bluuebunny/crossref_metadata_2025_split huggingface dataset:
Augmentation of adoptive T-cell therapy for Merkel cell carcinoma with avelumab.
Authors: Paulson Kelly Garneski , Perdicchio Maurizio , Kulikauskas Rima , Wagener Felecia , Church Candice , Bui Kieu-Thu , Vandeven Natalie , Thomas Hannah , McAfee Megan , Miller Natalie , Chin Kevin M. , Su Zhen , Greenberg Philip D , Parvathaneni Upendra , Bhatia Shailender , Nghiem Paul , Chapuis Aude 
Published: September 2018

3044 Background: 80% of Merkel cell carcinomas (MCCs) are caused by Merkel cell polyomavirus (MCPyV) oncoproteins. Although absent in most cases, abundant MCPyV-specific CD8+ TIL are associated with good MCC outcomes, implying tumor susceptibility to immune attack. Indeed, anti-PD-1 axis blockade has a response rate of 32-56%. However, half of patients do not respond, suggesting a lack of adequate MCPyV-specific T cells and/or tumor evasion from MCC-related reduced HLA expression. We hypothesized the combination of adoptive transfer of MCPyV-specific T cells with HLA upregulation and PD1 axis blockade would be more effective than either approach alone. Methods: 8 adult patients with MCPyV-associated metastatic MCC without pre-existing immune deficiencies were enrolled. The safety and efficacy of ex vivo expanded MCPyV-specific T-cells plus HLA-upregulation (radiation or interferon) with (triple therapy) and without (double therapy) avelumab (mAb against PD-L1, dose 10 mg/kg IV q2weeks) were compared in 2 related phase I/II studies. Results: All 4 patients who received triple therapy (100%) are alive (median follow-up 10 months), and experienced objective responses (RECIST 1.1) with 3 of 4 sustained complete responses (CRs) at last follow-up (longest 13 mo). This compared favorably to outcomes among the 4 patients who received double therapy (3 with progression and 1 CR (25%) for 14 months before progression) and published data for avelumab monotherapy – response rate 32% and CR rate 9% in patients who had failed chemotherapy (Kaufman et al, Lancet Oncol, 2016). Grade 3-4 T cell-related adverse events were similar and anticipated in both groups, including transient lymphopenia (n = 7) and modest cytokine release syndrome lasting < 24 hours, manageable on the general ward (n = 4). No grade 3-4 toxicities were attributed to avelumab. Among patients receiving triple therapy, transferred T cells persisted, and peak frequencies correlated with rate of tumor regression. Conclusions: The combination of MCPyV-specific T cells, avelumab and HLA upregulation is safe and correlative studies suggest avelumab enhances the T cell responses to MCC. This strategy has potential for MCC treatment, and can be readily applied to other solid tumors. Clinical trial information: NCT01758458 and NCT02584829.
Anti-PD-1 monoclonal antibody combined CD3-retronectin activated T cell in heavy-treated renal cell cancer.
Authors: Zhao Lingdi , Li Wei , Yang Yonghao , Zhang Yong , Ren Xiubao , Gao Quanli 
Published: September 2018

3047 Background: Metastatic renal cell carcinoma (MRCC) has a poor prognosis after failure of multitargeted tyrosine kinase inhibitors. New immunomodulators, such as anti-programmed death (PD)-1 antibody drugs, have made progress in the treatment of MRCC, but their objective response rate is only about 25%. Therefore, it is important to enhance the response rate of anti-PD-1 therapy. Methods: Patients with MRCC were eligible if they were failed to at least one kinase inhibitors, ECOG PS 0-2. Patients received nivolumab (2mg/kg, q2w) or keytruda ( 2mg/kg, q3w), followed by CD3-retronectin activated T cell, and the total number of CD3-retronectin activated T cell each time was about 5×109/L. The primary objective was to determine the objective response rate, secondary objectives included time to symptom relief, time to efficacy, safety. Results: 8 pts were enrolled (median age 58 [31-79], male 6). Pts had received a median of 2 (1-4) prior regimens. To date there is 2 patients that the efficacy can not be evaluated. The other 6 pts got remission (3 complete remission and 3 partial remission), the median time to efficacy was 10 weeks (6-12 weeks) and the time to symptom relief was 4 weeks (3-6 weeks). There was no grade 3/4 adverse effects. family:'';font-size:12.0000pt;mso-font-kerning:1.0000pt;" > 109/L. The primary objective was to determine the objective response rate, secondary objectives included time to symptom relief, time to efficacy, safety. Conclusions: CD3-retronectin activated T cell might improve the efficacy of anti-PD-1 therapy without increasing the side effects. This combination therapy has many implications in the age of immunotherapy, and should be explored across cancer types. mily:'';font-size:12.0000pt;mso-font-kerning:1.0000pt;" > 109/L. The primary objective was to determine the objective response rate, secondary objectives included time to symptom relief, time to efficacy, safety.
