bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interrogating resistance mechanisms to PD-1 blockade therapy with CRISPR.
Authors: Torrejon Davis Yuri , Zaretsky Jesse Meir , Shin Daniel Sanghoon , Onyshchenko Mykola , Abril-Rodriguez Gabriel , Vega-Crespo Agustin , Puig-Saus Cristina , Cheung-Lau Gardenia , Long Chris , Comin-Anduix Begonya , Hu-Lieskovan Siwen , Ribas Antoni 
Published: September 2018

3077 Background: We tested the biological significance of the loss of function (LOF) mutations in JAK1 or JAK2 within the IFN-receptor-pathway and in beta-2-microglobulin (B2M), which had been found in patient biopsies with resistance to anti-PD-1 therapy. Methods: We used CRISPR/Cas9 genome editing to generate JAK1, JAK2 and B2M knockout (KO) sublines of HLA-A*02:01 MART-1 or NY-ESO-1 positive human melanoma cell lines, tested using in-vitro T cell co-culture systems and in a syngeneic mouse model (MC38) to analyze the in-vivo antitumor activity with anti-PD1 therapy. Results: The JAK2-KO cell line was insensitive to IFN-gamma induced signaling and growth arrest (p < 0.001 compared with IFN-alpha or beta), while the JAK1-KO cell line was insensitive to all three IFNs. Baseline MHC class I expression after JAK1-KO was unaffected (baseline-MFI 1230 JAK1-KO vs 1570 parental, p = 0.66), but the magnitude of change was lower upon IFN-gamma exposure compared to the parental (MFI change with IFN-gamma, 26% decrease for JAK1-KO vs 50% increase for parental). There was no difference in in-vitro cytotoxicity by NY-ESO-1-TCR transgenic T-cells against JAK1-KO-NY-ESO-1+ melanoma cells compared to the parental (78% vs 82% cytotoxicity at 10:1 E:T ratio, p NS). However, B2M-KO was resistant to killing by MART-1 specific T-cells (2% vs 96% cytotoxicity at 10:1 E:T ratio, p < 0.0001). On the other hand, in the MC38 model the significant antitumor activity of anti-PD-1 against the wild type cells was lost in both JAK2-KO and B2M-KO. The percentage of CD8+ T cells has a trend of increase with anti-PD1 compared to untreated in the MC38 wild type (p = 0.1 d12), and a trend of decrease in MC38 B2M-KO (p = 0.2 d12), but no change in JAK2-KO tumors (p = 0.7 d12). Conclusions: JAK1/2 LOF mutations result in insensitivity to IFN induced antitumor effects, but does not impair T cell recognition and cytotoxicity, while B2M LOF results in lack of antigen presentation to T cells and loss of antitumor activity. However both lead to in-vivo resistance to anti-PD-1 therapy, suggesting they do so by independent mechanisms.
Ensituximab (E) in patients (pts) with refractory metastatic colorectal cancer (mCRC): Results of a phase I/II clinical trial.
Authors: Kim Richard D. , Arlen Philip M. , Tsang Kwong Y. , Mavroukakis Sharon , Zaki Anjum , Cui Karen , Azad Nilofer Saba , Tan Benjamin R. , Poplin Elizabeth , Morse Michael , Beg Muhammad Shaalan 
Published: September 2018

