A novel bispecific antibody platform to direct complement activity for efficient lysis of target cells.

Harnessing complement-mediated cytotoxicity by therapeutic antibodies has been limited because of dependency on size and density of antigen, structural constraints resulting from orientation of antibody binding, and blockade of complement activation by inhibitors expressed on target cells. We developed a modular bispecific antibody platform that directs the complement-initiating protein C1q to target cells, increases local complement deposition and induces cytotoxicity against target antigens with a wide-range of expression. The broad utility of this approach to eliminate both prokaryotic and eukaryotic cells was demonstrated by pairing a unique C1q-recruiting arm with multiple targeting arms specific for Staphylococcus aureus, Pseudomonas aeruginosa, B-cells and T-cells, indicating applicability for diverse indications ranging from infectious diseases to cancer. Generation of C1q humanized mice allowed for demonstration of the efficacy of this approach to clear disease-inducing cells in vivo. In summary, we present a novel, broadly applicable, and versatile therapeutic modality for targeted cell depletion.

Long term responders to palliative chemotherapy for advanced biliary tract cancer.

BACKGROUND: Patients with advanced biliary tract cancer (BTC) are often treated with palliative chemotherapy (PC). Standard PC since 2010 is a cisplatin/gemcitabine doublet, with median overall survival (OS) of 11.7 months from the ABC-02 trial. Prior to this, our institutional standard was gemcitabine and fluoropyrimidine. The ABC-02 study used 8 cycles of PC as standard with treatment stopped even in the absence of disease progression, but some patients may benefit from continuing PC longer than 8 cycles. METHODS: Patients treated with at least 2 cycles of PC for advanced BTC in Princess Margaret Cancer Centre between 1987 and 2015 were included, and divided into 2 groups for analysis-long-term responders (LTR) who received 9 or more cycles, and controls (2-8 cycles). Data was collected on demographics, clinicopathological features, PC regimen, toxicities, and survival. The primary outcome measure was OS, with secondary analyses including progression-free survival (PFS) and toxicity rates between groups. RESULTS: A total of 382 patients were identified, 123 who met the criteria for LTR and 259 who were included as controls. The baseline demographic and clinical characteristics were similar, although more patients in the control group had gallbladder cancer or extrahepatic cholangiocarcinoma than LTR (P=0.024), and more patients in the LTR group were treated with combination chemotherapy regimens (93% vs. 82% in controls, P=0.003). The LTR patients had significantly longer PFS (median 13.3 vs. 4.1 months, P<0.001) and longer OS than controls (median 22.1 vs. 9.2 months, P<0.001). In LTR patients, 15% had a break from chemotherapy of 3 months or more and restarted the same regimen. The LTR patients reported higher rates of nausea, cutaneous and hematologic toxicity, but also more frequently went on to receive second-line chemotherapy (47% vs. 33%, P=0.007). In multivariable analysis of OS, LTR, good performance status and intrahepatic site of cancer were associated with better survival. CONCLUSIONS: From this institutional dataset, a significant proportion of patients continued chemotherapy past 8 cycles, and appeared to derive benefit from longer duration of treatment. Toxicity rates were higher in this group, but manageable as evidenced by second-line treatment rates. Discontinuation of chemotherapy for reasons other than toxicity or progression may result in loss of disease control and impact survival in this population; these data suggest the use of continued chemotherapy to disease progression in patients with advanced BTC is a favorable option.

Patterns of care and treatment outcomes in older patients with biliary tract cancer.

BACKGROUND: Although biliary tract cancers (BTC) are common in older age-groups, treatment approaches and outcomes are understudied in this population. PATIENTS AND METHODS: Data from 913 patients diagnosed with BTC from January 1987 to July 2013 and treated at Princess Margaret Cancer Center, Toronto were analyzed. The differences in treatment patterns between older and younger patients were explored and the impact of age, patient and disease characteristics on survival outcomes was assessed. RESULTS: Three hundred and twenty one patients ≥ 70 years were identified. Older patients were more likely to receive best supportive care, 40% (n = 130), compared to younger patients 26% (n = 154); p < 0.0001. On multivariable analysis, factors associated with receipt of surgery included stage I/II disease (p < 0.0001) and ECOG PS < 2 (p < 0.0001). Older age was not associated with lack of surgical intervention. In comparison, older age was associated with non-receipt of palliative chemotherapy (p = 0.0007). Similar survival benefit from treatment was seen in older and younger patients. Of 626 patients that underwent either surgery or palliative chemotherapy (n = 188), the median survival was 21.1 months (95% CI 19.0-27.9) in patients >70 years of age, and 21.1 months in younger patients (n = 438) (95% CI 19.5-24.5). CONCLUSIONS: In this large retrospective analysis, older patients with BTC are less likely to undergo an intervention. However, active therapy when given is associated with similar survival benefits, irrespective of age.

Effects of Statin, Aspirin or Metformin Use on Recurrence-Free and Overall Survival in Patients with Biliary Tract Cancer.