Discovery of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG, for the treatment of cancer.
Authors: Liang Spencer , Levy Ofer , Ganguly Sudipto , Kotturi Maya , Vaknin Ilan , Dassa Liat , Azulay Meir , Alteber Zoya , Hansen Kyle , Chan Chris , Leung Ling , Kumar Sandeep , Levin Doron , Safyon Einav , Friedman Tal , Greenwald Shirley , Salomon Ran , Pardoll Drew M. , White Mark , Ophir Eran 
Published: September 2018

3074 Background: While inhibitors of CTLA4 and PD1 have emerged as effective cancer therapies, the majority of treated patients do not derive long term benefit. Employing our computational discovery platform, we discovered PVRIG as an immune suppressive molecule expressed on T and NK cells and identified COM701, an antibody (Ab) targeting human PVRIG that enhances T cell function and anti-tumor responses. Methods: Anti-human PVRIG Ab COM701 was identified as an antagonistic Ab that enhanced T cell function in multiple assays. Antagonistic anti-mouse PVRIG Abs and PVRIG deficient (PVRIG-/-) mice were generated and characterized using syngeneic tumor models. Results: PVRIG was induced upon T cell activation, with long term activation leading to the highest expression. PVRL2 was identified as the ligand for PVRIG, placing PVRIG in the DNAM/TIGIT immunoreceptor axis. Compared to normal adjacent tissues, PVRIG and PVRL2 were both induced in the tumor microenvironment of several human cancers. To target PVRIG for therapeutic intervention, we identified COM701, a high affinity Ab that disrupts the interaction of PVRIG with PVRL2. COM701 enhanced CD8 T cell proliferation and IFN-g production in vitro and had an additive or synergistic effect on T cell activation when further combined with an anti-PD1 or anti-TIGIT Ab. Consistent with a checkpoint function for human PVRIG, mouse PVRIG-/- T cells showed increased function compared to wild type T cells. A surrogate antagonistic anti-mPVRIG Ab reduced growth of CT26 and B16 tumors when combined with an anti-PDL1 Ab in vivo. MC38 tumors also grew slower in PVRIG-/- mice compared to wild type mice and ex vivo analysis pointed to functional differences in anti-cancer immunity. Conclusions: We demonstrated that targeting PVRIG with COM701, a high affinity antagonistic Ab, increased human T cell function. We further showed that PVRIG was induced in the tumor microenvironment and that disruption of PVRIG/PVRL2 interaction resulted in reduced tumor growth in preclinical models. These data demonstrate that PVRIG is a promising target for the treatment of cancer and provide the rationale for COM701 as a potential cancer immunotherapy.
Association of CMB305 or LV305-induced and baseline anti-NY-ESO-1 immunity with survival in recurrent cancer patients.
