Interleukin-12 (IL-12) is a potent, pro-inflammatory type 1 cytokine that has long been studied as a potential immunotherapy for cancer. Unfortunately, IL-12's remarkable antitumor efficacy in preclinical models has yet to be replicated in humans. Early clinical trials in the mid-1990's showed that systemic delivery of IL-12 incurred dose-limiting toxicities. Nevertheless, IL-12's pleiotropic activity, i.e., its ability to engage multiple effector mechanisms and reverse tumor-induced immunosuppression, continues to entice cancer researchers. The development of strategies which maximize IL-12 delivery to the tumor microenvironment while minimizing systemic exposure are of increasing interest. Diverse IL-12 delivery systems, from immunocytokine fusions to polymeric nanoparticles, have demonstrated robust antitumor immunity with reduced adverse events in preclinical studies. Several localized IL-12 delivery approaches have recently reached the clinical stage with several more at the precipice of translation. Taken together, localized delivery systems are supporting an IL-12 renaissance which may finally allow this potent cytokine to fulfill its considerable clinical potential. This review begins with a brief historical account of cytokine monotherapies and describes how IL-12 went from promising new cure to ostracized black sheep following multiple on-study deaths. The bulk of this comprehensive review focuses on developments in diverse localized delivery strategies for IL-12-based cancer immunotherapies. Advantages and limitations of different delivery technologies are highlighted. Finally, perspectives on how IL-12-based immunotherapies may be utilized for widespread clinical application in the very near future are offered.

No abstract

The gastrointestinal (GI) tract presents a notoriously difficult barrier for macromolecular drug delivery, especially for biologics. Herein, we demonstrate that ultrasound-stimulated phase change contrast agents (PCCAs) can transiently disrupt Caco-2 monolayers and improve the transepithelial transport of a macromolecular model drug. With ultrasound treatment in the presence of PCCAs, we achieved a maximum of 44±15% transepithelial delivery of 70 kDa FITCdextran, compared to negligible delivery through sham control monolayers. Among all tested rarefactional pressures (300-600 kPa), dextran delivery efficiency was consistently greatest at 300 kPa. To explore this unexpected finding, we quantified stable and inertial cavitation energy generated by various ultrasound exposure conditions. In general, lower pressures resulted in more persistent cavitation activity over 30 second exposure times, which may explain the enhanced dextran delivery efficiency. Thus, a unique advantage of using low boiling point PCCAs for this application is that the same low-pressure pulses can be used to induce vaporization and provide maximal delivery.

Acute Myeloid Leukemia, a hematological malignancy with poor clinical outcome, is composed of hierarchically heterogeneous cells. We examine the contribution of this heterogeneity to disease progression in the context of anti-tumor immune responses and investigate whether these responses regulate the balance between stemness and differentiation in AML. Combining phenotypic analysis with proliferation dynamics and fate-mapping of AML cells in a murine AML model, we demonstrate the presence of a terminally differentiated, chemoresistant population expressing high levels of PDL1. We show that PDL1 upregulation in AML cells, following exposure to IFNγ from activated T cells, is coupled with AML differentiation and the dynamic balance between proliferation, versus differentiation and immunosuppression, facilitates disease progression in the presence of immune responses. This microenvironment-responsive hierarchical heterogeneity in AML may be key in facilitating disease growth at the population level at multiple stages of disease, including following bone marrow transplantation and immunotherapy.

Background Teaching cultural humility is required by the Accreditation Council for Graduate Medical Education and can improve patient satisfaction and health care outcomes. Because one‐third of the 150,000 Somali immigrants and refugees in the United States live in Minnesota, we aimed to determine whether a brief cultural immersion experience, where small groups of residents share a meal with Somali interpreters at a Somali restaurant, would affect resident knowledge, attitudes, and behaviors when caring for Somali patients in a Minnesota emergency department. Methods From October 2017 to September 2018, emergency medicine residents were invited to dinners held outside of regular clinical/academic hours. Dinners took place at a Somali restaurant and were facilitated by a Somali interpreter and a faculty physician. While they were designed as learner‐driven sessions, facilitators were encouraged to discuss specific themes. In addition to an evaluation survey, participants underwent semistructured interviews after the experiences, and a qualitative analysis of derived themes is reported. Results Six dinners were hosted for a total of 20 residents, with 17 (85%) completing the evaluation survey and interview. Residents strongly agreed that this experience was worth their time and would recommend the program. Residents reported an increase in their knowledge of Somali culture, health care paradigms, and diet. Behavioral changes were described, including how residents greet patients, tailor clinical visits to patient expectations, and use interpreters as cultural brokers. Attitudinal changes were reported to a lesser degree but included an increased acceptance of cultural differences and an increased sense of connectedness to this population. Finally, residents reported that the benefits of this program were due to the authenticity of the experience, the informal small‐group setting, and their sense of being in the minority during the dinners. Conclusions A brief immersion experience at a Somali restaurant was sufficient to result in increased knowledge, attitudinal, and behavioral changes when caring for Somali patients.