Matthew J. Reilley

Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity

Intratumoral administration of myeloid agonists combined with a cocktail of T-cell checkpoint–modulating antibodies elicited systemic antitumor immunity against bilateral TRAMP-C2 prostate tumors. Limited agonist dosing coupled with intratumoral antibody injection reduced toxicity but preserved abscopal immunity. Coordinated manipulation of independent immune regulatory pathways in the tumor microenvironment—including blockade of T-cell checkpoint receptors and reversal of suppressive myeloid programs—can render aggressive cancers susceptible to immune rejection. Elevated toxicity associated with combination immunotherapy, however, prevents translation of the most efficacious regimens. We evaluated T-cell checkpoint–modulating antibodies targeting CTLA-4, PD-1, and 4-1BB together with myeloid agonists targeting either STING or Flt3 in the TRAMP-C2 model of prostate cancer to determine whether low-dose intratumoral delivery of these agents could elicit systemic control of multifocal disease. Intratumoral administration of the STING agonist cyclic di-GMP (CDG) or Flt3 Ligand (Flt3L) augmented the therapeutic effect of systemic triple checkpoint modulation and promoted the cure of 75% of mice with bilateral TRAMP-C2; however, when all agents were administered locally, only CDG mobilized abscopal immunity. Combination efficacy correlated with globally enhanced ratios of CD8+ T cells to regulatory T cells (Treg), macrophages, and myeloid-derived suppressor cells, and downregulation of the M2 marker CD206 on tumor-associated macrophages. Flt3L improved CD8+ T-cell and dendritic cell infiltration of tumors, but was diminished in efficacy by concomitant Treg expansion. Although intratumoral CDG/checkpoint therapy invokes substantial ulceration at the injection site, reduced CDG dosing can preserve tissue integrity without sacrificing therapeutic benefit. For high-order combinations of T-cell checkpoint antibodies and local myeloid agonists, systemic antibody administration provides the greatest efficacy; however, local administration of CDG and antibody provides substantial systemic benefit while minimizing the potential for immune-related adverse events. Cancer Immunol Res; 5(8); 676–84. ©2017 AACR.

Activation of 4-1BB on Liver Myeloid Cells Triggers Hepatitis via an Interleukin-27–Dependent Pathway

Purpose: Agonist antibodies targeting the T-cell costimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across preclinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist–driven tumor immunity from hepatotoxicity. Experimental Design: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without coadministration of checkpoint blockade, via (i) measurement of serum transaminase levels, (ii) imaging of liver immune infiltrates, and (iii) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines, and chemokines. Results: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27 that is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage, triggering transaminase elevation. FoxP3+ regulatory T cells limit liver damage, and their removal dramatically exacerbates 4-1BB agonist–induced hepatitis. Coadministration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma. Conclusions: 4-1BB agonist antibodies trigger hepatitis via activation and expansion of interleukin-27–producing liver Kupffer cells and monocytes. Coadministration of CTLA-4 and/or CCR2 blockade may minimize hepatitis, but yield equal or greater antitumor immunity. Clin Cancer Res; 24(5); 1138–51. ©2018 AACR.

Integrating Storytelling into a Communication Skills Teaching Program for Medical Oncology Fellows

Oncology training focuses primarily on biomedical content rather than psychosocial content, which is not surprising in light of the enormous volume of technical information that oncology fellows assimilate in a short time. Nonetheless, the human connection, and specifically communication skills, remains as important as ever in caring for highly vulnerable patients with cancer. We previously described a year-long communication skills curriculum for oncology fellows that consisted of monthly 1-hour seminars with role play as the predominant teaching method (Epner and Baile, Acad Med. 89:578–84, 2014). Over several years, we adapted the curriculum based on learner feedback and reflection by faculty and teaching assistants and consolidated sessions into quarterly 3–4-hour workshops. We now describe integrating stories into the curriculum as a way of building empathy and warming fellows to the arduous task of dealing with highly emotional content, such as conversations with young patients about transitioning off disease-directed therapy. Learners read and discussed published, medically themed stories; discussed their own patient care stories; and completed brief writing reflections and discussions. They then worked in small groups facilitated by faculty and upper level fellows who functioned as teaching assistants to work on applying specific skills and strategies to scenarios that they chose. Fellows completed anonymous surveys on which they rated the curriculum highly for relevance, value, organization, content, and teaching methods, including storytelling aspects. We conclude that sharing stories can help highly technical learners build reflective ability, mindfulness, and empathy, which are all critical ingredients of the art of medicine.

Role of Systemic Therapy

Management of resectable and borderline resectable pancreatic adenocarcinoma (BRPC) represents a significant challenge. Unfortunately, in most patients, PDAC is a systemic disease at presentation. Even in the presence of excellent perioperative supportive care and low mortality in high-volume centers, approximately 80 % of patients who undergo resection will develop metastases and die of their disease within 5 years [1, 2]. This is because most patients likely have micrometastatic disease at the time of attempted curative resection [3].

Implementing innovative, learner-centered methods to teach oncology fellows how to face difficult conversations.

27 Background: Oncologists engage in emotionally charged conversations with patients and families about prognosis, goals of care, and end of life transitions. Many oncologists lack key skills for guiding patients through such conversations. Key skills include posing open ended questions to elicit the patients perspective, using silence effectively, and responding to emotion with empathy. We previously described a communication skills curriculum for first year medical oncology fellows consisting of a series of one hour monthly seminars (Epner and Baile, Academic Medicine, 2014). We now describe improvements in the curriculum based on extensive feedback from learners and teaching assistants. METHODS Anonymous feedback from first year fellows indicated longer sessions would allow for sufficient warm up and more in depth reflection and opportunity to practice. We therefore consolidated the sessions into quarterly 4 hour workshops. Several fellows also expressed discomfort with participating in role play of clinical scenarios in front of colleagues, so we implemented small group learning in which 3-4 fellows practiced communication skills in facilitated role play scenarios. We also replaced large group role play with narrative medicine techniques, such as reading and discussing medically-themed short stories and reflective writing exercises to allow the greatest amount of participation among learners. RESULTS Fellows completed anonymous surveys on which they rated items on a 4 point scale, with 1 being best and 4 worst. The average score of the two survey items pertaining to large group role play was 2.6. After changes in the curriculum, items pertaining to narrative medicine averaged 1.3, which was very favorable. Items pertaining to relevance and value of the curriculum also averaged less than 1.5 for all years. Attendance was 100% with the exception of fellows who were on vacation. CONCLUSIONS Learner-centered, interactive innovations to our previous communication skills curriculum were highly rated by fellows and addressed issues of enhanced participation in a learning environment in which fellows felt safe to actively participate, reflect, and interact extensively with their peers.