Fc-Silent Anti-TIGIT Antibodies Potentiate Antitumor Immunity without Depleting Regulatory T Cells.

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated the activation of tumor-specific exhausted CD8+ populations in a lymph node-dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor. SIGNIFICANCE: Fcs-silent anti-TIGIT antibodies enhance the activation of tumor-specific pre-exhausted T cells and promote antitumor efficacy without depleting T regulatory cells.

Atezolizumab Plus nab-Paclitaxel in the Treatment of Metastatic Triple-Negative Breast Cancer With 2-Year Survival Follow-up: A Phase 1b Clinical Trial.

Importance: The humanized monoclonal antibody atezolizumab targets programmed death-ligand 1 and has demonstrated durable single-agent activity in a subset of metastatic triple-negative breast cancers. To extend the observed activity, combinatorial approaches are being tested with standard cytotoxic chemotherapies known to induce immunogenic tumor cell death. Objective: To examine the safety, tolerability, and preliminary clinical activity of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancers. Design, Setting, and Participants: This phase 1b multicohort study enrolled 33 women with stage IV or locally recurrent triple-negative breast cancers and 0 to 2 lines of prior chemotherapy in the metastatic setting from December 8, 2014, to April 30, 2017, at 11 sites in the United States. The median follow-up was 24.4 months (95% CI, 22.1-28.8 months). Interventions: Patients received concurrent intravenous atezolizumab and intravenous nab-paclitaxel (minimum 4 cycles). Main Outcomes and Measures: The primary end point was safety and tolerability. Secondary end points included best overall response rate by Response Evaluation Criteria in Solid Tumors, version 1.1; objective response rate; duration of response; disease control rate; progression-free survival; overall survival; and biomarker analyses. Results: The 33 women had a median age of 55 years (range, 32-84 years) and received 1 or more doses of atezolizumab. All patients (100%) experienced at least 1 treatment-related adverse event, 24 patients (73%) experienced grade 3/4 adverse events, and 7 patients (21%) had grade 3/4 adverse events of special interest. No deaths were related to study treatment. The objective response rate was 39.4% (95% CI, 22.9%-57.9%), and the median duration of response was 9.1 months (95% CI, 2.0-20.9 months). The disease control rate was 51.5% (95% CI, 33.5%-69.2%). Median progression-free survival and overall survival were 5.5 months (95% CI, 5.1-7.7 months) and 14.7 months (95% CI, 10.1-not estimable), respectively. Concurrent nab-paclitaxel neither significantly changed biomarkers of the tumor immune microenvironment (programmed death-ligand 1, tumor-infiltrating lymphocytes, CD8) nor impaired atezolizumab systemic immune activation (expansion of proliferating CD8+ T cells, increase of CXCL10 chemokine). Conclusions and Relevance: In this phase 1b trial for metastatic triple-negative breast cancers, the combination of atezolizumab plus nab-paclitaxel had a manageable safety profile. Antitumor responses were observed, including in patients previously treated with a taxane. Trial Registration: ClinicalTrials.gov identifier: NCT01633970.

A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma.

BACKGROUND: Cabozantinib (XL184), an orally bioavailable inhibitor of vascular endothelial growth factor receptor 2 and MET, was assessed in a cohort of ovarian carcinoma patients as part of a phase 2 randomised discontinuation trial (RDT) with cohorts from nine different tumour types. PATIENTS AND METHODS: Patients received 100-mg cabozantinib daily. Those with stable disease (SD) per Response Evaluation Criteria in Solid Tumors at week 12 were randomised to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) after random assignment. RESULTS: Seventy patients with ovarian carcinoma, 50% of whom were platinum refractory/resistant, were enrolled in this RDT. Median PFS from day 1 was 5.5 months for all patients. The ORR at week 12 was 21%; one patient achieved a complete response (CR), and 14 patients (20%) achieved a confirmed partial response (PR). The overall disease control rate (CR + PR + SD) at week 12 was 50%. Throughout the study, 70% of the patients with ≥1 postbaseline scan had tumour regression, and randomisation was discontinued early. For patients with SD randomised to cabozantinib, PFS was 5.9 months after randomisation. The most common grade 3/4 adverse events were diarrhoea (14%), palmar-plantar erythrodysesthesia syndrome (6%), asthenia (6%), hypertension (6%) and neutropenia (6%). Dose reductions were required in 37% of the patients during the first 12 weeks. CONCLUSION: Cabozantinib demonstrates clinical activity, with acceptable toxicities, in patients with ovarian carcinoma based on ORR and regression of tumour target lesions. REGISTRATION: This trial is registered at ClinicalTrial.gov (NCT00940225).

The first structure of an RNA m5C methyltransferase, Fmu, provides insight into catalytic mechanism and specific binding of RNA substrate.

The crystal structure of E. coli Fmu, determined at 1.65 A resolution for the apoenzyme and 2.1 A resolution in complex with AdoMet, is the first representative of the 5-methylcytosine RNA methyltransferase family that includes the human nucleolar proliferation-associated protein p120. Fmu contains three subdomains which share structural homology to DNA m(5)C methyltransferases and two RNA binding protein families. In the binary complex, the AdoMet cofactor is positioned within the active site near a novel arrangement of two conserved cysteines that function in cytosine methylation. The site is surrounded by a positively charged cleft large enough to bind its unique target stem loop within 16S rRNA. Docking of this stem loop RNA into the structure followed by molecular mechanics shows that the Fmu structure is consistent with binding to the folded RNA substrate.