tbuckley/cabot-search huggingface dataset:
Ad5 immunity after multiple safe, homologous immunizations against tumor-associated antigens with new recombinant Ad5 vector.
Authors: Elizabeth Susan Gabitzsch, Michael Morse, Amy Hobeika, Younong Xu, Joseph Balint, Stephanie Balcaitis, H. Kim Lyerly, Frank R. Jones
Journal: Journal of Clinical Oncology (2012)

85 Background: The major limitation for the use of Ad5 and other vectored vaccines is the inability to be effective in the presence of pre-existing or concomitant vector immunity. An Ad5-based vector with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), by virtue of diminished late phase viral protein expression, avoids immunological clearance and induces immune responses. Methods: The Ad5 [E1-, E2b-] platform encoding tumor associated antigen(s) (TAA) such as a modified carcinoembryonic antigen (CEA(6D)), HER2 and HPV E6/E7, were evaluated for the induction of TAA specific immune responses and anti-tumor effects in murine models. In a phase I/II clinical trial, cohorts of patients (n=25 total) with advanced colorectal cancer, refractory to prior therapies, received escalating doses of Ad5 [E1-, E2b-]-CEA(6D) (10 9 to 10 11 vp) subcutaneously every 3 weeks for 3 immunizations. CEA-specific cell mediated immunity was measured by ELISPOT. Results: In murine immunotherapy studies, mice implanted with tumors expressing TAA and subsequently treated with the Ad5 [E1-, E2b-] platform expressing that TAA had significant inhibition of tumor progression. Pre-vaccination against the TAA utilizing the Ad5 [E1-, E2b-]-TAA resulted in inhibition of tumor establishment. In a clinical trial, patients who received the highest dose of Ad5 [E1-, E2b-]-CEA(6D) exhibited the highest levels of CEA-specific CMI responses. The induction of CEA-specific CMI responses increased over the course of the 3 injections despite the presence of pre-existing Ad5 immunity in the majority (75%) of patients. There were no drug related grade 3/4 toxicities. Conclusions: The results demonstrate that the novel Ad5 [E1-, E2b-] gene delivery platform can both break tolerance and generate significant CMI responses to the TAA CEA in the setting of both naturally acquired Ad5-specific immunity and/or immunization-induced Ad5 immunity.
Dose escalation of five-fraction SABR for prostate cancer: Biochemical outcome and toxicity comparison of two prospective trials.
Authors: Hima Bindu Musunuru, Harvey Charles Quon, Liying Zhang, Patrick Cheung, Colin I Tang, Geordi Pang, Alexandre Mamedov, Laura D'Alimonte, Andrea Deabreu, D. Andrew Loblaw
Journal: Journal of Clinical Oncology (2015)

224 Background: To compare the biochemical outcomes and toxicities of two different 5 fraction stereotactic ablative body radiotherapy (SABR) schedules for the treatment of localized prostate cancer. Methods: Two sequential phase I/II studies of 5-fraction SABR for the treatment of low and intermediate risk (LR and IR) prostate cancer have been conducted. In the first trial, 84 LR patients(pts) received 35 Gy in 5 fractions, once per week over 29 days (Group 1). In the second trial, 30 pts (18 LR, 11 IR) received 40 Gy in 5 fractions, once per week over 29 days (Group 2). Treatment was delivered to the prostate with intensity modulated radiotherapy using daily image guidance and a 4mm (Group 1) or 5 mm (Group 2) CTV-PTV margin. PSA nadir and bRFS(nadir+2 definition) were compared between the two groups. Acute (CTCv3.0), late (RTOG) and cumulative toxicity for late grade ≥ 2 GU/GI toxicities were also compared. Results: Median follow up was 74 (IQR 67-81) and 36 (IQR 32-39) months. Median PSA nadir was 0.4 ng/ml and 0.3 ng/ml. Time to PSA nadir was 54 and 32.5 months. 44.0% in group 1 and 30% in Group 2 experienced benign PSA bounce. There were 3 and 0 PSA failures in Groups 1 and 2. 2-, 4- and 6-year bRFS was 100%, 98.7% and 95.9% and 100%, 100% and not reached in groups 1 and 2, respectively (p=0.91). The only acute grade 3 toxicity was noticed in Group 1 (1 pt, GU). Late grade 4 GI toxicity was noted in Group 1 (1 pt, GI, fistula). Up to 4 years of follow-up, Group 2 pts have had a greater percentage of grade 2+ cumulative GU (5.0% vs 24.2%) and GI (7.6% vs 26.2%) toxicities. Conclusions: Pts receiving a dose escalated SABR had slightly lower PSA nadir and similar bRFS - longer follow up is needed to better estimate biochemical outcomes in Group 2. There seemed to be a greater risk of grade 2 toxicities in the higher dose cohort but grade 3+ toxicities were not increased. Quality of life analyses will be presented separately. Clinical trial information: NCT01578902 , NCT01146340 .[Table: see text]
Inactivation of O6 methylguanine DNA methyltransferase and nitrogen oxide in colorectal cancer.
