bluuebunny/crossref_metadata_2025 huggingface dataset:
The expression level and prognostic value of PD-L1 and PD-1 in cervical carcinoma patients.
Authors: Zhang Songan , Bao Yong Xing , Huerxidan Niyazi , Liu Pan , Zhao Huarong , Gulixian Tuluwengjiang , Zhang Yang , Xiao Lei , Su Weipeng , Dilidaer Sidike , Ye Jianwei ,   Cancer Center of 1st Affliated Hospital XinJiang Medical University
Published: September 2018

e14501

Background: By testing the expression of PD-L1 in tissues and expression of PD-1 in matched blood samples in the cohort of cervical cancers patients and cervical benign disease patients, investigate the correlation between the expression level and their prognostic value. Methods: 70 tissue samples of cervical squamous cell carcinoma and 70 tissue samples of cervical benign lesion were collected respectively, and 24 cases of the cervical squamous cell carcinoma had matched peripheral blood samples, compared to 30 cases with matched peripheral blood samples in benign lesions. Immunohistochemistry was used to detect the expression of PD-L1 in the tissues. Flow cytometry was used to detect the proportion of CD4+PD-1+ and CD8+PD-1+ subsets in peripheral blood. Log-rank and COX regression were employed to analyze the survival time, clinical features and the information above. Results: There was no difference among age, marriage age, times of pregnancy, age of menarche, menopause, ethnic cultural level and occupation, except for family history of cancer. The portion of CD4+PD-1+ T cells and CD8+PD-1+ T cells in peripheral blood positively correlated with the expression of PD-L1 in tissue samples of cervical squamous cell carcinoma patients (R2 = 0.734, P = 0.000; R2 = 0.66, P = 0.000), while there were less correlation in cervical benign patients (R2 = 0.138, P = 0.043; R2 = 0.174, P = 0.022). There were significantly differences in the portion of CD8+PD-1+T cells and PD-L1+ cancer cells between cervical cancer group and cervical benign disease group (P = 0.000, P = 0.002). The portion of CD8+PD-1+ T cells correlated with the status of menopause (chi square = 7.152, P = 0.012). There was no relationship among the tumor size, differentiation, depth of invasion and PD-1 expression in peripheral blood cervical cancer group or cervical benign disease group. Conclusions: The cervical squamous cancer patients had more CD4+PD-1+ T cells in peripheral blood and PD-L1+ cells in tissues, which correlated to the grading and prognosis of the tumor.
Non-invasive, blood-based DNA and RNA profiling for cancer immunotherapy and PARP inhibitor clinical trials.
Authors: Yu Jianjun , Zhao Zhixin , Wang Amy , Cheung Tak , Du Pan , Jia Shidong
Published: September 2018

e14527

Background: The response to cancer immunotherapy (CI) and other target therapies varies widely across patients, making it difficult for physicians to select right treatment for a given patient. Studies report that patients with high PD-L1 gene expression are likely to respond to checkpoint blocking drugs, but there are still many patients whose tumor test for the PD-L1 protein are negative respond to the drugs. Recent publications show that tumor mutation burden and microsatellite instable (MSI) are good indicators of the cancer immunotherapy responses. However, as tissue biopsy remains a practical challenge in clinic due to its insufficient quantity or lack of access, non-invasive molecular test has provided a new alternative option to detect or monitor genomic alternations of tumors in clinical drug development. Methods: Based on Predicine’s Gene RADAR (RNA and DNA Single Molecule Digital Reading) technology platform, here we introduce PrediSeq-CI and PrediSeq-HRD (homologous recombination deficiency) blood tests, a non-invasive, next-generation sequencing (NGS)-based multiplex assay that enables real-time monitoring of temporal change of tumor heterogeneity and sensitive detection of genomic alterations related to cancer immunotherapy and DNA-repair homologous recombination pathways at both RNA and DNA levels. Results: Technical validation was performed to evaluate assay sensitivity, specificity and accuracy using reference samples with known genetic profiling. The panels have been further tested using tissue biopsy and plasma samples from cancer patients. Conclusions: The successful development of PrediSeq-CI and PrediSeq-HRD liquid biopsy tests offer an efficient solution to stratify and monitor cancer patients who may benefit from cancer immunotherapy as well as HRD-targeted therapeutics.
Active specific immunotherapy for lethal canine hemangiosarcoma: A model system for the treatment of angiosarcoma with curative intent.
Authors: Decker William Karl , Douglass Laurel , Halpert Matthew M , Konduri Vanaja , Chen Yunyu , Liang Dan , Levitt Jonathan M , Neal Brittany , Hudson Caleb , Hottinger Heidi , Piscoya Sindy , Wilson Nicola , DiBernardi Lisa , Stallings Shonda , Omarbekov Zharkyn , Seelhoff Lori , Ramirez Oscar , Yao Qizhi Cathy , Bhardwaj Ratan D , Ravi Vinod
Published: September 2018