3081 Background: E is an investigational, novel, chimeric monoclonal IgG1 antibody derived from an immunogenic neoantigen with sequence homology to MUC5AC that is preferentially expressed with exquisite specificity to pancreatic cancer and CRC. Its mechanism of action is via antibody-dependent cellular cytotoxicity (ADCC). The efficacy and safety of E was evaluated in a single-arm, open-label, phase 1/2 clinical trial of adult pts with refractory mCRC. Methods: Pts were selected based on > 20% expression of tumor antigen, as measured by immunohistochemistry. Based on phase 1 results, E was administered 3 mg/kg IV every 2 weeks until unacceptable toxicity or disease progression. Primary endpoint was overall survival (OS). Serum cytokine levels were analyzed at baseline, day 4, and day 15. E-mediated ADCC of CD16 genotype V/V, V/F, and F/F pt PBMCs was measured with an IN-111 release assay using the E target-expressing ASPC-1 pancreatic cancer cell line. Results: Fifty-seven and 63 pts were evaluable for OS and safety, respectively. Median OS was significantly longer than historical control: 6.8 vs 5.0 months (mo); p = 0.007; 95% CI: 5.39,8.02. Three pts were alive at end of study (21, 21, and 24 mo); 21 pts survived ≥ 12 mo. Pts had a median of 4 prior therapies (range 2-9); 25% had received regorafenib. Forty-seven pts were evaluable by RECIST, and 20 (43%) had stable disease of target lesions at end of first course (day 57). E was well tolerated, with < 2% grade 3 and no grade 4 toxicities. There were no trends in serum cytokine and chemokine levels. Analysis of 56 samples (8 V/V, 26 V/F, 17 F/F, and 5 undetermined) showed that V/V PBMCs had significantly higher E-mediated ADCC than PBMCs harboring other genotypes. No correlation between CD16 polymorphism and pt outcome was observed. Conclusions: E demonstrated excellent tolerability and encouraging OS in this heavily pretreated population. Correlative in vitro data suggest that E can mediate higher levels of ADCC activity in individuals with a V/V versus other genotypes. The lack of correlation between CD16 polymorphism and pt outcomes in this study suggests that other immune-related factors (under investigation) may impact the efficacy of E in vivo. Clinical trial information: NCT01040000.
First-in-human clinical trial with intratumoral BO-112 in solid malignancies: A novel immunotherapy based in double-stranded RNA (dsRNA).
Authors: Marquez Rodas Ivan , Rodriguez-Ruiz Maria E. , Lopez-Tarruella Sara , Perez-Gracia Jose Luis , de Miguel Enrique , Calvo Aitana , Blanco-Codesido Montserrat , Martin-Algarra Salvador , Martin Miguel , Melero Ignacio 
Published: September 2018

3082 Background: BO-112 is a double stranded synthetic RNA, formulated with the cationic carrier polyethyleneimine that preclinically improves its intracellular delivery and resistance towards nuclease degradation. In melanoma mouse models, systemic administration activates MDA-5 and NOXA, leading to anti-tumoral activity connected to a sustained and extended expression of IFN-response genes. Intratumoral (IT) delivery, seeking a safer and more focused enhancement of local and systemic antitumor effects has been tested in transplanted mouse models. The potential of its IT use as an immune-modulatory treatment, as well as its toxicity profile, is being analyzed in this first in human, proof of concept, clinical trial (NCT02828098). Methods: Four patients with malignant solid tumors and palpable cutaneous/subcutaneous or lymph node metastases >1 cm were treated with a single BO-112 dose of 0.6 mg/ml IT. Pre and post treatment biopsies from the injected metastatic lesion were obtained. Pharmacokinetics, serum cytokines and circulating immune cells were sequentially studied in pre and post treatment samples. Results: Patients did not experience relevant toxicity with the exception of a single episode of completely reversible grade 4 thrombocytopenia in one patient, attributed to the drug. BO-112 was not detectable in bloodstream following IT delivery. No changes in circulating cytokines were detected. Main immunobiological effects are summarized in the table. Conclusions: BO-112 has shown changes in tumoral immune cells in 1/4 patients, while in 3/4 induced both necrosis and changes in circulating immune cells. This ongoing trial will compile more safety data with repeated sequential administrations, escalated to higher doses of BO-112, and will thoroughly characterize its biological effects in humans with solid malignancies amenable to IT injection. Clinical trial information: NCT02828098. [Table: see text]
PEGylated human IL-10 (AM0010) in combination with pembrolizumab in anti-PD1 and CTLA-4 refractory melanoma.
Authors: Naing Aung , Wong Deborah Jean Lee , Infante Jeffrey R. , Patel Manish R. , Pant Shubham , Chmielowski Bartosz , Janku Filip , Tapia Coya , Ratti Navneet , Van Vlasselaer Peter , Brown Gail Linda , Hung Annie , Oft Martin , Diab Adi 
Published: September 2018

