bluuebunny/crossref_metadata_2025_split huggingface dataset:
Target cell killing effects of CD20 targeting chimeric antigen receptor T cells derived from the type II anti-CD20 antibody.
Authors: Yao Yihong , Yao Xin , Zhu Shigui , Zhu Wei , Li Zhiyuan , Wang Qingxia , Zhu Lin , Ma Anyun , Li Yanfeng , Wei Yutian , Dai Chengxiang , Zhang Li , Huang Jiaqi , Liu Bizuo 
Published: September 2018

e14548 Background: Chimeric Antigen Receptor T cells (CAR-Ts) targeting CD19 have shown very promising clinical outcomes in treatment of B-cell linage hematological malignancies. However, many patients with relapsed diseases were found to have down-regulated/loss of CD19 surface expression after CD19 CAR-T therapy. To solve this issue of CD19 single-targeting escape, we explored the application of another B-cell antigen, CD20, for targeted CAR-T therapy. Methods: We constructed four CD20 targeting CARs (all with 4-1BB co-stimulatory signaling) base on single-chain variable fragments (scFV) derived from four well-studied CD20 specific antibodies: Leu16, Rituximab, Obinutuzumab, and Ofatumumab. Leu16, Rituximab, and Obinutuzumab belong to the type I anti-CD20 antibody family and appear to bind to different epitopes located on the large loop of CD20, whereas Ofatumumab is the type II anti-CD20 antibody which has been shown to interact with the hydrophobic residues on the small loop surrounding a deep binding cleft. Results: All four CAR-T cells can specifically recognized CD20 positive target cells in our pre-clinical studies. They all showed up-regulated antigen-specific cell activation and high level of IFN-g release upon CD20 stimulation, and CAR-T20-Ofatumumab cells appeared to have significantly higher cell activation and more than 2-fold increase in IFN-g release compared to the other three CAR-T20 cells with their scFVs deriving from type I anti-CD20 antibodies. CAR-T20-Ofatumumab cells also showed higher degranulation upon stimulation, and it displayed ~50% of increase in ability to kill CD20 positive cells in cytotoxicity assays. Conclusions: Our data suggested that CAR-T20-Ofatumumab has better in vitro function and appears to be a CAR superior to those derived from other three antibodies. A possible explanation for this observation is that Ofatumumab interacts with the hydrophobic residues on the small loop, which is very close to cell membrane and confers more extensive binding to the small loop with striking slow off-rate. Our results suggest that CAR-Ts targeting CD20 with the scFVs from the type II anti-CD20 antibody may have superior cell killing effects.
HVEM: A novel cosignaling molecule of major interest in melanoma.
Authors: Malissen Nausicaa , Macagno Nicolas , Granjeaud Samuel , Granier Clemence , Moutardier Vincent , Gaudy Marqueste Caroline , Habel Nadia , Mandavit Marion , Guillot Bernard , Pasero Christine , Tartour Eric , Ballotti Robert , Grob Jean Jacques , Olive Daniel 
Published: September 2018

e14591 Background: Herpes Virus Entry Mediator (HVEM) is a member of the TNF superfamily, its ligation of the immunoglobulin family member B-lymphocyte and T-lymphocyte attenuator (BTLA) activates inhibitory signaling in T-cells and could play a role in evading host anti-tumor immunity. Ectopic overexpression of HVEM is associated with poor survival in some solid tumors. Our objectives were: -to evaluate HVEM expression in melanoma (MM) -to explore potential link of its overexpression with clinical outcomes -to understand the mechanisms by which HVEM was ectopically expressed in MM, and how HVEM-BTLA may play a role in MM. Methods: HVEM expression was analyzed by IHC in formalin-fixed samples of mm metastases and was correlated with OS in 130 patients. To better understand how HVEM could interfere with prognosis, relation of HVEM with its ligand BTLA was studied in the tumor and tumor microenvironment on 15 fresh metastases by flow cytometry after tumor dissociation. Bioinformatic studies based on TCGA and CCLE data combined to targeting of candidate genes by siRNA were used to investigate HVEM regulation on MM. Results: Patients with high HVEM expression on mm cells in their metastases have a significantly (p = 0.0142) poorer overall survival than those with a low expression. TCGA transcriptomic data support these results. From the mechanistic point of view, we could show that 1-HVEM expressed at the tumor cell surface interacts with BTLA expressed by tumor-infiltrated lymphocytes. 2-HVEM expression is neither linked to the mm mutational status nor inducible by IFN 3-Genes co-regulated with HVEM are associated with an aggressive gene signature 4- HVEM strongly correlate with MITF expression, MITF binds HVEM promoter, and its downregulation by siRNA results in a decrease in HVEM expression. Conclusions: A high expression of HVEM by mm metastases seems to be a pejorative prognostic marker. HVEM-BTLA interaction is a co-signaling system similar to the PD1-PDL1 one, but seem to be constitutive rather than inducible. HVEM and its co-regulated genes may constitute a signature of aggressiveness associated to MITF. High HVEM expression on mm cells may dampen anti-tumor immune responses, making HVEM and BTLA potential new targets for “checkpoint blockade” therapy.
Measurement of PD-1, TIM-3 and LAG-3 protein in non-small cell lung carcinomas (NSCLCs) with acquired resistance to PD-1 axis blockers.
Authors: Datar Ila , Mani Nikita , Henick Brian S. , Wurtz Anna , Kaftan Edward , Herbst Roy S. , Rimm David L. , Gettinger Scott N. , Politi Katerina A. , Schalper Kurt Alex 
Published: September 2018