Authors: R. A. Coudry, L. Assaf, R. Crespo, E. M. Santos
Journal: Journal of Clinical Oncology (2011)

461 Background: O 6 Methylguanine DNA methyltransferase (MGMT or AGT) activity plays an important role in colorectal carcinogenesis. Inactivation of MGMT can occur by promoter CpG island hypermetilation or through inhibition caused by nitrogen oxide (NO) and species derived from it. NO is synthesized from L-arginine by nitric oxide syntases (NOS) and plays a critical role in various biological processes and many disorders including cancer. Methods: We evaluated the expression of NOS1, NOS2, NOS3 and MGMT protein by immunohistochemistry. Plasma concentrations of nitrate/nitrite were analyzed by spectrophotometry. Methylation in the promoter region of MGMT was investigated by pyrosequencing. Results: Methylation of MGMT and loss of MGMT expression was detected in 68.8% and 32.6% of tumors, respectively. There was no significant association between MGMT methylation and protein expression with NOS1, NOS2 and NOS3 or nitrate/nitrite. Significant association was found between MGMT expression and methylation status (p &lt; 0.001). NOS2 immunoreactivity was observed in the cytoplasm of the malignant cells (95.7%) and was positively associated with lymph node involvement (p = 0.046) and advanced stage (p = 0.048). Nitrite also showed association with lymph node involvement (p = 0.010). Conclusions: Loss of expression of MGMT protein is frequently caused by promoter hypermethylation at the MGMT gene and both are not associated with NOS enzymes or nitrate/nitrite. NOS2 overexpression and plasma concentration of nitrite may serve as a predictor for the prognosis of patients with CRC. No significant financial relationships to disclose.
Phase I study of DKN-01, an anti-DKK1 antibody, in combination with paclitaxel (pac) in patients (pts) with DKK1+ relapsed or refractory esophageal cancer (EC) or gastro-esophageal junction tumors (GEJ).