3084 Background: Melanoma has a high response rate to anti-PD-1 alone. More than 50% of melanoma on anti-PD-1 progress within one year. IL-10 inhibits inflammation and stimulates the cytotoxicity and proliferation of tumor infiltrating CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are induced on activated CD8 T cells, providing a mechanistic rationale for combining AM0010 and anti-PD1. AM0010 alone has established tolerability and anti-tumor activity in a phase 1 study. Objective responses were observed in 4 of 15 pts with RCC, one patient with uveal melanoma and cutaneous T cell lymphoma, each. Methods: 25 melanoma pts who had progressed on prior anti-CTLA4 and on prior anti-PD-1 containing regimen were treated with AM0010 (20mg/kg qd, SQ) and pembrolizumab (2mg/kg, q3wk IV). Patients had a median of 3.5 prior therapies (range 2-6) and a median of 2 prior immune therapies (range 1-6). Tumor responses were monitored following irRC. Immune responses were measured by analysis of serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Results: AM0010 plus pembrolizumab was well tolerated. All treatment related adverse events (TrAE) were reversible. DLTs and SAEs leading to study discontinuation were not observed. G3/4 TrAEs were observed in 11 of 25 pts and included fatigue (8) thrombocytopenia (6), anemia (4), rash (1) and hypertriglyceridemia (1). There were no objective tumor responses. 9 of 20 evaluable pts had stable disease (DCR = 45%). As of Jan. 31 2017, the mPFS was 2.0 mo. and the mOS was not reached, with a mFU of 15.5 mos (range 10.0-18.4). AM0010 plus pembrolizumab increased Th1 cytokines as well as the number and proliferation of PD1+ Lag3+ activated CD8 T cells in the blood while reducing inflammatory cytokines and TGFb. A de-novo oligoclonal expansion of T cell clones in the blood and an increase of tumor infiltrating Granzyme+ PD1+ CD8+ T cells in tumor biopsies of treated patients was observed. Conclusions: AM0010 in combination with anti-PD1 is well-tolerated in refractory melanoma pts. The clinical activity and the observed CD8+ T cell activation may suggest to study AM0010 in combination with an anti-PD-1 in melanoma patients with less prior treatments. Clinical trial information: NCT02009449.
LTX-315, an oncolytic peptide, to convert immunogenically ‘cold' tumors to ‘hot' in patients with advanced or metastatic tumours: Results from an ongoing phase I study.
Authors: Spicer James F. , Baurain Jean-Francois , Awada Ahmad , Kristeleit Rebecca Sophie , Jossang Dag Erik , Marabelle Aurelien , Loirat Delphine , Wold Hedda , Nicolaisen Berit , Rekdal Oystein , Olsen Wenche Marie , Saunders Andrew , Brunsvig Paal 
Published: September 2018

3085 Background: Intratumoral LTX-315 disintegrates cytoplasmic organelles with release of tumor antigens in preclinical models accompanied by increase in tumor-infiltrating lymphocytes (TILs). LTX-315 induced complete regression in several rodent models, with systemic immune responses. LTX-315 is strongly synergistic preclinically with immune checkpoint inhibitors (ICI). We are conducting a phase 1 trial to evaluate LTX-315 in combination therapy. Methods: Patients with advanced metastatic solid tumours received injections of LTX-315 into a single accessible tumour over 6 weeks. Additional injections could be administered thereafter every 2 weeks. Biopsies of injected lesions were taken at baseline, and on treatment. Results: 28 have been enrolled to date, median age is 58 (range 32-80) and median prior treatments 2 (range 1-14). LTX-315 monotherapy was administered at doses of 2-7mg to a median of 1.8 tumour lesions (range 1-6) for a median of 9 weeks (range 1-33). In 24 patients all LTX-315-related adverse events were CTC grade 1 or 2, most commonly local erythema, flushing, pruritis and hypotension, most resolving within minutes of injection. Related grade 3 (3 patients) or 4 (1) allergic/anaphylaxis adverse event occurred and resolved without sequelae. Best response in 44 injected lesions in 20 evaluable patients included 2 complete responses, > 50% reduction in 5 tumours, and 20 stable (injected ). Significant increases in TILs occurred in 67% (14 of 21) patients with biopsies of injected tumours available. Regression of distant non-injected tumour has been observed clinically on biopsy (abscopal effect). No irRC response in non-injected tumours has been observed in 16 evaluable patients. Stable disease (median duration 14 weeks) occurred in 50% of patients as best response (melanoma (4), sarcoma (3), breast (1)). Conclusions: This phase 1 study demonstrates that intratumoural LTX-315 has a manageable safety profile and induces increases in TILs in pre-treated patients. Partial and complete regression was seen in some injected tumours. Evaluation of LTX-315 in combination with ICIs in breast and melanoma is ongoing. Clinical trial information: NCT01986426.
FOLFOX4/XELOX in stage II–III colon cancer: Efficacy results of the Italian three or six colon adjuvant (TOSCA) trial.
Authors: Sobrero Alberto F. , Lonardi Sara , Rosati Gerardo , Di Bartolomeo Maria , Ronzoni Monica , Pella Nicoletta , Scartozzi Mario , Banzi Maria , Zampino M. Giulia , Pasini Felice , Marchetti Paolo , Cantore Maurizio , Zaniboni Alberto , Rimassa Lorenza , Ciuffreda Libero , Ferrari Daris , Zagonel Vittorina , Maiello Evaristo , Rulli Eliana , Labianca Roberto 
Published: September 2018