Authors: Pollack Seth , Lu Hailing , Somaiah Neeta , Chawla Sant P. , Morris John Charles , Do Khanh Tu , Kim Joseph W. , Block Matthew Stephen , Vignali Marissa , Rytlewski Julie , Yusko Erik , Hsu Frank J. , Bohac Gerry C. , Gnjatic Sacha , Ter Meulen Jan 
Published: September 2018

3090 Background: The correlation of immune response (IR) and clinical benefit in patients (pts) who receive active immunotherapy remains controversial. CMB305 is an active immunotherapy designed to generate and expand anti-NY-ESO-1 T cells, consisting of LV305 (a DC targeting lentiviral vector encoding NY-ESO-1) and a boost (NY-ESO-1 recombinant protein plus GLA-SE, a TLR-4 agonist). Phase 1 studies of LV305 and CMB305 evaluated the IR and survival of pts with NY-ESO-1 positive tumors. Methods: 62 pts with recurrent NY-ESO-1 expressing (by IHC) solid tumors were enrolled in 2 Phase 1 trials (31 pts each: 43 sarcomas, 12 ovarian, 4 melanomas, and 3 NSCLC). Peripheral blood was assessed pre and post therapy for anti-NY-ESO-1 T cell responses (IFNγ ELISPOT) and antibodies (Ab) (ELISA) (n = 62), TCR-β CDR3 repertoire and conserved (public) TCR (n = 28), and antigen spreading (ELISA, ELISPOT) (n = 23). Relationship between progression-free survival (PFS), overall survival (OS) and up to 15 biomarkers were analyzed by the Kaplan-Meier method. Results: Preexisting anti-NY-ESO-1 T cells and Ab were identified in 34% and 40% of pts. LV305 and CMB305 induced (de novo or increased) anti-NY-ESO-1 T-cells in 51% and 65% pts, and anti-NY-ESO-1 Ab responses in 13% and 68% pts, respectively. LV305 and CMB305 induced antigen spreading in 17% and 36% pts. TCR clonality increased after CMB305 as compared to LV305. The TCRβ-CDR3 amino acid sequences of three NY-ESO-1 specific TCR clones in a patient with a > 2-year response were fully conserved in 20/28 patients. Biomarkers showing the strongest association with OS and PFS were pre-existing anti-NY-ESO-1 T-cell response and Ab, integrated IR (T cells and antibodies), and NY-ESO-1 expression level. Presence of public TCRs was associated with longer survival, particularly in pts with high ( > 50%) NY-ESO-1 expression. Conclusions: While LV305 and CMB305 are both immunogenic, CMB305 resulted in a stronger and broader integrated IR, including antigen spreading. The three identified survival variables, preexisting and treatment-induced NY-ESO-1 IR and the presence of public TCRs, warrant validation in randomized studies of CMB305.
Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance).
Authors: Lenz Heinz-Josef , Ou Fang-Shu , Venook Alan P. , Hochster Howard S. , Niedzwiecki Donna , Goldberg Richard M. , Mayer Robert J. , Bertagnolli Monica M. , Blanke Charles David , Zemla Tyler , Qu Xueping , Innocenti Federico , Kabbarah Omar 
Published: September 2018

3511 Background: CALGB 80405 was a randomized Ph3 trial showing no OS or PFS difference in mCRC pts treated with Bevacizumab (BV) or Cetuximab (Cet) in the first line. A Nanostring platform was used to determine the CMS classification of 392 KRAS wt (codon 12 and 13) primary tumors and correlated it with OS and PFS in patients enrolled in 80405. Methods: CMS for 392 of 431tumors were defined using a custom CRC Nanostring panel (39 CMS classification not possible). Stratified Cox proportional hazard model was used to evaluate the effect of CMS classification stratified by prior radiation, prior chemotherapy, adjusting for age, sex, race, primary in place, liver met only, and sidedness. Results: We found CMS1 (14%), CMS2 (47%), CMS3 (2%), CMS4 (29%), NonConsensus (8%). Results are shown in Table 1. Patients with CMS1 who received BV had significantly longer OS than those who received Cet (HR 0.47, 95% CI [0.24, 0.92]). Patients with CMS2 who received BV tended to have shorter OS than those who received Cet (HR 1.41, CI [0.95, 2.08]). Conclusions: Our data suggest that CMS is associated with OS and PFS in first line therapy in mCRC patients. Preliminary data suggest that certain CMS may be associated with efficacy of Bev and Cet based chemotherapy. CMS classification should be explored as a stratification factor in future trials. Support: U10CA180821, U10CA180830, U10CA180882 Clinical trial information: NCT00265850. [Table: see text]
Tumor sidedness and intrinsic subtypes in patients with stage II/III colon cancer: Analysis of NSABP C-07 (NRG Oncology).