e14611 Background: PD-1 axis blockade induces lasting clinical responses in ~20% of patients with advanced NSCLC. However, most patients eventually develop resistance. Acquired resistance is poorly understood, but may be mediated by alternative immune suppressive pathways. Methods: Using multiplex immunofluorescence we simultaneously measured levels of DAPI, CD3 (D7AE6), PD-1 (EH33), TIM-3 (D5D5R) and LAG-3 (17B4) in 11 whole tissue sections obtained from patients with NSCLC before PD-1 axis blockade and after acquired resistance (8 cases with progression on-treatment and 3 with progression off-therapy). Markers were measured in the whole tumor area or in CD3+ T-cells using fluorescence co-localization. The association between markers and changes upon acquired resistance were studied. Results: Expression of PD-1, TIM-3 and LAG-3 was seen in all cases with membranous staining pattern and signal predominantly located in CD3+ T-cells. Levels of TIM-3 and LAG-3 in T-cells were significantly correlated (Spearman’s R = 0.65, P = 0.001), but were not associated with PD-1 (R = -0.03, P = 0.86 for TIM-3 and PD-1; and R = 0.24, P = 0.28 for LAG-3 and PD-1). Compared to pre-treatment samples, 6 cases (55%) showed significantly higher levels of PD-1 or LAG-3 on acquired resistance and 5 cases (45%) had higher TIM-3. Of these, 4 cases had higher levels of the 3 markers and were on-therapy at progression. Lower levels of PD-1, TIM-3, and LAG-3 were found on acquired resistance in 5 (45%), 6 (55%), and 4 (36%) cases, respectively. Four of these cases showed lower levels of all inhibitory receptors, 3 of which were off-therapy at progression. Only one case had no change in LAG-3 levels. Conclusions: PD-1, TIM-3 and LAG-3 were expressed in the majority of NSCLCs with signal predominantly located in T-lymphocytes. Among acquired resistance cases, higher levels of PD-1, TIM-3 and LAG-3 were associated with progression on-treatment. Lower levels of the markers were associated with progression off-therapy. Although multiple mechanisms may exist, up-regulation of alternative immune inhibitory receptors such as TIM-3 and LAG-3 could mediate acquired resistance to PD-1 axis blockers in a proportion of NSCLCs.
Cancer peptide vaccine to suppress postoperative recurrence in esophageal SCC patients with induction of antigen-specific CD8+ T cell.
Authors: Yasuda Takushi , Nishiki Kohei , Yoshida Koji , Shiraishi Osamu , Iwama Mitsuru , Kato Hiroaki , Yasuda Atsushi , Shinkai Masayuki , Chiba Yasutaka , Okuno Kiyotaka , Nakamura Yusuke 
Published: September 2018