3501 Background: Six months of oxaliplatin-based treatment has been the standard of care as adjuvant therapy for stage III colon cancer and an accepted option for high-risk stage II. Given the cumulative neurotoxicity associated to oxaliplatin, a shorter duration of therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods: TOSCA was an open-label, phase III, multicenter, non-inferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months or 6 months of FOLFOX4/XELOX. Primary end-point was relapse-free survival. Results: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Two thirds were stage III. At the cut-off time for analysis the median time of follow-up was 62 months and 772 relapses or deaths have been observed. The RFS rate at 8 years is 75%. This analysis was done when 82% of the planned number of events was reached, with a power of 72% instead of 80%. The decision to anticipate the analysis was based on the participation to the IDEA joint collaborative analysis of studies sharing this clinical question. The Hazard Ratio of the 3months vs 6 months for relapse/death was 1.14 (95%CI 0.99-1.31, p for non inferiority = 0.253) and the confidence interval crossed the non inferiority limit of 1.20. Conclusions: TOSCA was not able to demonstrate that 3 months of oxaliplatin-based adjuvant treatment is as efficacious as 6 months. Nevertheless , because the absolute difference in RFS between the two treatment durations is small ( less than 3 % at 5 years ), the decision to complete the whole 6-month program should be individualized based on toxicity and patients’ attitude. This study is registered with ClinicalTrials.gov Registration Number: NCT00646607. It was supported by a grant from AIFA (Agenzia Italiana del Farmaco) Grant Code FARM5RWTWZ. Clinical trial information: NCT00646607.
MABp1 to improve clinical outcomes of patients with symptomatic refractory metastatic colorectal cancer patients: Per-protocol population analysis of phase III study (PT026).
Authors: Wyrwicz Lucjan , Saunders Mark P. , Andre Thierry , Sarosiek Tomasz , Nemecek Radim , Rogowski Wojciech , Leśniewski-Kmak Krzysztof , Fisher George A. , Stecher Michael , Mohanty Prasant , Simard John , Hickish Tamas 
Published: September 2018

3530 Background: Refractory metastatic colorectal cancer (mCRC) patients derive minimal benefit from further exposure to toxic agents. MABp1 is an anti-interleukin 1 alpha antibody that is shown to prolong survival (NCT01767857) and improves outcomes when assessed with a primary endpoint based on a constellation of objective and patient self-reported measures (NCT02138422) (Hickish T. et al Lancet Oncology 2017). In the latter study, clinically advanced patients were enrolled (symptomatic, ECOG 1,2), and 18% of patients progressed prior to reaching the endpoint assessments. Here we present the outcomes in per-protocol population (PP), those patients completing week 8 assessments. Methods: 309 patients randomized 2:1 to receive MABp1 versus placebo. Patients were ECOG 1-2, with mCRC refractory to chemotherapy, any degree of weight loss, and cancer-associated symptoms. The composite primary endpoint assessed the rate of patients achieving stabilization or improvement in lean body mass (LBM) and two of three symptom measures (pain, fatigue, appetite loss) from screening to the week 8 assessment. The study was designed for placebo cross-over, thus OS analysis for MABp1 vs placebo was not possible. Results: 57 patients (38 MABp1 [18%] and 19 placebo [19%]) discontinued study prior to the week 8 assessment due to disease progression, including 17 (8%) and 11 (11%) deaths in MABp1 and placebo respectively. 62% of placebo patients received MABp1 after 8 weeks. 252 patients, 40% in MABp1 (68/169) vs 23% in placebo (19/83) met the primary endpoint (p = 0.003). 139 patients were available for PP survival analysis (90 MABp1 vs 49 Placebo). Median OS of those achieving the primary endpoint was 11.7 months vs 5.7 months for those that did not (HR 0.39; p < 0.0001). Radiographic stable disease was improved (42% vs 12%; p < 0.001) and incidence of SAEs (6% vs 15%; p = 0.11) reduced in those achieving the primary endpoint. Conclusions: Achieving the primary endpoint was associated with improvement in outcomes, RECIST stabilization, SAEs and survival. Further study should confirm the effect of MABp1 on survival in this population. Clinical trial information: NCT02138422.
Neoadjuvant radiotherapy vs. surgery alone for stage II/III mid-low rectal cancer with or without high risk factors: A multicenter randomized trial.
Authors: Wang Ziqiang , Deng Xiangbing , Liu Ping , Wang Xin , Jiang Dan , Wei Mingtian , Zhang Yuanchuan , Wu Qingbin , He Wanbin , Yang Xuyang , Yang Tinghan , Wang Meng , Wu Bing , Liu Yanjun , Meng Wenjian , Qiu Meng , Zhuang Hua , Li Yunfeng , Xu Feng , Zhou Zongguang 
Published: September 2018