Authors: Johanna C. Bendell, Janet E. Murphy, Devalingam Mahalingam, Balazs Halmos, Cynthia A. Sirard, Steven B. Landau, David P. Ryan
Journal: Journal of Clinical Oncology (2016)

111 Background: DKK1, a secreted protein, is an indirect inhibitor of canonical Wnt signaling and was recently shown to directly activate non-canonical Wnt pathways including Rho, ROCK and JNK. High DKK1 concentrations in EC tumor tissue correlate with shorter overall survival (OS); published data suggests increased activity of non-canonical signaling by DKK1 may be a reason for shortened OS. DKN-01 is a humanized monoclonal antibody to DKK1 with demonstrated activity in non-small cell lung cancer. This study evaluated the MTD, safety and early activity of DKN-01 in combination with pac in EC and GEJ cancer pts. Methods: In Part A, pts with DKK1+ EC or GEJ cancer by IHC staining received DKN-01 in two dose escalation cohorts (150 or 300 mg) with pac 80 mg/m 2 on days 1, 8, 15 and 22 of each 28 day cycle. Part B (dose expansion) is ongoing. Responses were assessed using RECIST version 1.1. Results: &gt; 90% of screened EC (70 pts) had DKK1+ tumor tissue. In Part A, 9 pts with advanced EC or GEJ cancer were enrolled: 3 in Cohort 1 (150 mg) and 6 in Cohort 2 (300 mg); 5 pts had a diagnosis of EC [3 with adenocarcinoma (AC); 2 with squamous cell] and 4 pts with GEJ AC. Median number of prior therapies was 2 (range 1, 8). One DLT, G3 peripheral neuropathy, was seen at 300 mg. Frequent adverse events (AEs) were cough (5 pts), alopecia, leukopenia, neutropenia and peripheral/sensory neuropathy (each 4 pts) and fatigue, anemia, and nausea (each 3 pts); AEs were mostly Grade 1/2. The MTD of DKN-01 + pac was determined to be 300 mg. Among the 7 AC pts, 3 pts had a partial response (one having had prior pac); 3 pts had stable disease. Responders were on therapy between 3 and 10 mos. Conclusions: Part A is complete. Most EC and GEJ pts express tumor DKK1 and have obviated the need for evaluation of tumor DKK1+ expression as a study entry prerequisite. Combination of DKN-01+ pac is well-tolerated; the addition of DKN-01 to pac does not appear to alter the known pac safety profile. There are initial signs of enhanced clinical activity with DKN-01; further investigation is ongoing. Clinical trial information: NCT02013154. Clinical trial information: NCT02013154.
Understanding the patient experience with soft tissue sarcoma: A systematic review of the literature.
Authors: Lisa M. Hess, Randall Winnette, Steven Nicol, Datchen Fritz Tai, Kati Copley-Merriman
Journal: Journal of Clinical Oncology (2016)

61 Background: Soft tissue sarcomas (STS) are a heterogenous group of rare tumors that involve the connective tissue in the body. As with many rare tumors, little is known about the impact of STS on patient well-being. The objective of this review was to understand patient experience and quality of life (QOL) following diagnosis of STS. Methods: This was a systematic review of English language articles published between 2005-2015 in PubMed/Medline, Embase, PsychINFO, and Evidence-Based Medicine. The review included recent conference proceedings and resources from advocacy websites. Articles were considered relevant if they included adult STS patient reported outcomes (PROs) or details on patient experience. Results: Of the 3,430 articles identified, 20 were eligible for inclusion. Of these, 14 were clinical studies that included PRO measures, 1 summarized PRO measures used in STS studies, and 5 described the STS patient experience. Patients with STS report a variety of concerns including emotional well-being (e.g. anxiety, depression), body image, functional deficit following surgery, and practical considerations such as obtaining child care and ability to work. Reports of patient experience vary widely given the heterogeneity of STS and individualized treatment. In clinical studies that used PROs, the European Organization for Research and Treatment of Cancer QOL Questionnaire Core 30 (EORTC QLQ-C30) was the most commonly used cancer-specific measure (N = 5) followed by the Functional Assessment of Cancer Therapy–General (N = 2). The generic EQ-5D was used in 5 publications but was limited to the visual analog scale portion of the measure in two of these studies. Similar to other cancers, STS patients report lower QOL when compared to the general population. Conclusions: Few studies have published either qualitative or quantitative data on the patient experience with STS. While STS has a measurable impact on QOL, there is a lack of detailed information in the published literature. Although PROs are often used in clinical studies of STS, they are not STS-specific tools and may not capture the unique needs of this population. There is a need for qualitative research to better understand the patient perspective of STS.