Authors: Kim S. Rim , Song Nan , Yothers Greg , Gavin Patrick , Allegra Carmen Joseph , Paik Soonmyung , Pogue-Geile Katherine L. 
Published: September 2018

3514 Background: The predictive value of tumor sidedness in colorectal cancer is currently of interest especially in metastatic setting for anti-EGFR therapy response. We tested whether intrinsic molecular subtype classification predictive of treatment benefit in stage II/III colon cancer is an independent novel marker in association with tumor sidedness. Methods: All available cases included in the NSABP/NRG C-07 trial for which we had both gene expression data and anatomical data (n=1603) were used to determine the molecular subtypes using the following classifiers; the Colorectal Cancer Assigner (CRCA), the Colon Cancer Subtypes (CCS) and the Consensus Molecular Subtypes (CMS). Frequency of tumor sidedness in each subtype and recurrence-free survival were analyzed. Results: Intrinsic subtypes were differentially distributed in right- and left-colon tumors with the exception of the stem-like or CMS4 (mesenchymal) subtype (Table 1). Sidedness was not associated with prognosis (p=0.82, HR: 1.022 [CI: 0.851-1.227]) or prediction of patients with greater benefit from oxaliplatin when combined with 5-Fu+LV (interaction p=0.484). Conclusions: Although tumor sidedness is associated with distribution of intrinsic subtypes in stage II/III colon cancer, it is not predictive of survival benefit from oxaliplatin in C-07. Support: -180868, -180822, U24-CA196067; HI13C2162; PA DOH; Sanofi-Synthelabo Clinical trial information: NCT00004931. [Table: see text]
The potential of circulating tumor DNA (ctDNA) to guide adjuvant chemotherapy decision making in locally advanced rectal cancer (LARC).
Authors: Tie Jeanne , Cohen Joshua , Wang Yuxuan , Li Lu , Kinde Isaac , Elsaleh Hany , Wong Rachel , Kosmider Suzanne , Yip Desmond , Lee Margaret , Tran Ben , Burge Matthew E. , Goldstein David , Singh Madhu Sudan , Diaz Luis A. , Tomasetti Cristian , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Gibbs Peter 
Published: September 2018

3521 Background: The optimal approach to adjuvant chemotherapy for rectal cancer is keenly debated. Routine practice and clinical guidelines vary widely. After pre-operative chemoradiation (CRT), a pathologic complete response (pCR) or nodal involvement (pN+) are prognostic markers that can guide clinical decision-making, but markers that better define the patients (pts) that are likely or unlikely to benefit from chemotherapy are urgently needed. We investigated the potential role of ctDNA as a biomarker to guide therapy. Methods: We conducted a prospective, multi-centre study in pts with LARC (T3/T4 and/or N+) planned for CRT and curative resection. Serial plasma samples were collected pre-CRT, post-CRT, and 4-10 weeks after surgery. Somatic mutations in individual pts’ tumor were identified via sequencing of 15 genes commonly mutated in colorectal cancers. We then designed personalized assays to quantify ctDNA in plasma samples. Pts received adjuvant therapy at clinician discretion. Results: 200 pts were enrolled between Apr-2012 and Dec-2015. Median age was 62 years (range 28-86), 67% were male and 159 pts had pre-CRT and post-op ctDNA samples available for analysis. Of these, 122 (77%) pts had detectable ctDNA prior to therapy. After surgery, 19 pts had detectable ctDNA and 11 of these 19 (58%) have recurred during a median follow up of 22 months. Recurrence occurred in only 12 of 140 (8.6%) with negative ctDNA (HR 12, p < 0.001). One hundred and two (64%) pts received adjuvant chemotherapy. Post-op ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy (chemo: HR 10, p < 0.001; no chemo: HR 16, p < 0.001). Thirty-four pts (21%) achieved a pCR, 43 (27%) had pN+ disease. pCR (vs non-pCR) was associated with a trend for lower recurrence risk (HR 0.31, p = 0.089) and pN+ (vs pN0) with a higher recurrence risk (HR 4.2, p < 0.001). ctDNA detection remained predictive of recurrence among pts with a pCR (HR 14, p = 0.014) or with pN+ disease (HR 11, p < 0.001). Conclusions: Post-op ctDNA analysis stratifies pts with LARC into very high and low risk groups. ctDNA analysis remains strongly predictive of recurrence among pts with both lower risk (pCR) and higher risk (pN+) disease.