e14635 Background: This is a following report of the exploratory phase II study of adjuvant peptide vaccine for thoracic esophageal squamous cell carcinoma (TESCC) (abstract #3087 in ASCO2016), focusing on an association of immunological responses with clinical outcomes. Three HLA-A-24-restricted epitope peptides derived from cancer-testis antigens, up-regulated lung cancer 10 (URLC10), cell division cycle associated 1 (CDCA1) and KH domain-containing protein overexpressed in cancer 1 (KOC1), were used in this study. Methods: TESCC patients who underwent neoadjuvant therapy followed by curative resection (Dec./2009 to Sep./2014) and were found LN metastasis were enrolled. One mg each of three peptides mixed with Montanide was injected to patients with HLA-A*2402 20 times in a 6-months period. No other adjuvant therapy was given until recurrence occurred. Primary endpoint is relapse-free survival (RFS). Immunological responses were examined by ELISPOT assay and immunohistochemistry (IHC). Results: 33 patients were enrolled in the vaccine group (VG) and 30 with non-HLA-A*2402 were used as controls (CG). There was no significant difference in clinical backgrounds between the two groups. 5-year RFS in the VG was 44.6% while that in the CG group was 31.6% (p = 0.207); patients who showed CD8+ CTL induction to multiple peptides tend to show better RFS rate [3/2/1 peptides = 69.0(n = 20)/46.8(n = 11)/0%(n = 2), respectively]. Five-year esophageal cancer-specific survival (ECSS) were 58.4% in the VG compared with 35.4% in the CG (p = 0.156); 90.0% (n = 11) vs. 50.0% (n = 15) and 43.8% (n = 22) vs. 24.0%(n = 15) in pN1 and pN2-3 groups, respectively. Regarding the CD8+ positivity, ECSS was improved only in the negative group (56.6% in VG vs. 26.7% in CG). Classification by T cell positivity and PD-L1 expression [type I(+/+), II(-/-), III(-/+) and IV(+/-)] showed 5-year ECSS to be 100%(n = 3), 66.4%(n = 19), 20.0%(n = 5) and 44.4%(n = 6). Conclusions: Our cancer peptide vaccines induced the antigen-specific CD8+ T cell highly and efficiently, and suppressed recurrence with the strong immune responses. Clinical trial information: UMIN000003557.
Tumor bulk as an independent marker of anti-EGFR therapeutic benefit in metastatic colorectal cancer.
Authors: Kratz Jeremy D. , LoConte Noelle K. , Lubner Sam Joseph , Mulkerin Daniel , Matkowskyj Kristina , Uboha Nataliya Volodymyrivna , Lubner Meghan G. , Kim David H. , Pickhardt Perry J. , Deming Dustin A. 
Published: September 2018

e15054 Background: Molecular testing and location of the primary tumor (right-sided (R) versus (vs) left-sided (L)) are useful in predicting the clinical benefit of the anti-epidermal growth factor receptor (EGFR) antibodies, cetuximab (cet) and panitumumab (pan), in metastatic colorectal cancer (mCRC). We hypothesized that tumor bulk might also be predictive of treatment benefit given the potential for increased intra-tumor heterogeneity and reduced penetration of antibodies into bulkier lesions. Methods: A single institution retrospective cohort of 69 patients (pts) with KRAS wild-type mCRC were identified who received either cet or pan in the late-line setting +/- chemotherapy. Metastatic sites were cataloged including independent review of CT imaging prior to initiation of anti-EGFR therapy. Disease bulk was defined categorically as single metastatic lesion with diameter measuring > 3.0 cm. Results: This cohort represents a diverse group having received varying prior lines of therapy and having assorted disease sites including mediastinal, pulmonary, hepatic, omental, and osseous lesions. When treated with anti-EGFR therapies, pts with pre-treatment metastases ≤3.0 cm in diameter had significant improvement in median progression free survival (mPFS) (6.2 months (mos)) vs pts with metastases > 3.0 cm (3.9 mos, p < 0.01). A trend towards improvement in overall survival was observed for pts with non-bulky (15.8 mos) vs bulky disease (8.6 mos, p = 0.08). A trend towards increased mPFS existed in L (5.1 mos) vs R cancers (2.5 mos, p = 0.11). In R cancers, no significant difference in mPFS was noted between bulky (2.5 mos) and non-bulky disease (2.9 mos, p = 0.53). Non-bulky L cancers had a significantly improved mPFS of 7.5 mos compared to 3.9 mos with L bulky disease (p < 0.01). Non-bulky L cancers trended towards improved overall survival of 17.0 mos compared to 9.6 mos with L bulky disease (p = 0.08). Conclusions: Despite limited small sample size, these data indicate that tumor bulk is a potential predictor of the therapeutic benefit of anti-EGFR agents in left-sided mCRCs across a heterogeneous pt population. Disease bulk deserves further evaluation in larger datasets of mCRC across targeted therapeutics.
ADXS11-001 Lm-LLO Immunotherapy, Mitomycin, 5-fluorouracil (5-FU) and Intensity-modulated radiation therapy (IMRT) for Anal Cancer.
Authors: Safran Howard , Leonard Kara Lynne , DiPetrillo Thomas A. , Klipfel Adam , Schechter Steven , Oldenburg Nicholas , Vrees Matthew , Roth Leslie , Shah Nishit , Mantripragada Kalyan C. , Rosati Kayla , Rajdev Lakshmi 
Published: September 2018

