Evolution and diversity of Rickettsia bacteria

Background: Rickettsia are intracellular symbionts of eukaryotes that are best known for infecting and causing serious diseases in humans and other mammals. All known vertebrate-associated Rickettsia are vectored by arthropods as part of their life-cycle, and many other Rickettsia are found exclusively in arthropods with no known secondary host. However, little is known about the biology of these latter strains. Here, we have identified 20 new strains of Rickettsia from arthropods, and constructed a multi-gene phylogeny of the entire genus which includes these new strains.Results: We show that Rickettsia are primarily arthropod-associated bacteria, and identify several novel groups within the genus. Rickettsia do not co-speciate with their hosts but host shifts most often occur between related arthropods. Rickettsia have evolved adaptations including transmission through vertebrates and killing males in some arthropod hosts. We uncovered one case of horizontal gene transfer among Rickettsia, where a strain is a chimera from two distantly related groups, but multi-gene analysis indicates that different parts of the genome tend to share the same phylogeny.Conclusion: Approximately 150 million years ago, Rickettsia split into two main clades, one of which primarily infects arthropods, and the other infects a diverse range of protists, other eukaryotes and arthropods. There was then a rapid radiation about 50 million years ago, which coincided with the evolution of life history adaptations in a few branches of the phylogeny. Even though Rickettsia are thought to be primarily transmitted vertically, host associations are short lived with frequent switching to new host lineages. Recombination throughout the genus is generally uncommon, although there is evidence of horizontal gene transfer. A better understanding of the evolution of Rickettsia will help in the future to elucidate the mechanisms of pathogenicity, transmission and virulence

A pilot trial of pre-operative (Neoadjuvant) letrozole in combination with bevacizumab in post-menopausal women with newly diagnosed estrogen and/or progesterone receptor positive breast cancer.

Purpose: Tumor content or expression of vascular endothelial growth factor (VEGF) is associated with impaired efficacy of anti-estrogen adjuvant therapy. We designed a pilot study of neoadjuvant letrozole and bevacizumab (anti-VEGF) to assess feasibility and short term efficacy in post-menopausal women with stage II/III, ER/PR positive breast cancer. Patients and Methods: Patients were treated with a neo-adjuvant regimen of letrozole, 2.5mg/day (P.O.) and bevacizumab 15mg/kg Q3 weeks (I.V.) for a total of 24 weeks prior to surgical treatment of their breast cancer. Patients were followed for toxicity at 3 week intervals and tumor assessment (physical exam and tumor ultrasound) at 6 week intervals. PET scans were carried out prior to therapy and 6 weeks after initiation of therapy. Surgery was done 4 weeks after the last dose of bevacizumab. Results: Twenty five evaluable patients were treated. The regimen was well tolerated except for 2 patients who were taken off-study for difficult to control hypertension. Objective clinical response occurred in 17/25 patients (68%) including 16% CR and 52% PR. The 4 patients with clinical CR had pathologic CR in their breasts (16%) although one had residual tumor cells in axillary nodes. 8/25 patients (32%) attained stage 0 or 1 status. PET scan response at 6 weeks correlated with clinical CR and breast pathologic CR at 24 weeks (p \u3c 0.0036). Conclusion: Combination neo-adjuvant therapy with letrozole and bevacizumab was well tolerated and resulted in impressive clinical and pathologic responses. The Breast Cancer Translational Research Consortium has an ongoing randomized phase II trial of this regimen in this patient population

A phase I study of CS-1008 (humanized monoclonal antibody targeting death receptor 5 or DR5), administered weekly to patients with advanced solid tumors or lymphomas

Background: CS-1008 is an IgG1 agonistic humanized monoclonal antibody targeting the human death receptor 5 (DR5). CS- 1008 triggers apoptosis after binding to DR5 resulting in death of targeted cells; it has demonstrated cytotoxic activity against DR5-positive human tumor cell lines in vitro, and in vivo it has shown significant anti-tumor activity against human tumor xenografts in nude mice. Methods: A phase I trial in patients with relapsed/refractory solid tumors and lymphomas was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety profile of CS-1008 administered intravenously every week (a cycle was defined as 3 consecutive weeks). Three to six patients were enrolled in successive dose escalating cohorts at doses from 1 to 8 mg/kg weekly (1, 2, 4 and 8). The MTD was defined as the highest dose at which 0/3 or 1/6 patients experience dose limiting toxicities (DLT). Results: Seventeen patients were enrolled, with a median age of 57 years (range, 31–88 years). Nine patients were enrolled in the 1, 2, and 4 mg/kg dose cohorts (3 in each one) and 8 patients in the 8m/kg dose cohort. CS-1008 was well tolerated, with no DLTs observed and the MTD was not reached. There were no infusion related toxicities, grade 3 or 4 toxicities related with CS-1008, or renal/ hepatic/hematological toxicities. Nine non-related severe adverse events were reported, all of them related to the primary tumor or disease progression. PK results demonstrated a half-life of 8 to 16 days. Seven patients had stable disease: 2 in the 1 mg/kg dose cohort (hepatocellular carcinoma 497+ days, head and neck cancer 225 days), 1 in the 2 mg/kg cohort (colon cancer 77 days), 2 in the 4 mg/kg dose cohort (colon cancer 78 days, cholangiocarcinoma 155 days), and 2 in the 8 mg/kg dose cohort (colon cancer 79 days, hepatocellular carcinoma 78 days). Conclusions: CS-1008 is well tolerated, and the MTD was not reached. The high number of patients with stable disease in this phase I trial suggests anti-tumor activity. Clinical trials of CS-1008 in combination with chemotherapy for the treatment of DR5 positive epithelial tumors have been initiated

