4073 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Transcatheter arterial chemoembolization (TACE), radiofrequency (RFA) and cryoablation (CA) have been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment. Methods: Patients with HCC [Childs Pugh A/B7; BCLC B/C; ECOG 0/1; post-sorafenib (BCLC stage C only)] or refractory BTC were enrolled in a study of Tremelimumab combined with subtotal TACE, RFA or CA performed on week 6. All BTC patients received RFA in combination with tremelimumab. Tumor biopsies were performed at baseline and at time of RF/TACE. Results: 41 pts enrolled (32 HCC, 9 BTC). Characteristics: M:F 31:10; Median age 54(range 42-76); In HCC pts cirrhosis present in 22pts, BCLC Stage B/C: 9/23; Hepatitis B/C/neg: 5/18/9. 14 pts received TACE, 19 underwent RFA (inc all 9 BTC pts), 5 CA during week 6 of tremelimumab therapy. 3 pts did not receive an ablative procedure (due to PD). No DLT encountered. Most common toxicity was pruritus. Of N = 17 pts evaluable for response outside of TACE/RFA-treated lesion 4 (23.5%) achieved confirmed partial responses. 10 of 12 pts with quantifiable HCV experienced a marked reduction in viral load. 6-week tumor biopsies showed clear increase in CD8+ T cells only in pts showing a clinical response. Flow cytometry of PBMC revealed statistically significant changes in CD4/Treg and CD8/Treg ratio only in patients showing clinical response. Median PFS for evaluable HCC population was 5.7m. Conclusions: Tremelimumab in combination with subtotal TACE, RFA or CA in patients with advanced HCC and BTC is safe and leads to the accumulation of intratumoral CD8+ T cells, activation of CD4+ and CD8+ T cells in peripheral blood in responding patients. Encouraging clinical activity seen with objective confirmed responses, PFS 5.7m and possibly surrogate reductions in HCV viral load. Clinical trial information: NCT01853618.
This news section offers Cancer readers timely information on events, public policy analysis, topical issues, and personalities.This edition looks at how research institutions are consolidating vast amounts of data to produce innovative research and patient-centered care, a new study that concludes that e-cigarettes do not help smokers quit, and a new report from the American Cancer Society that shows wide variation in cancer rates among Asian Americans, Native Americans, and Pacific Islanders.
Abstract Introduction: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Patients with advanced hepatocellular carcinoma, who progressed on standard of care, were treated with tremelimumab and tumor ablation (radiofrequency ablation and transcatheter arterial chemoembolization) to augment anti-tumor immunity. Treatment was safe and feasible. Encouraging clinical activity has been seen with objective confirmed partial responses in 4/12 (33%) evaluable patients and a time to progression of 7.4 months. Here we report first results from immunoanalysis evaluating tumor biopsies, immune cell subsets in peripheral blood and serum viral loads in patients with chronic HBV or HCV infection. Methods: 20 Patients with HCC were treated with tremelimumab and tumor ablation on clinical trial NCT01853618. Tumor biopsies were taken at the time of ablation and peripheral blood mononuclear cells (PBMC) were collected before and during treatment in a subset of patients. Serum samples were tested for viral load (quantitative HCV RNA). Serum HBsAg titers were measured by chemiluminescent microparticle immunoassay (CMIA) using the ARCHITECT platform (Abbott Laboratories, Chicago, IL), as per the manufacturer's instructions. Tumor biopsies with analyzed by immunohistochemistry for CD3, CD4, CD8, CD20 and Granzyme B. Eleven-color flow cytometry was performed to study PBMC using the following antibodies: CD4, CD3, CD4, CD8, CD11c, CD14, CD19, CD20, CD25, CD38, CD45RA, CD56, CD123, CD127, CCR7, CCR4, CXCR3, PD-1, 4-1BB, TIM3, CTLA4, PD-L1, ICOS, HLA-DR. Statistical analysis was done using the Wilcoxon signed rank test. Results presented are preliminary and update data will be presented at meeting. Results: Immunohistochemical analysis of tumor biopsies demonstrated an increase in the CD3+CD8+ T cell population in tumors. CD8+ T cells stained positive for Granzyme A. No changes in the number of CD68+ macrophages were seen. Multi-color flow cytotometry PBMC revealed statistically significant changes after the 1st cycle of activated CD4+ and CD8+ T cells. There was a trend towards a reduction in CD4+ Tregs. Activated CD8+ T cells remained elevated for more than three months. Eight of 9 patients with quantifiable HCV experienced a marked reduction in viral load. Four of 4 HBV patients experienced a reduction in quantitative HepBsAg. Analysis of immune cell phenotype and more in depth analysis of tumor samples is ongoing and will be reported. Conclusions: Tremelimumab in combination with subtotal TACE or RFA leads to an accumulation of intratumoral CD8+ T cells, an activation of CD4+ and CD8+ T cells in peripheral blood and reductions in HCV viral load and HBsAg. Citation Format: Firouzeh Korangy, Mei ElGindi, Drew Pratt, David Venzon, Austin Duffy, Oxana Makarova-Rusher, Sid Kerkar, David Kleiner, Bradford Wood, Tim Greten. Tremelimimab activates CD4 and CD8+ T cells in patients with hepatocellular carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A195.