BACKGROUND/AIMS: The impact of statins, aspirin and metformin use on recurrence-free (RFS) and overall survival (OS) of patients with biliary tract cancer (BTC) has not been evaluated. METHODOLOGY: Baseline demographics/comorbidity and use of statins, aspirin or metformin at diagnosis were evaluated in patients with BTC from January/1987-July/2013. RESULTS: Median age at diagnosis; 65.7 years, performance status < 2; 795 patients, male; 461 (50.5%). Among 913 patients; 151 (16.5%) reported statin use at diagnosis, 146 (16%) aspirin use, and 81 (9%) metformin use. Charlson Comorbidity index score was not significantly associated with RFS or OS. Stage was prognostic on multivariable analysis for RFS and OS (both P ≤ 0.001) and age, performance status ≥ 2 and site were also prognostic for OS (P < 0.05, P < 0.001, and P < 0.05 respectively). Recurrence-free and OS among statin-users and nonusers was similar (RFS Hazard Ratio [HR]1.11, 95% confidence interval [CI] 0.78 - 1.58, P = 0.57), (OS HR0.98, 95% CI 0.77-1.24, P = 0.86), and among aspirin-users and nonusers (RFS HR0.83, 95% CI 0.57-1.23, P = 0.35), (OS HR1.07, 95% CI 0.85 - 1.34, P = 0.58), and among metformin-users and non-users (RFS HR0.75, 95% CI 0.43-1.30, P = 0.30), (OS HR0.96, 95% CI 0.69-1.33, P = 0.79). CONCLUSION: In this large retrospective cohort of BTC patients, comorbidity, statin, aspirin or metformin use did not have significant effects on RFS or OS.

Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and meta-analysis.

CONTEXT: Clinical data supporting the use of targeted agents for the treatment of metastatic renal cell carcinoma (RCC) are based predominantly on patients with clear cell histology. Little is known about the efficacy of these drugs in non-clear cell variants. OBJECTIVE: To evaluate the efficacy of different clear cell RCC (ccRCC)-approved targeted agents among patients with non-ccRCC compared with ccRCC. EVIDENCE ACQUISITION: We conducted a systematic review of electronic databases to identify publications evaluating the outcomes of patients with non-ccRCC treated with targeted agents approved for treatment of ccRCC. Patients with sarcomatoid variant RCC were excluded from the main analysis but were evaluated as an independent cohort. End points of interest were response rate, median progression-free survival (PFS), and median overall survival (OS). Where possible, data were pooled in a meta-analysis. For studies of unselected patients with RCC, the outcomes of patients with non-ccRCC histology were compared with ccRCC. In exploratory analyses, outcomes of non-ccRCC with nonapproved agents were assessed. EVIDENCE SYNTHESIS: A total of 49 studies comprising 7771 patients were included in the analysis. Of these, 1244 patients (16.0%) had non-ccRCC, 6300 (83.1%) had ccRCC, and 227 (2.9%) had sarcomatoid tumours. The overall response rate for non-ccRCC with targeted agents was 10.5%. In studies directly comparing non-ccRCC and ccRCC, there were significantly lower response rates for non-ccRCC (odds ratio for response: 0.52; 95% confidence interval, 0.40-0.68; p<0.001). For non-ccRCC treated with targeted agents, median PFS and OS were 7.4 and 13.4 mo, respectively; for patients with ccRCC, these were 10.5 mo and 15.7 mo, respectively (p value for difference<0.001 for both parameters). CONCLUSIONS: Patients with non-clear cell renal cell carcinoma (non-ccRCC) have significantly lower response rates and poorer median progression-free survival and overall survival than those with ccRCC. The optimal treatment of patients with non-ccRCC remains unclear and warrants further study. PATIENT SUMMARY: Systemic treatments for patients with renal cell carcinoma (RCC) tend to be significantly less effective for non-clear cell RCC, with lower response rates and worse progression-free survival and overall survival when compared with clear cell RCC. Optimal therapy remains unclear and warrants further study.

Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis.

BACKGROUND: Inflammation may play an important role in cancer progression, and a high neutrophil-to-lymphocyte ratio (NLR) has been reported to be a poor prognostic indicator in several malignancies. Here we quantify the prognostic impact of this biomarker and assess its consistency in solid tumors. METHODS: A systematic review of electronic databases was conducted to identify publications exploring the association of blood NLR and clinical outcome in solid tumors. Overall survival (OS) was the primary outcome, and cancer-specific survival (CSS), progression-free survival (PFS), and disease-free survival (DFS) were secondary outcomes. Data from studies reporting a hazard ratio and 95% confidence interval (CI) or a P value were pooled in a meta-analysis. Pooled hazard ratios were computed and weighted using generic inverse-variance and random-effect modeling. All statistical tests were two-sided. RESULTS: One hundred studies comprising 40559 patients were included in the analysis, 57 of them published in 2012 or later. Median cutoff for NLR was 4. Overall, NLR greater than the cutoff was associated with a hazard ratio for OS of 1.81 (95% CI = 1.67 to 1.97; P < .001), an effect observed in all disease subgroups, sites, and stages. Hazard ratios for NLR greater than the cutoff for CSS, PFS, and DFS were 1.61, 1.63, and 2.27, respectively (all P < .001). CONCLUSIONS: A high NLR is associated with an adverse OS in many solid tumors. The NLR is a readily available and inexpensive biomarker, and its addition to established prognostic scores for clinical decision making warrants further investigation.