Molecular targeting of prostate cancer with cytotoxins and radioisotopes linked to fully human monoclonal antibodies against prostate-specific membrane antigen
Authors: D. Ma, C. E. Hopf, A. D. Malewicz, D. Fisch, J. P. Gardner, G. P. Donovan, N. Schülke, W. F. Goeckeler, P. J. Maddon, W. C. Olson
Journal: Journal of Clinical Oncology (2005)

2560 Background: Prostate-specific membrane antigen (PSMA) is an attractive target for immunotherapy of prostate cancer due to its abundant expression on prostate cancer cells and its up-regulation on metastatic disease. The objectives of this study were to evaluate the ability of fully human anti-PSMA monoclonal antibodies (mAbs) to specifically deliver cytotoxic payloads to prostate cancer cells in vitro and in vivo. Methods: Using novel recombinant forms of PSMA and the XenoMouse™ technology, we previously generated a panel of fully human mAbs against PSMA. Characterization of these antibodies was conducted using Biacore, ELISA, flow cytometry, anti-PSMA Western blot and other functional assays. In this study, the therapeutic potential of radiolabeled mAbs and immunotoxins was comparatively evaluated in cell-based in vitro cytotoxicity assays and in vivo xenografted animals. Results: We demonstrated that these fully human mAbs specifically recognize conformational, dimer-specific epitopes on PSMA with subnanomolar affinity. The mAbs were modified with bifunctional chelates for radiolabeling or conjugated with potent cytotoxins. The binding of the mAbs to cell-surface PSMA was virtually unchanged following conjugation. The conjugated mAbs were internalized rapidly upon binding to PSMA on tumor cells (∼60% in 2 hours) which provides efficient delivery of cytotoxins. Immunotoxins killed PSMA-expressing tumor cells with pM potency and ∼1000-fold selectivity. In tumor-bearing animal models, mAbs radiolabeled with Lu-177, a beta-emitting isotope, selectively targeted PSMA-expressing tumors, with a high tumor uptake of 30% injected dose per gram of tumor. In an aggressive tumor model using 3T3-PSMA cells, a single 400 μCi dose of Lu-177 labeled antibody significantly delayed tumor growth and increased median survival time by 3.5-fold compared to untreated control animals (p<0.005). Additional xenograft studies have been initiated using the androgen-independent human prostate cancer cell line C4-2. Conclusions: Fully human PSMA mAbs can selectively deliver cytotoxic payloads to control prostate tumor growth in vitro and in vivo. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PSMA Development Company, LLC
A multicenter, phase II study of trastuzumab plus capecitabine and oxaliplatin (XELOX) as first-line chemotherapy for HER2-positive advanced gastric cancer: Update results of efficacy and toxicity.
Authors: Jifang Gong, Tianshu Liu, Qingxia Fan, Li Bai, Feng Bi, Shukui Qin, Jinwan Wang, Nong Xu, Ying Cheng, Yuxian Bai, Wei Liu, Liwei Wang, Lin Shen
Journal: Journal of Clinical Oncology (2014)

102 Background: The ToGA study showed trastuzumab plus chemotherapy prolonged OS in patients with HER2-positive AGC. Result of REAL2 study suggested that oxaliplatin may be as effective as cisplatin but more tolerable. To further improve treatment options, we initiated a study to evaluate the efficacy and safety of trastuzumab plus XELOX in Chinese patients with HER2-positive AGC. Methods: Simon two-stage design with primary endpoint of best confirmed response rate by RECIST 1.0 was applied. The sample size is calculated to be 46, assuming H 0 =40%, H 1 =60%, a=0.05, b =0.2. Considering 10% drop-out rate, the total number of subjects was planned to be 51. Patients with previously untreated, HER2-positive (IHC2+/Dual SISH positive, or IHC 3+), histologically confirmed adenocarcinoma of the stomach or gastro-esophageal junction were eligible. Trastuzumab was administered at a loading dose of 8 mg/kg followed by 6 mg/kg infusion every 3 weeks (q3w). Oxaliplatin was administrated as a 130mg/m 2 infusion, q3w, up to 6 cycles. Capecitabine was given orally with 2000mg/m 2 d, d1-14, q3w. Trastuzumab and capecitabine were continued until disease progression or intolerable toxicity. The NCI-CTCAE version 4.0 is used to evaluate safety profiles. Results: 72 patients (362 patients at 13 centers were screened) were HER2 positive, of which 51 patients were enrolled. The majority of patients were HER2 IHC 3+ (38/51). Response was evaluated in 46 patients, one patient achieved CR and thirty-three patients achieved PR. Till June 2013, 29 patients progressed, 14 cases died, showing PFS of 312 days (95%CI:211-360). The most common AEs that are higher than grade 3 were thrombocytopenia (21.6%), neutropenia (13.7%), anemia (7.84%), leucopenia (3.92%), nausea/vomiting (3.92%), hand-foot syndrome (3.92%). 6 patients possess LVEF decrease by ≥10% and one patient discontinued trastuzumab infusion. Conclusions: The addition of trastuzumab to XELOX was well tolerated and the results demonstrated encouraging efficacy. Survival benefit of this regimen needs further follow-up of patients to be concluded. Clinical trial information: NCT01364493.