e15072 Background: Human papillomavirus (HPV) DNA is present in the majority of anal cancer. ADXS11-001 Lm-LLO immunotherapy is a live attenuated Listeria monocytogenes ( Lm) bioengineered to secrete a HPV-16-E7 fusion protein targeting HPV transformed cells. The Lmvector is phagocytosed by antigen presenting cells where it cross presents, stimulating MHC class 1 and 2 pathways resulting in specific T-cell immunity. The objective of this study was to determine the safety of ADXS11-001 with mitomycin, 5-FU and IMRT (chemoradiation therapy, CRT) and obtain preliminary data on progression free survival (PFS) in locally advanced anal cancer. Methods: Eligibility included patients (pts) with anal squamous cell cancer and stages T1N2-N3; T2( < 4 cm)N1-N3; T2(≥4cm)N0-N3, T3N0-3, T4N0-3; without evidence of metastases. Pts received standard 54 Gy IMRT with 2 cycles of mitomycin and 5-FU. ADXS11-001, 1x109colony forming units IV, was given x 1 dose before CRT then x 3 additional monthly doses after CRT. Results: The study enrolled the first pt in April 2013. Ten patients were treated (median age 62.5, range 37-71) including 5 with pelvic adenopathy. Two patients had grade 3 toxicities related to the vaccine including chills/rigors (n = 2), back pain (n = 1), hyponatremia (n = 1). All toxicities were within 24 hours of the vaccine and resolved successfully with standard care. There was no exacerbation of CRT toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment which was judged to be unlikely related to ADXS11-001and possibly related to CRT. Eight patients treated on the study had a complete response at six-month sigmoidoscopy. One additional patient who did not undergo six-month sigmoidoscopy had complete response on sigmoidoscopy performed at approximately one year. Eight of 9 patients (89%) are disease-free at a median follow-up of 34 months. Conclusions: ADXS11-001 can be safely administered with CRT for anal cancer. Promising PFS was observed in patients with locally advanced disease. Clinical trial information: NCT01671488.
HER2 overexpression and amplification in patients with colorectal cancer: a large-scale retrospective study in Chinese population.
Authors: Ni Shujuan , Peng Junjie , Huang Dan , Xu Midie , Wang Lei , Tan Cong , SUN Hui , Cai Sanjun , Sheng Weiqi 
Published: September 2018

e15099 Background: Recent studies have shown that human epidermal growth factor receptor 2 (HER2) overexpression or amplification may be a potentially predictive factor for anti-HER2 response and anti-EGFR resistance in colorectal cancer (CRC). However, the prevalence of HER2 positivity in CRC patients and its correlation with clinicopathologic features are not clear. Methods: HER2 expression was tested by immunohistochemistry (IHC) in 4,913 consecutive patients with CRC treated with surgical resection of primary tumor during 2011-2014 in our institution. The formalin-fixed, paraffin-embedded samples of the primary tumors were used. Dual color silver-enhanced in situ hybridization (DISH) was performed in all IHC 3+/2+ cases and randomly selected IHC 1+/0 cases subsequently. The scoring criteria of HER2 status in gastric cancer was used. Results: HER2 positivity was found in 160 (3.3%) out of 4,913 cases of CRC. Among them, 68 cases were IHC 3+, while 92 cases were IHC 2+ and DISH+. 157 cases (3.2%) were HER2 amplified determined by DISH, including 66 (97.1%, 66/68) IHC 3+ and 92 (35.6%, 92/258) IHC 2+ cases. None of the 50 cases of IHC 1+/0 was HER2 amplified. HER2 positivity was correlated with perineural invasion, vascular invasion, lymph node metastases, and higher TNM stage. HER2 positivity was more common in younger patients ( < 60 year old). Only one HER2 positive case had mismatch repair protein (MMR) deficiency. HER2 positivity was found not related to tumor location. Conclusions: To our knowledge, this is the largest study of HER2 status in Asian patients with CRC. HER2 overexpression or amplification of tumor cells occurred in a small number of patients with CRC. HER2 positivity was related to unfavorable prognostic factors, more common in younger patients and rare in MMR deficiency cases. The further study of molecular heterogeneity of HER2 expression or amplification in patients with CRC was ongoing.
Effect of neoadjuvant chemoradiation on the tumor microenvironment in rectal cancer.
Authors: Jani Prashant Mukesh , Renz Paul , Brem Candice , Abel Stephen , Raj Moses S. , Monga Dulabh K. , McCormick James , Silverman Jan F , Kirichenko Alexander V. , Finley Gene Grant 
Published: September 2018

