The success of checkpoint inhibitors has validated immunomodulatory agents as a valuable class of anticancer therapeutics. A promising co-stimulatory immunologic target is 4-1BB, or CD137, a member of the tumor necrosis factor receptor superfamily. Ligation of 4-1BB induces an activating signal in CD8+ T cells and natural killer cells, resulting in increased pro-inflammatory cytokine secretion, cytolytic function, and antibody-dependent cell-mediated cytotoxicity. Targeting 4-1BB with agonistic monoclonal antibody (mAb) therapy demonstrated potent antitumor effects in murine tumor models. While anti-4-1BB mAbs have entered clinical trials, optimal efficacy of 4-1BB-targeted agents will inevitably come from combination therapeutic strategies. Checkpoint blockade is a compelling combination partner for 4-1BB agonism. This novel immunotherapeutic approach has the potential to active antitumor immune effectors by a complementary mechanism: simultaneously “removing the brakes” via blocking inhibitory signaling and “stepping on the accelerator” via co-stimulation. While important considerations should be given to 4-1BB-mediated toxicities, the current understanding of 4-1BB biology suggests it may play a key role in advancing the capabilities of cancer combination therapy.

Introduction: The BTK inhibitor, ibrutinib is FDA-approved in MCL and CLL, with activity in the majority of CD20+ B-cell malignancies. As rituximab-combination chemotherapy is today's standard of care in CD20+ B-cell malignancies, we previously investigated and determined ibrutinib antagonizes rituximab-dependent NK-cell mediated cytotoxicity (ADCC) due to ibrutinib's secondary irreversible binding to interleukin-2 inducible tyrosine kinase (ITK) which is required for FcR-stimulated NK cell function including calcium mobilization, granule release, and overall ADCC. We hypothesized that BTK inhibitors, BTK-InhA (ACP-196), BTK-InhB (BGB-3111) and BTK-InhC (undisclosed), each with lower ITK binding, may preserve NK cell function and therefore synergize rather than antagonize rituximab. Methods: Rituximab and trastuzumab-dependent NK-cell mediated cytotoxicity was assessed using lymphoma and HER2+ breast cancer cell lines as well as autologous CLL tumor cells. In vitro NK cell cytokine secretion, degranulation and cytotoxicity were assessed by IFN-g release, CD107a mobilization and chromium release. Results: FcR-stimulated NK cells following exposure to rituximab-coated lymphoma cells or trastuzumab-coated HER2+ breast cancer cells express high and moderate levels of ITK and BTK, respectively. Ibrutinib, in a dose-dependent manner (0.1 and 1uM), and not BTK-InhA, BTK-InhB or BTK-InhC (each at 1uM), inhibited both rituximab- and trastuzumab-induced NK cell cytokine secretion in vitro (Fig A *p=.018, **p=.002, ***p<.001). Similarly, BTK-InhA, BTK-InhB, and BTK-InhC had no inhibitory effect while ibrutinib prevented rituximab- and trastuzumab-stimulated NK cell degranulation by ~50% and ~85% at 1uM, respectively (Fig B *p=.034, **p=.024, ***p=.004, ****p=.002). Interestingly, BTK-InhA, BTK-InhB, and BTK-InhC each resulted in greater in vitro cytotoxicity of rituximab-coated, chromium-labeled lymphoma cells compared to ibrutinib at high NK:target cell ratios (Fig C *p=.048, **p=.009). Similarly, only ibrutinib abrogated in vitro cytotoxicity of trastuzumab-coated, chromium-labeled breast cancer cells with no impact due to BTK-InhA, BTK-InhB, or BTK-InhC (Fig C ***p<.001). At a constant NK:target cell ratio (25:1) and at all concentrations of rituximab tested (range 0.1 to 10ug/mL), 1uM of ibrutinib but not CGI-1746, BTK-InhA, BTK-InhB or BTK-InhC, reduced lysis of chromium-labeled Raji and autologous CLL tumor cells by ~4-fold (Fig D *p<.001). Conclusions: Ibrutinib is clinically effective as monotherapy and in combination with rituximab, despite inhibition of ADCC in vitro and in vivo murine models due to ibrutinib's secondary irreversible binding to ITK. Preclinically, the efficacy of therapeutics which do not inhibit NK cell function, including three novel BTK inhibitors, is superior to ibrutinib. Clinical investigation is needed to determine the impact of this finding on patients with lymphoma receiving rituximab. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Wang: BeiGene: Employment. Lannutti:Acerta Pharma: Employment. Johnson:Acerta Pharma: Employment.

Background Research shows that emerging adults face numerous stressors as they transition from adolescence to adulthood. This paper investigates university students’ lived experiences of maintaining mental well-being during major life events and challenges associated with this transitional period. As we continue to design health technology to support students’ mental health needs, it is imperative to understand the fundamental needs and issues particular to this phase of their life to effectively engage and lower the barriers to seeking help. Objective This study first aimed to understand how university students currently seek and receive support to maintain their mental well-being while going through frequent life events during this period of emerging adulthood. The study then aimed to provide design requirements for how social and technical systems should support the students’ mental well-being maintenance practice. Methods Semistructured interviews with 19 students, including graduate and undergraduate students, were conducted at a large university in the Midwest in the United States. Results This study’s findings identified three key needs: students (1) need to receive help that aligns with the perceived severity of the problem caused by a life event, (2) have to continuously rebuild relationships with support givers because of frequent life events, and (3) negotiate tensions between the need to disclose and the stigma associated with disclosure. The study also identified three key factors related to maintaining mental well-being: time, audience, and disclosure. Conclusions On the basis of this study’s empirical findings, we discuss how and when help should be delivered through technology to better address university students’ needs for maintaining their mental well-being, and we argue for reconceptualizing seeking and receiving help as a colearning process.

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