4083 Background: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including in HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and causes ADCC and apoptosis of proliferating endothelium. Sorafenib is the only FDA-approved drug in HCC and anti-endoglin antibody potentiates sorafenib in preclinical models Methods: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks plus sorafenib 400mg bid. Correlative biomarkers included DCE-MRI, color Doppler ultrasonography, circulating endothelial and endothelial progenitor cells, plasma levels of angiogenic factors, soluble CD105 and tumor IHC for CD105. Samples were also collected for analysis of immune subsets and pharmacokinetics. Results: 21 pts were enrolled (N = 2 inevaluable); 12 with cirrhosis; Hep B/C/NA: 2/10/7; M:F 13:6; Mean age of 60 (range 18-76); 1 DLT (increased AST) occurred at 10mg/kg. The most frequent toxicity was low grade epistaxis. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction and one patient developed G3 cerebral tumor hemorrhage. Four of sixteen (25%) pts evaluable for response achieved PR by RECIST (3/6 at Dose Level 4). Four patients had confirmed stable disease, one of whom was treated for 22 months. Median PFS was 4.1 months for first N = 18 patients, 5 months at dose level 4. Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity (PR rate 25%) was observed and the study is now in the phase 2 stage. Full correlative and clinical data will be presented. Clinical trial information: NCT01306058.
The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second‐generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose‐limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m 2 biweekly. Efficacy was evaluated in 15 patients with irinotecan‐refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre‐ and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre‐ and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.
220 Background: Although squamous metaplasia is commonly detected in pancreatic parenchyma, primary pancreatic squamous cell carcinoma (SCC) is a rare malignancy with unknown incidence and unclear prognosis. Methods: Using SEER-18 database primary code C25 in conjunction with histology codes for SCC (8052-8053, 8070-8078, 8083-8084) and for adenocarcinoma (AC) (8052-8053, 807-8078, 8083-8084), we identified cases diagnosed from 2000 to 2012. Age-adjusted incidence rates and trends over time were calculated. Patients with SCC were compared with AC by clinical features (TNM categories and histological differentiation), and 1-year and 2-year relative survival (RS) outcomes. Chi-square tests for categorical variables and t-tests for continuous variables were conducted. Kaplan-Meier method was used to estimate RS and Z-test was used to compare RS rates. SEERStat and GraphPad were used for analysis. Results: We identified 214 patients with microscopically confirmed SCC and 72,860 patients with AC. SCC constituted less than 1% of all cases of primary pancreatic cancer; however, age-adjusted incidence rates for this subtype tripled between 2000 and 2012. The annual percent increase of SCC incidence rate was 5.5%. Significant differences were observed by age, gender and race: older age groups, blacks and males had higher SCC incidence rates. Compared to AC, a greater proportion of patients with SCC had poorly differentiated histology (15.8% vs. 30.4%, p < 0.01). Similar to AC, the majority of patients with SCC had stage IV disease at diagnosis, 54.3% for AC vs. 56.4% SCC. The 1-year and 2-year relative survival rates were significantly lower in patients with SCC than AC. The 1-year relative survival rate was 15.8% (95%CI = 10.4-22.3) for SCC, compared with 24.7% (95%CI = 24.3-25.1) for AC, p < 0.001. Conclusions: Although primary squamous pancreatic carcinoma is a rare neoplasm, incidence rates for this subtype are markedly rising. Relative to adenocarcinoma, pancreatic squamous cell carcinoma is characterized by poorly differentiated histology and worse survival.