Genetic variation in vitamin D pathway and graft-versus-host disease risk after blood and marrow transplantation.
Authors: K. Robien, L. G. Strayer, T. E. DeFor, B. Thyagarajan, D. Lazovich, S. A. Cooley, J. A. Ross, K. S. Baker
Journal: Journal of Clinical Oncology (2011)

6599 Background: Recent evidence suggests that in addition to calcium homeostasis, vitamin D has immunomodulatory activity. Thus, we hypothesized that genetic variation in the vitamin D metabolism pathway may alter risk of graft-vs-host disease (GVHD) following blood and marrow transplantation (BMT). We evaluated the associations between single nucleotide polymorphisms (SNPs) in vitamin D synthesis (CYP2R1, CYP3A4, CYP27A1, CYP27B1), transport (vitamin D binding protein), gene expression (vitamin D receptor, VDR), and catabolism (CYP24A1) and risk of acute GVHD (aGVHD, grades II-IV) to day 100 and chronic GVHD (cGVHD) to 2 years following BMT. Methods: DNA was obtained for 437 individuals who underwent an allogeneic BMT for hematologic malignancies at the University of Minnesota between 1995-2005. A total of 86 SNPs were selected for genotyping, including Hapmap tagSNPs and those documented as having functional relevance. Proportional hazard regression modeling was used to evaluate associations between SNPs and aGVHD and cGVHD, treating SNPs as continuous variables. Statistical significance was defined as p≤0.01 to minimize the likelihood of reporting false positive findings. Results: After adjustment for race, age at transplant, donor type (sibling/unrelated/cord blood), disease status (standard/high risk), conditioning regimen and GVHD prophylaxis, 5 SNPs in VDR were statistically significantly associated with increased cGVHD risk. Four of the SNPs (rs2525044, 7305032, 11168268, 987849), all located in introns, were in strong linkage disequilibrium (R2>0.8). Rs10783215, located in the 3'UTR, was associated with the highest risk of cGVHD (HR 1.4, 95% CI: 1.1-1.8, p<0.01). VDR rs11168268 was associated with aGVHD incidence (p=0.03), but did not meet the p≤0.01 criteria. Unlike two smaller previous studies, we did not observe an association between the VDR FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) and risk of aGVHD. Conclusions: While preliminary, our study suggests that VDR genetic variation may alter risk of cGVHD, but not aGVHD. Further studies are needed to confirm these findings, and should consider potential effect modification by vitamin D status.
