 U.S. Census, there are 15.5 million Asian Americans in the United States, and 17% are students enrolled in a university (Shea & Yeh, 2008). Asian American college students in higher education are oftentimes perceived as the “model minority” with high academic achievements and few mental and/or behavioral problems (Park, 2010). In contrast to this general assumption, studies have shown that many Asian American college students suffer from psychological distress (Abe-Kim et al., 2007; Breaux, Matsuoka, & Ryujin, 1997; Lee et al., 2009; Mallinckrodt, Shigeoka, & Suzuki, 2005; Nguyen & Anderson, 2005). In fact, the Centers for Disease Control and Prevention (2008) highlighted considerable disparities in mental health among racial/ethnic groups, including the fact that Asian Americans 15–24 years old have significantly higher suicidal rates than do other racial/ethnic groups of the same age range. Researchers have attributed this mental health disparity to Asian students’ underutilization of professional services. Consequently, a growing number of empirical studies have been conducted to identify the contributors to low mental health service utilization (Abe-Kim et al., 2007; Kim & Park, 2009; Lee et al., 2009; Nguyen & Anderson, 2005; Umemoto, 2004). These studies have found that acculturation, cultural barriers, and stigma attached to mental health problems are common factors that significantly contribute to Asian American college students’ low mental-health-seeking behaviors. However, based on the authors’ knowledge, these studies have focused on Asian American students who attend 4-year colleges. There is very little known about Asian American students attending 2-year community colleges, who comprise over 40% of Asian American undergraduates enrolled in higher education (Park, 2010).

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In this study, the attitudes toward and beliefs about serious mental illness (SMI) held by a group of graduate social work students in the northwestern United States were examined. Mental health stigma was examined with relation to the following factors:participants'level of social contact with SMI populations, adherence to stereotypes about SMI populations, belief in the ability to recover from SMI, and the belief that SMI defines an individual's identity. Measures used to identify mental health stigma included the desire for social distance and restrictions with relation to the SMI population. Survey results from 71 graduate social work students found that a significant number of participants who engaged in friendships with SMI-diagnosed individuals had less desire for social distance from and restrictions toward SMI populations. Participants who indicated that they believed in stereotypes of dangerousness and believed that SMI defines an individual's identity were more likely to express desire for both social distance and restrictions. Implications for social work and further research on the matter are discussed.

Informed by acculturation, ecological, and social capital theories, the study examined the contribution of parental acculturation, parental involvement, and intergenerational relationship to well-being in Southeast Asian American adolescents. Using data from the Children of Immigrants Longitudinal Study, 491 Southeast Asian American adolescents and their parents comprised the sample. Path analysis showed that parental involvement fully mediated the effect of parental acculturation on intergenerational relationship, whereas intergenerational relationship mediated the effect of parental involvement on child outcomes. Service implications are discussed.