Abstract Background: Population-based studies have reported elevated Carcinoembryonic Antigen (CEA) level as an independent prognostic factor in patients with colon cancer, thus supporting inclusion of CEA-based C stage in classical TNM staging for colon cancer. However, the effect of C-stage incorporation on outcomes for patients with rectal adenocarcinoma is unknown. Methods: The Surveillance, Epidemiology and End Result (SEER) database was used to collect data from 2004 to 2007 for patients with rectal adenocarcinoma by topography code C20.9 and histology codes 8140-8144, 8210-8211, 8220-8221, 8260-8263, 8440, 8480-8481, and 8490. CEA stage C0 = normal CEA or C1 = elevated CEA was assigned to patients with known pretreatment CEA levels. Observed survival (OS) by American Joint Committee on Cancer (AJCC) stages I-IV and CEA stage C0 or 1 was determined using Kaplan Meier method. Relative survival (RS) as a net measure of cancer survival adjusted for sex, race, age and date was calculated in addition to observed survival (OS). Log-rank was used to compare observed survival. Z-test with corresponding p values was used to compare 5-year relative survival. Results: We identified 25,241 patients with a record of histologically confirmed invasive rectal adenocarcinoma. Approximately half (N = 13,151) of these patients had records of pretreatment CEA levels: N = 6,360 stage C1, N = 6,690 stage C0 and a small number (101) with borderline CEA levels. Mean age at diagnosis was similar in both groups, 64.2 for C0 and 64.7 for C1. Among patients with C1 disease the leading AJCC stage was distant metastatic, stage IV (33.8%) followed by 25.8% stage III, 20.7% stage II, 13.8% stage I, and 5.9% unknown stage. In contrast to CI disease, the most common stage for C0 was stage I (35.2%), and only 6.3% of patients with C0 were diagnosed with stage IV disease. Observed survival by each of I-IV AJCC TNM stages was decreased for C1 stage relative to C0, p<0.001. The 5-year OS by AJCC TNM stage for C1 was as follows: 56.7% for IC1 (CI = 53.3-59.9), 55.4% for IIC1 (CI = 52.7-58.1), and 53.4% for IIIC1 (CI = 51.0-55.8). The 5-year OS by AJCC TNM stage for C0 was 75.8% for IC0 (CI = 74.1-77.5), 68.8% for IIC0 (CI = 66.5-71.0), 65.4% for IIIC0 (63.3-67.5). Stage shifting was observed with IIIC0 disease, which had superior OS as compared to stage IIC1 and IC1 (p<0.001). For stage IV disease, the 5-year OS for C0 was more than double the 5 year OS for C1, 20.8 (17.1-24.9) vs. 7.9 (6.8-9.1), p<0.001. In concordance with this OS data, the 5-year relative survival analysis also showed a significant difference between C1 and C0 stages of rectal adenocarcinoma in the respective AJCC TNM stages, p<0.001. Conclusion: Our study suggests that pretreatment CEA levels predict survival in patients with rectal adenocarcinoma, in accordance with previous data in colon cancer. Therefore, our study supports C-stage inclusion in AJCC TNM staging for this neoplasm. Further prospective confirmatory studies are warranted. Citation Format: Oxana V. Makarova-Rusher, Julius Strauss, Susanna Ulahannan, Chul Kim, Jaydira Del Rivero, Austin Duffy, Tim F. Greten. Pretreatment carcinoembryonic antigen levels predict survival in patients with rectal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5015.
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