Up-regulation of natural killer (NK) cell activating receptors and increase in NK mediated cytotoxicity using interleukin-15 in patients with newly diagnosed acute myeloid leukemia (AML)
Authors: M. J. Szczepanski, M. Czystowska, M. E. Szajnik, A. Welsh, K. A. Foon, T. L. Whiteside, M. Boyiadzis
Journal: Journal of Clinical Oncology (2008)

3076 Background: NK cell cytotoxicity is tightly controlled through a balance of signals from the functionally opposing activating and inhibitory receptors found on each cell. Interleukin-15 (IL-15) has a major role in NK cell homeostasis. IL-15 induces the differentiation of NK cells from hematopoietic progenitors, stimulates the expansion of peripheral NK cells and supports their survival. Modulation of the relative frequency and intensity of expression of the NK cell receptors by IL-15 may increase NK mediated cytotoxicity in cancer patients. Methods: We investigated the receptor repertoire and measured NK cell activity in the peripheral blood of 21 patients with newly diagnosed AML prior to any treatment and 15 normal donors. Ex-vivo effects of IL-15 on the NK cell repertoire and NK cell cytotoxicity were investigated. Results: The expression of the activating natural cytotoxicity (NCR) receptors NKp30 and NKp46 and the C-type lectin receptors NKG2D and NKG2C were significantly decreased in the AML patients compared to the NK cells of healthy donors (p<0.0001–0.03). Furthermore, NK cytotoxicity was significantly lower (p<0.0003) in the AML patients at diagnosis compared to that of healthy donors. When NK cells obtained from AML patients were cultured with IL-15, expression of the activating receptors was significantly increased compared to pre-culture levels: NKp30, 84 vs 20% p<0.001; NKp44, 71 vs 4% p<0.0001; NKp46, 83 vs 32% p<0.0002; NKG2D 87 vs 43% p<0.01; NKG2C, 58 vs 18% p<0.005. Concomitantly, cytotoxic activity of NK cells sorted from AML patients increased following IL-15 stimulation (790 vs 2211 LU, p<0.05). This IL-15 induced increase in the activity was blocked by neutralizing antibodies against the NK cell activating receptors. Conclusions: We determined that IL-15, a homeostatic NK cell cytokine, can upregulate the expression of the NK activating receptors and concomitantly increase the NK lytic activity in patients with AML. These data support the use of IL-15 as a platform for NK- based therapies for AML patients. No significant financial relationships to disclose.
Prognostic significance of ADAM17 expression in patients with gastric cancer who underwent curative gastrectomy.
Authors: Ahmet Bilici, Dincer Aydin, Dilek Yavuzer, Hatice Odabas, Ozlem Ercelep, Sinemis Yuksel, Aslihan Guven Mert, Melike Ozcelik, Mehmet Aliustaoglu
Journal: Journal of Clinical Oncology (2015)

60 Background: Tumor invasion and metastasis are complex processes, involving regulation at the molecular level of adhesive molecules, proteolitic enzymes, and cell growth and angiogenesis factors. A Disintegrin and Metalloproteinase (ADAM)17 has been indicated to be indispensable regulator of celular event from proliferation to migration.Although prognostic importance of ADAM17 expression has been investigated in several tumors, its clinical utility as a useful prognostic molecular marker remains unclearin gastric cancer.In the present study, we evaluated the expression of ADAM17 and its prognostic significance in gastric cancer patients after surgery. Methods: Prognostic significance of ADAM17 expression was analyzed by immunohistochemically in 158 patients with gastric cancer and the relationship between its expression and clinicopathological factors was also evaluated. Results: High expression of ADAM17 was detected in 81 patients(51%),while low expression was found in 77 cases (49%). There was significant correlation between gender, histology, lymph node metastasis, vascular invasion, the presence of recurrence and high ADAM17 expression. Recurrence in patients with high ADAM17 expression was significantly higher than that for patients with low ADAM17 expression(p=0.032). The median disease-free survival (DFS) time for patients with high ADAM17 expressed tumors were worse than those of patients with low ADAM17 expressed tumor (16.6 vs. 44.2 months, p=0.004).In addition, patients with low ADAM17 expression had a higher median overall survival (OS)interval than those of high ADAM17 expressed patients (49.6 vs. 26.9 months, p=0.019). Multivariate analysis indicated that the rate of ADAM17 expression was an independent prognostic factor for DFS, in addition to known important clinicopathological prognostic indicator for DFS. But its' prognostic importance could not be proved by multivariate analysis for OS. Conclusions: The potential value of ADAM17 expression as a useful molecular marker in gastric cancer progression should be evaluated comprehensively,it may predict recurrence and poor prognosis in patients with gastric cancer after curative resection.