Integrating a Disease-Focused Tumor Board as a Delivery-of-Care Model to Expedite Treatment Initiation for Patients With Liver Malignancies.

BACKGROUND: Patients with hepatobiliary malignancies are especially vulnerable to treatment delays. This study sought to evaluate the impact of implementing a new delivery-of-care model centered around a hepatobiliary multidisciplinary tumor board (HB-MTB) and integrated with an optimized patient workflow process to expedite treatment initiation. METHODS: A hybrid type 2 study (effectiveness-implementation) was performed. Implementation measures were examined prospectively using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) approach during 5 years after the HB-MTB program deployment (2015-2020). The primary outcome was effectiveness, measured as time to treatment initiation (TTI) using a before and after design (1 year each). The patients were grouped into before (BP) and after (AP) categories based on date of HB-MTB program implementation. Multivariable Cox and linear regression analyses were performed to examine and compare time to treatment initiation between groups. RESULTS: The HB-MTB program enrolled 2457 patients (reach). The RE-AIM measures were favorable and improved over time (P < 0.01 for all). The median TTI was lower for the AP group than for the BP group (17 vs 24 days; P < 0.01). In the multivariable Cox and linear regressions, treatment in the AP group was associated with a faster TTI (hazard ratio, 1.75; 95 % confidence interval, 1.31-2.35; p < 0.01), and a mean of 13 days faster treatment initiation than the BP group (P < 0.01). CONCLUSIONS: Implementation of an HB-MTB program integrated with an optimized patient workflow was successful and led to faster treatment initiation. This delivery-of-care model can serve as a blueprint to expedite treatment of patients with cancer.

Blocking Short-Form Ron Eliminates Breast Cancer Metastases through Accumulation of Stem-Like CD4+ T Cells That Subvert Immunosuppression.

Immunotherapy has potential to prevent and treat metastatic breast cancer, but strategies to enhance immune-mediated killing of metastatic tumors are urgently needed. We report that a ligand-independent isoform of Ron kinase (SF-Ron) is a key target to enhance immune infiltration and eradicate metastatic tumors. Host-specific deletion of SF-Ron caused recruitment of lymphocytes to micrometastases, augmented tumor-specific T-cell responses, and nearly eliminated breast cancer metastasis in mice. Lack of host SF-Ron caused stem-like TCF1+ CD4+ T cells with type I differentiation potential to accumulate in metastases and prevent metastatic outgrowth. There was a corresponding increase in tumor-specific CD8+ T cells, which were also required to eliminate lung metastases. Treatment of mice with a Ron kinase inhibitor increased tumor-specific CD8+ T cells and protected from metastatic outgrowth. These data provide a strong preclinical rationale to pursue small-molecule Ron kinase inhibitors for the prevention and treatment of metastatic breast cancer. SIGNIFICANCE: The discovery that SF-Ron promotes antitumor immune responses has significant clinical implications. Therapeutic antibodies targeting full-length Ron may not be effective for immunotherapy; poor efficacy of such antibodies in trials may be due to their inability to block SF-Ron. Our data warrant trials with inhibitors targeting SF-Ron in combination with immunotherapy. This article is highlighted in the In This Issue feature, p. 2945.

Pilot trial of remote monitoring to prevent malnutrition after hepatopancreatobiliary surgery.

BACKGROUND: Patients undergoing hepatopancreatobiliary (HPB) surgery, such patients with pancreatic, periampullary, and liver cancer, are at high risk for malnutrition. Malnutrition increases surgical complications and reduces overall survival. Despite its severity, there are limited interventions addressing malnutrition after HPB surgery. The aim of this pilot trial was to examine feasibility, acceptability, usability, and preliminary efficacy of a remote nutrition monitoring intervention after HPB surgery. METHODS: Participants received tailored nutritional counseling before and after surgery at 2 and 4 weeks after hospital discharge. Participants also recorded nutritional intake daily for 30 days, and these data were reviewed remotely by registered dietitians before nutritional counseling visits. Descriptive statistics were used to describe study outcomes. RESULTS: All 26 patients approached to participate consented to the trial before HPB surgery. Seven were excluded after consent for failing to meet eligibility criteria (e.g., did not receive surgery). Nineteen participants (52.6% female, median age = 65 years) remained eligible for remote monitoring post-surgery. Nineteen used the mobile app food diary, 79% of participants recorded food intake for greater than 80% of study days, 95% met with the dietitian for all visits, and 89% were highly satisfied with the intervention. Among participants with complete data, the average percent caloric goal obtained was 82.4% (IQR: 21.7). CONCLUSIONS: This intervention was feasible and acceptable to patients undergoing HPB surgery. Preliminary efficacy data showed most participants were able to meet calorie intake goals. Future studies should examine intervention efficacy in a larger, randomized controlled trial. TRIAL REGISTRATION: Clinicaltrials.gov. Registered 16 September 2019, https://clinicaltrials.gov/ct2/show/NCT04091165 .

A pipeline for identification and validation of tumor-specific antigens in a mouse model of metastatic breast cancer.

Cancer immunotherapy continues to make headway as a treatment for advanced stage tumors, revealing an urgent need to understand the fundamentals of anti-tumor immune responses. Noteworthy is a scarcity of data pertaining to the breadth and specificity of tumor-specific T cell responses in metastatic breast cancer. Autochthonous transgenic models of breast cancer display spontaneous metastasis in the FVB/NJ mouse strain, yet a lack of knowledge regarding tumor-bound MHC/peptide immune epitopes in this mouse model limits the characterization of tumor-specific T cell responses, and the mechanisms that regulate T cell responses in the metastatic setting. We recently generated the NetH2pan prediction tool for murine class I MHC ligands by building an FVB/NJ H-2q ligand database and combining it with public information from six other murine MHC alleles. Here, we deployed NetH2pan in combination with an advanced proteomics workflow to identify immunogenic T cell epitopes in the MMTV-PyMT transgenic model for metastatic breast cancer. Five unique MHC I/PyMT epitopes were identified. These tumor-specific epitopes were confirmed to be presented by the class I MHC of primary MMTV-PyMT tumors and their T cell immunogenicity was validated. Vaccination using a DNA construct encoding a truncated PyMT protein generated CD8 + T cell responses to these MHC class I/peptide complexes and prevented tumor development. In sum, we have established an MHC-ligand discovery pipeline in FVB/NJ mice, identified and tracked H-2Dq/PyMT neoantigen-specific T cells, and developed a vaccine that prevents tumor development in this metastatic model of breast cancer.

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth.

The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.