A study of pre-operative (neoadjuvant) letrozole in combination with bevacizumab in post-menopausal women with newly diagnosed operable breast cancer: A preliminary safety report

Background: Our preclinical studies suggest that up-regulation of tumor cell VEGF is a mechanism to subvert estrogen dependence in hormone responsive breast cancer resulting in reduced efficacy or acquired resistance; we hypothesized that the combination of Bevacizumab (an anti-VEGF MoAb) and hormonal therapy would be more effective than hormonal therapy alone for breast cancer. Methods: Post-menopausal patients with ER and/or PR positive and Her-2-neu negative operable (T2–4a-c/N 0–2/M0) breast cancer were enrolled. Patients received letrozole (2.5 mg po daily) and Bevacizumab (15 mg/kg IV q 3 wks). Patients were reevaluated every 6 wks for a total of 24 wks; patients with CR/PR/SD in the first evaluation continued in the trial; after an additional 6 weeks of therapy patients with PD or SD were taken off-study and only patients with PR/CR completed 24 weeks of therapy. Definitive surgery was performed at the discretion of the surgeon no sooner than 4 wks after the last dose of bevacizumab. Patients continued letrozole while waiting for surgery. Up to December 2006, 27 patients have been enrolled with 13 patients too early to evaluate. Results: The 14 patients off-study had a median age of 63 years (range; 56 to 79) and an ECOG score of 0 for all patients. None of the patients received therapy for breast cancer before enrollment in the trial. 11 patients were stage II and 3 patients stage III. No treatment-related severe adverse events were seen. Treatment related toxicities were: grade 3 hypertension (n=1), grade 2 hypertension (n=7), grade 2 fatigue (n=2), grade 2 joint pain (n=3), grade 2 hot flashes (n=2), grade 1 proteinuria (n=1); 2 patients were taken off-study because of uncontrolled hypertension occurring on initial infusion of bevacizumab (not evaluable for efficacy). Of the 12 patients evaluable for response, 2 patients had pCR, 8 PR and 2 PD (at 9 weeks and 16 weeks). There have been no problems with wound healing or bleeding related to surgery or progressive disease while awaiting surgery. Conclusions: Combination letrozole and bevacizumab has substantial clinical efficacy and is well tolerated. The combination therapy will be evaluated in a randomized Breast Cancer Research Consortium Trial

A pilot open-label trial of preoperative (neoadjuvant) letrozole in combination with bevacizumab in postmenopausal women with newly diagnosed operable breast cancer

Background: Preclinical studies suggest that up-regulation of tumor cell VEGF is a mechanism to subvert estrogen dependence in hormone responsive breast cancer resulting in reduced efficacy or acquired resistance; we hypothesized that the combination of bevacizumab (an anti-VEGF MoAb) and hormone therapy would be more effective than hormone therapy alone for the treatment of breast cancer. Methods: Postmenopausal, ER and/or PR positive and Her-2-neu negative, operable (T2–4a-c/N 0–2/M0) breast cancer patients were enrolled. Patients received letrozole (2.5 mg po daily) and bevacizumab (15 mg/kg IV q 3 wks). Patients were evaluated every 6 wks; patients with CR/PR/SD in the first evaluation continued; after an additional 6 weeks of therapy patients with PD or SD were taken off-study and those patients with PR/CR completed 24 weeks of therapy. Definitive surgery was performed no sooner than 4 wks after the last dose of bevacizumab. Patients continued letrozole while waiting for surgery. 26 patients were enrolled with 1 patient too early to evaluate (Dec 2007). Results: The 25 patients that completed the study had a median age of 63 years (range; 54 to 79) and an ECOG score of 0 for all patients. 20 patients were stage II and 6 patients stage III. No treatment-related severe adverse events were seen. Treatment-related toxicities were as follows: 2 patients were taken off-study because of uncontrolled hypertension occurring on initial infusion of bevacizumab, grade 3 hypertension (n=5), grade 2 hypertension (n=7), grade 2 fatigue (n=4), grade 2 joint pain (n=3), grade 2 hot flashes (n=2), grade 1 proteinuria (n=1). Of the 22 patients evaluable for response, 4 patients had pCR in the breast (18%) and 3 of them had negative lymph nodes, 6 patients had a PR greater than 80% (28%), 6 patients had a PR between 20–80% (28%) and 2 patients had PD (at 9 weeks and 16 weeks). Overall response (CRs and PRs) 74%. There have been no problems with wound healing or bleeding related to surgery or progressive disease while awaiting surgery. Conclusions: Combination of letrozole and bevacizumab has substantial clinical efficacy and is well tolerated. The combination therapy will be evaluated in a randomized Breast Cancer Research Consortium Trial

SAPPHIRE:phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer

Background: Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance. Patients and methods: In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1: 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m2 every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety. Results: A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel [median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144]. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively. Conclusions: Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports.</p

SAPPHIRE:phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer

Background: Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance. Patients and methods: In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1: 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m2 every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety. Results: A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel [median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144]. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively. Conclusions: Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports.</p