3537 Background: Neoadjuvant (chemo)radiotherapy (NRT) is the standard treatment for locally advanced rectal cancer (RC),which reducing local recurrence (LR) without survival benefit. There are also reports claiming similar local control achieved by surgery alone in selected patients, that raising the issue of omitting NRT in low risk patients. The aim of this study was to clarify the benefit of NRT in stage II/III RC with or without high risk factors. Methods: Eligible participants with mid-low cT3-4aN± RC were included and classified as high risk patients and low risk patients according to the clinical staging. High risk was defined as T3 tumor with extramural spread > 5mm, T4a or lymph node > 8mm. High and low risk patients were both randomized into two groups: high risk radiotherapy (HRR) or high risk surgery (HRS), low risk radiotherapy (LRR) or low risk surgery (LRS) separately. Patients in HRR and LRR received short term NRT (5*5Gy) + TME, while patients in HRS and LRS underwent surgery alone. The primary endpoint was 3-y LR. The secondary endpoints were OS, DFS, quality of surgery and safety. Results: From Jun. 2011 to Dec. 2015,401 consecutive patients were analyzed (LRS 99, LRR 97, HRS 102, HRR 103). As for primary endpoint, 3-y LR was obviously lower in low risk patients (3% vs. 9%, p = 0.026), but comparable in LRR vs. LRS (3% vs. 2%, p = 0.32) and HRR vs. HRS (11% vs. 7%, p = 0.42). Concerning secondary endpoints, low risk patients were favorable in 3-y OS (p < 0.001), DFS (p < 0.001), and distant metastasis (p = 0.001), compared to the high risk. And 3-y OS in HRR was higher than that in HRS (82% vs. 70%, p = 0.032). NRT caused 1.5% grade 3/4°radiation-related complications with a higher rate of late leakage (4.5% vs 0.0%, p = 0.004). Besides, positive CRM was higher in HRS (HRS 14.7% vs. HRR 4.9%, p = 0.017). Conclusions: Depth of extramural spread and lymph node status are favorable predictors for LR and survival. NRT may improve OS for high-risk RC. Low-risk RC has very low LR, suggesting against routine use of NRT. Relatively high LR and better OS in high risk patients justify use of NRT or NCR. Short-term radiation is safe for Asian patients, given caution be paid to more late leakage. Clinical trial information: NCT01437514.
Conditional survival analysis of stage IV colorectal cancer patients living >24 months.
Authors: Ali Nadia Dawn , Zandieh Shadi , Donohue Kristen , Chen Chunxia , Moore Dirk , Poplin Elizabeth , Carpizo Darren R. 
Published: September 2018

3566 Background: The overall survival of patients with stage IV colorectal cancer (both in unresectable and resectable settings) has been increasing over recent decades due to improvements in chemotherapy, liver surgery and other liver-directed therapies. As a result of more patients living longer, there is a need to refine prognostic information to more accurately predict survival to assist multi-disciplinary cancer management teams in treatment decisions but also for patient quality of life. Methods: We performed a retrospective analysis of all patients with stage IV colorectal cancer seen at Rutgers Cancer Institute of New Jersey between Jan 1, 2005 to March 10, 2015 by ICD-9 code (N = 318 patients). This included patients who were deemed unresectable and patients who were resected with curative intent. Our study population was patients with documented survival for > 24 months (N = 158). Variables gathered included patient demographics, disease related (primary location, KRAS status, metastasis location, interval to metastases) and treatment related (chemotherapy regimens, radiation and surgery) data. Survival curve estimates are conditional on having survived 24 months. Results: Complete data was available for 125 patients (75 were resected for cure and 50 were not). Median overall survival of resected patients was not reached. The median overall survival of non-resected patients was 75.9 months. Univariate and multivariate analysis for surgery and non-surgery groups was performed. No statistically significant covariates were found beyond surgical resectability. The conditional survival probabilities of living 1, 2 or 3 years longer after 24 months of survival are 91.7%, 71.6% and 51.6% respectively in the patients with unresectable disease, and 98.1%, 92.2% and 88.8% in patients who were able to be resected with curative intent. Conclusions: These results indicate that patients who survive 24 months with stage IV colorectal cancer have an excellent prognosis. For patients who are unresectable and survive 24 months, this study suggests that they may benefit from resection of remaining metastatic sites if feasible. For resected patients this information may propose a possible benefit from repeat metastasectomy.