e15115 Background: Chemoradiotherapy (CRT) followed by surgery is standard treatment for most rectal cancers. This creates an inflammatory reaction which recruits and enhances T-cell mediated killing. Tumors can evade destruction by expressing immune modulating proteins such as PD-L1. Inhibitors of PD-L1 can circumvent immune evasion potentially enhancing neoadjuvant treatment. We assessed CD8+ infiltrates and PD-L1 expression before and after neoadjuvant CRT. We correlated these changes with clinical and pathological endpoints. Methods: We obtained tissue from 22 patients treated with neoadjuvant CRT followed by primary surgery for rectal adenocarcinoma from 2005-2015. Patients received 5FU based chemotherapy with concurrent radiation (mean 51.2 Gy in 27 fractions). Pre- and post-CRT samples were stained with VENTANA PD-L1 (SP263) Rabbit Monoclonal Primary Antibody to quantitate PD-L1 expression. CD8 + lymphocytes were assessed over one high power field (40x objective) in the area of densest expression. Analysis of 8 patients was completed at the time of this submission. Results: 37.5% of cases had upregulated PD-L1 expression post-CRT. 62.5% maintained similar PD-L1 expression in the biopsy and resection specimen. All patients had a CD8+ infiltrate after CRT with 87.5% demonstrating an increase in CD8+ lymphocytes. Patients without increased PD-L1 expression had a trend toward improved pathologic response. Conclusions: A majority of patients had an increased inflammatory infiltrate post-CRT indicating immune activation within the tumor microenvironment. A subset of tumors had increased PD-L1 expression. This population might benefit from neoadjuvant PD-L1 inhibition, which could translate to better pathological response and clinical outcomes. We will present the results from 22 patients currently under study. [Table: see text]
Prognostic impact of MSI in stage II colon cancers: An additional translational study of the SACURA trial.
Authors: Ishikawa Toshiaki , Ishiguro Megumi , Nakatani Eiji , Uetake Hiroyuki , Ueno Hideki , Murotani Kenta , Matsui Shigeyuki , Tomita Naohiro , Shimada Yasuhiro , Takahashi Keiichi , Kotake Kenjiro , Watanabe Masahiko , Mochizuki Hidetaka , Teramukai Satoshi , Sugihara Kenichi ,   SACURA Study Group
Published: September 2018

e15155 Background: The SACURA trial is a phase III study to evaluate the superiority of 1-year adjuvant treatment with oral tegafur-uracil (UFT) to surgery alone for stage II colon cancer. Superiority of adjuvant treatment with UFT to surgery alone was not demonstrated (ASCO2016 abst#3617). In an additional translational study, we assessed microsatellite instability (MSI) status of cancer tissues and prospectively examined the association of MSI with prognosis in stage II colon cancer patients. Methods: Formalin-fixed, paraffin-embedded samples were prospectively collected from 1026 patients enrolled in the SACURA trial. MSI was evaluated using 5 markers; BAT25, BAT26, D2S123, D5S346, and D17S250. MSI-high (MSI-H) was defined as the presence of instability in more than 20% of the markers. Median follow-up time was 69.6 months. Results: MSI-H, MSI-low (MSI-L) and microsatellite-stable (MSS) was observed in 74 (7.2%), 24 (2.3%), and 928 (90.5%) samples, respectively. Patients with MSI-H was significantly frequent in female, right-sided colon cancers, > 5cm tumors, poor histological type, and elevated CEA. Relapse rate for MSI-H patients (4.1%) was significantly lower than that for MSI-L/MSS cancer (13.4%, p = 0.02). Relapse free survival (RFS) in MSI-H patients was significantly better than in MSI-L/MSS patients (hazard ratio: 0.40, 95%CI: 0.17-0.98, p = 0.045), as well as adjusted results by prognostic factors. The 5-year RFS rates in MSI-H and MSI-L/MSS patients were 92.9% and 84.1%, respectively. Although there was no statistical significance, the 5-year RFS rate in MSI-H patients was tended to be better than that in MSI-L/MSS patients in the surgery alone group (94.3% vs. 83.1%, p = 0.086) as well as in the UFT group (91.7% vs. 85.1%, p = 0.233). Conclusions: MSI was an independent prognostic factor in stage II colon cancers. By considering their favorable RFS, adjuvant chemotherapy for stage II colon cancer patients with MSI-H may be unnecessary. Clinical trial information: NCT00392899.