Combination of nivolumab (nivo) + ipilimumab (ipi) in the treatment of patients (pts) with deficient DNA mismatch repair (dMMR)/high microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC): CheckMate 142 study.
Authors: Andre Thierry , Lonardi Sara , Wong Ka Yeung Mark , Morse Michael , McDermott Raymond S. , Hill Andrew Graham , Hendlisz Alain , Lenz Heinz-Josef , Leach Joseph W. , Moss Rebecca Anne , Cao Z. Alexander , Ledeine Jean-Marie , Chan Emily , Kopetz Scott , Overman Michael J. 
Published: September 2018

3531 Background: Nivo, a fully human anti-PD-1 mAb, provided an ORR of 31%, durable responses (median DOR not reached), and a 12-mo OS rate of 73.8% in pts with dMMR/MSI-H mCRC (Overman M, et al. 2017). Preliminary analysis of nivo + ipi, a humanized anti-CTLA-4 mAb, demonstrated manageable safety and promising efficacy in pts with dMMR/MSI-H mCRC (Overman M, et al . 2016). Here we report interim safety and efficacy of nivo + ipi in this pt population from the Checkmate 142 study (NCT02060188). Methods: Pts with dMMR/MSI-H mCRC who progressed on or were intolerant of ≥1 prior line of therapy received nivo 3 mg/kg + ipi 1 mg/kg q3w × 4 doses followed by nivo 3 mg/kg q2w until discontinuation due to disease progression or other reason. Primary endpoint was investigator-reported ORR by RECIST 1.1. Other endpoints included DOR, PFS, OS, safety, and tolerability. Results: 27 pts with dMMR/MSI-H mCRC treated with nivo + ipi received the first dose ≥6 mo prior to the database lock (DBL; Sept 2016). Of these pts, 93% received ≥2 prior lines of therapy. At the time of DBL, 44% of pts remained on treatment, and 14 pts had discontinued therapy due to disease progression (n=8) or TRAEs (n=6). ORR was 41% and disease control rate (DCR) was 78% (Table). The median time to response was 2.7 mo, and 82% of responses (9/11) were ongoing at 6 mo. The medians for DOR, PFS and OS had not been reached. Grade 3–4 TRAEs occurred in 10 pts (37%).TRAEs leading to discontinuation included acute kidney injury, increased transaminases, necrotizing myositis, sarcoidosis, dyspnea, and thrombocytopenia (1 each). No deaths were attributed to therapy. Conclusions: Initial analysis ofnivo + ipi in pts with ≥6-mo follow-up demonstrated a manageable safety profile and clinical activity characterized by a high DCR and encouraging survival benefit. This study is ongoing, and updated efficacy and biomarker analyses of ≈80 pts with ≥6-mo follow-up will be presented. Clinical trial information: NCT02060188. [Table: see text]
Velour trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity.
