Single-cell transcriptional profiling uncovers the association between EOMES+CD8+ T cells and acquired EGFR-TKI resistance.

Acquired resistance to tyrosine kinase inhibitors (TKIs) is reportedly inevitable in lung cancers harboring epidermal growth factor receptor (EGFR) mutations, emphasizing the need for novel approaches to predict EGFR-TKI resistance for clinical monitoring and patient management. This study identified a significant increase in eomesodermin (EOMES)+CD8+ T cells in the TKI-resistant patients, which was correlated with poor survival. The increase in EOMES+CD8+ T cells was further confirmed in both tissue samples and peripheral blood of patients with TKIs resistance. The integrated analysis of pseudotime and Gene set variation showed that the increase in EOMES+CD8+ T cells may be attributed to TRM T cell conversion and metabolic reprogramming. Overall, this work suggested an association between the increased number of EOMES+CD8+ T cells and acquired TKI drug resistance, supporting the utility of EOMES+CD8+ T cells as a biomarker for TKI treatment response.

Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer.

BACKGROUND: MVA-BN-brachyury-TRICOM is a recombinant vector-based therapeutic cancer vaccine designed to induce an immune response against brachyury. Brachyury, a transcription factor overexpressed in advanced cancers, has been associated with treatment resistance, epithelial-to-mesenchymal transition, and metastatic potential. MVA-BN-brachyury-TRICOM has demonstrated immunogenicity and safety in previous clinical trials of subcutaneously administered vaccine. Preclinical studies have suggested that intravenous administration of therapeutic vaccines can induce superior CD8+ T cell responses, higher levels of systemic cytokine release, and stronger natural killer cell activation and proliferation. This is the first-in-human study of the intravenous administration of MVA-BN-brachyury-TRICOM. METHODS: Between January 2020 and March 2021, 13 patients were treated on a phase 1, open-label, 3+3 design, dose-escalation study at the National Institutes of Health Clinical Center. The study population was adults with advanced solid tumors and was enriched for chordoma, a rare sarcoma of the notochord that overexpresses brachyury. Vaccine was administered intravenously at three DLs on days 1, 22, and 43. Blood samples were taken to assess drug pharmacokinetics and immune activation. Imaging was conducted at baseline, 1 month, and 3 months post-treatment. The primary endpoint was safety and tolerability as determined by the frequency of dose-limiting toxicities; a secondary endpoint was determination of the recommended phase 2 dose. RESULTS: No dose-limiting toxicities were observed and no serious adverse events were attributed to the vaccine. Vaccine-related toxicities were consistent with class profile (ie, influenza-like symptoms). Cytokine release syndrome up to grade 2 was observed with no adverse outcomes. Dose-effect trend was observed for fever, chills/rigor, and hypotension. Efficacy analysis of objective response rate per RECIST 1.1 at the end of study showed one patient with a partial response, four with stable disease, and eight with progressive disease. Three patients with stable disease experienced clinical benefit in the form of improvement in pain. Immune correlatives showed T cell activation against brachyury and other tumor-associated cascade antigens. CONCLUSIONS: Intravenous administration of MVA-BN-brachyury-TRICOM vaccine was safe and tolerable. Maximum tolerated dose was not reached. The maximum administered dose was 109 infectious units every 3 weeks for three doses. This dose was selected as the recommended phase 2 dose. TRIAL REGISTRATION NUMBER: NCT04134312.

Antegrade Conduction Rescues Right Ventricular Pacing-Induced Cardiomyopathy in Complete Heart Block.

BACKGROUND: Right ventricular (RV) pacing-induced cardiomyopathy (PICM) occurs in ∼30% of patients with RV leads. This study evaluated the long-term effects of restoring antegrade conduction with a biological pacemaker in a porcine model of RV PICM. OBJECTIVES: The goal of this study was to determine if antegrade biological pacing can attenuate RV PICM. METHODS: In pigs with complete atrioventricular (AV) block, transcription factor T-box 18 (TBX18) was injected into the His bundle region in either of 2 experimental protocols: protocol A sought to prevent PICM, and protocol B sought to reverse PICM. In protocol A, we injected adenoviral vectors expressing TBX18 (or the reporter construct green fluorescent protein) after AV node ablation, and observed the animals for 8 weeks. In protocol B, PICM was established by using AV node ablation and 4 weeks of electronic RV pacing, at which point TBX18 was injected into the His bundle region. RESULTS: In protocol A, TBX18 biological pacing led to superior chronotropic support (62.4 ± 3 beats/min vs. 50.4 ± 0.4 beats/min; p = 0.01), lower backup pacemaker utilization (45 ± 2.6% vs. 94.6 ± 1.4%; p = 0.001), and greater ejection fraction (58.5 ± 1.3% vs. 46.7 ± 2%; p = 0.001). In protocol B, full-blown RV PICM was evident 4 weeks after complete AV block in both groups; subsequent intervention led to higher mean heart rate (56 ± 2 beats/min vs. 50.1 ± 0.4 beats/min; p = 0.05), less backup pacemaker utilization (53 ± 8.2% vs. 95 ± 1.6%; p = 0.003), and a greater ejection fraction (61.7 ± 1.3% vs. 49 ± 1.6%; p = 0.0003) in TBX18-injected animals versus control animals. CONCLUSIONS: In a preclinical model, pacemaker-induced cardiomyopathy can be prevented, and reversed, by restoring antegrade conduction with TBX18 biological pacing.

Quick efficacy seeking trial (QuEST1): a novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer.

Advances in immunotherapy utilizing immune checkpoint inhibitors (ICIs) have transformed the treatment landscapes of several malignancies in recent years. Oncologists are now tasked with extending these benefits to a greater number of patients and tumor types. Metastatic castration-resistant prostate cancer (mCRPC) infrequently responds to ICIs, while the cellular vaccine approved for mCRPC, sipuleucel-T, provides a 4-month survival benefit but does not produce clinical responses as monotherapy. However, many novel and generally well-tolerated immune oncology agents with potential for immune synergy and/or additive effects are undergoing clinical development. This availability presents opportunities to develop adaptive-design combination clinical trials aimed to generate, expand, and facilitate antitumor immune responses. Here we describe a currently accruing phase I/II trial (NCT03493945) testing a brachyury-targeted antitumor vaccine, TGF-ß TRAP/anti-PD-L1 antibody, an IL-15 agonist, and an IDO1 inhibitor in mCRPC. TRIAL REGISTRATION: This trial ( NCT03493945 ) was registered in National Clinical Trials on April 11th 2018.