Authors: Wirapati Pratyaksha , Pomella Valentina , Vandenbosch Ben , Kerr Peter , Maiello Evaristo , Jeffery Grahame Mark , Curca Razvan-Ovidiu D. , Karthaus Meinolf , Bridgewater John A. , Mihailov Anca C. , Kiss Igor , Merino Sandra , McKendrick Joseph James , Saridaki Zacharenia , Sagaert Xavier JA , Tejpar Sabine 
Published: September 2018

3538 Background: Addition of (ziv)-aflibercept (A) to FOLFIRI in second-line therapy for metastatic colorectal cancer (CRC) has been shown to be beneficial in phase III VELOUR trial (NCT00561470). A follow-up study (NCT01754272) was undertaken to acquire tumor samples for biomarker analyses and identify subgroups of patients with differential treatment effects. The primary results assessing efficacy according to well-established CRC subgroups defined by RAS, BRAF status and sidedness are reported here. Methods: Tissue specimens were collected for 666 patients from 1226 ITT pts. Suitable specimens were assayed for somatic mutation using NGS targeting extended RAS and BRAF genes. NGS assays with no missing values were obtained for 482 pts. Affymetrix gene chip technology was used for whole-transcriptome profiling; sidedness was extracted from available pathological reports. Differences between subgroups were assessed by interaction analysis. Results: The treatment effects on overall survival (OS) for the 482 pts is still significant HR=0.80 (CI 0.65-0.99), and similar to the ITT (n=1226) results (HR=0.82, CI 0.71-0.93). Two established ways of defining mutations (traditional KRAS exon 2 and extended RAS using NGS) show a trend for a differential effect across mutation groups.(see table for OS). Interestingly, BRAF mutants (which are all RAS wild type) show a trend for better outcome Same is seen for PFS and RR. Sidedness did not affect efficacy (HR: 0.83 (0.63- 1.1) for left and HR: 0.83 (0.54-1.3) for right. Conclusions: None of the mutations subgroup results shows significant interaction, although the ratios of treatment HR favor RAS wild types. Similar trends were observed in published trials with bevacizumab or ramucirumab. Sanofi supported this ISS. Clinical trial information: NCT01754272. [Table: see text]
Regorafenib (REG) versus trifluridine/tipiracil (TAS-102) as salvage-line in patients with metastatic colorectal cancer refractory to standard chemotherapies (REGOTAS): A propensity score analysis from a JSCCR multicenter observational study.
Authors: Fukuoka Shota , Moriwaki Toshikazu , Taniguchi Hiroya , Takashima Atsuo , Kumekawa Yosuke , Kajiwara Takeshi , Yamazaki Kentaro , Esaki Taito , Makiyama Akitaka , Denda Tadamichi , Hatachi Yukimasa , Suto Takeshi , Sugimoto Naotoshi , Katsumata Kenji , Ishikawa Toshiaki , Kashiwada Tomomi , Oki Eiji , Yuki Satoshi , Gosho Masahiko , Shimada Yasuhiro 
Published: September 2018

3540 Background: It is unclear which drug of REG or TAS-102 should be used earlier for the patients with metastatic colorectal cancer (mCRC) who have access to both drugs. This study investigated the comparison of the efficacy between REG and TAS-102 in patients with refractory to standard chemotherapies. Methods: The clinical data of patients who were treated with REG or TAS-102 among these drugs naive mCRC patients between Jun 2014 and Sep 2015 were retrospectively delivered from 24 institutions of Japanese Society for Cancer of the Colon and Rectum (JSCCR). The primary endpoint was overall survival (OS). Propensity score (PS) was calculated with a logistic regression, in which using baseline parameters were included. Two methods, adjusted and matched analysis, to take propensity score were used. The clinical outcomes were evaluated with Kaplan-Meier method and Cox models based on PS adjustment and matching. Results: Total of 589 patients were enrolled and 550 patients (223 patients in the REG group and 327 patients in the TAS-102 group) met criteria for inclusion in the analysis. The results from PS adjusted analyses showed that OS was similar between the two groups (HR of TAS-102 to REG, 0.96; 95% confidence interval, 0.78–1.18). There were also no statistically significant differences between two groups for progression-free survival (HR 0.94) and time to ECOG Performance status≥2 (HR 1.00), expect for time to treatment failure (HR 0.81; P = 0.025). In the subgroup analysis, REG showed favorable survival compared with TAS-102 in the age of < 65 years patients and unfavorable survival in ≥65 years patients (P for interaction = 0.012). In the PS matched sample (174 patients in each group), the clinical outcomes were similar to the results of the PS adjusted analysis. Conclusions: Although REG and TAS-102 showed a similar efficacy in mCRC patients with refractory to standard chemotherapies, the choice of the drug by age might affect the survival. Supported by JSCCR. Clinical trial information: UMIN000020416