e14539

Background: Angiosarcoma is a deadly malignant neoplasm of the vascular endothelium. Metastases are often present at diagnosis, and 5-year survival is only 10-30%. Though it comprises only 1% all soft tissue sarcoma diagnoses, it is a major killer among companion canines, responsible for an estimated 120,000 deaths per year in the US. The canine disease (termed HSA) closely mimics the human disease in both pathology and genetics. It frequently presents in the dog as acute hemoabdomen secondary to splenic rupture. Even if life-saving splenectomy is performed, median OS is only 48 days, and 1 year OS hovers at 0%. Given the accelerated timeline of the canine disease, the outbred dog is an ideal system in which to translate novel therapeutic approaches. Here we report an analysis of a phase I multi-site, open-label veterinary trial of chemo-immunotherapy performed on consecutively-presenting splenectomized companion canines with histopathologically-verified HSA. Methods: Subjects were administered two cycles of 20 mg/m2 (low-dose) doxorubicinand an autologous cell-therapy reported to generate durable CD8+ memory similar to that of physiologic viral infection. Vaccine was generated from mobilized peripheral blood and cryopreserved tumor antigen and was administered with type I interferon. Disease burden was monitored monthly by abdominal ultrasound, chest x-ray, and echocardiogram. Results: At the time of submission, median OS had not been reached in the per protocol population, with 75% of animals alive and healthy (NED or ongoing PR) at up to 1 year post-splenectomy (p < 0.0002). Ultrasound documented resolution of local mesenteric disease in one animal, sternal lymphadenopathy in another, and hepatic metastases in a third. In the intent-to-treat population, median OS was 109 days with 43% of animals alive and healthy at up to 1 year post-splenectomy. Conclusions: Administration of autologous cell therapy with low-dose doxorubicin is feasible, safe, and highly efficacious in the companion canines. If subjects survived long enough to begin treatment, prognosis became favorable. The results suggest that additional clinical studies in both canines and humans are warranted.
Antitumor effect of a whole tumor cell vaccine expressing human fibroblast activation protein in murine tumor models.
Authors: Chen Meihua , Lang Jin Yi , Li Tao , Wang Qifeng , Xu Guangchao , Lu Shun
Published: September 2018

e14542

Background: Immunosuppressive factors in the tumor microenvironment reduce the therapeutic efficacy of cancer vaccines; therefore, dampening the tumor immunosuppressive environment while activating antitumor immunity should be a useful approach for cancer therapy. Cancer-associated fibroblasts (CAFs) are among the most important cellular components of the tumor microenvironment and play an important role in the development and progression of tumors. Fibroblast activation protein α (FAPα) is a type II transmembrane protein specifically expressed by CAFs in most epithelial cancers. Gene sequence homology between human and murine FAPα is 90%. Heterogeneity of genes in the evolution of the formation of such nuances can be utilized to break immune tolerance, enhance immunogenicity, induce tumour cell autoimmune responses and thus inhibit tumor growth. Methods: Tumor cells were transfected with human FAPα plasmids employing the cationic lipid DOTAP. Its antitumor effects were investigated in three established tumor models. The potential immune mechanisms were investigated through adoptive immunotherapy and 51Cr release assay. The distributions of the immune cells in the tumor microenvironment were detected by immunohistochemical staining and flow cytometry. Results: Our results shown that whole tumor cell vaccine expressing human FAPα significantly inhibit tumor growth and prolong the survival of tumor bearing mice. This antitumor immune response was involved both of cellular and humoral immune responses. FAPα specific neutralizing antibodies were found in the serum of vaccinated mice and CAFs were significantly reduced within the tumors. Furthermore, this vaccine enhanced the infiltration of CD4+ T cells and CD8+ T cells, and suppressed the accumulation of immunosuppressive cells in the tumor microenvironment. Conclusions: These findings suggest that whole tumor cell vaccine expressing human FAPα inhibit tumor growth by producing FAPα specific neutralizing antibodies and CTLs, and targeting tumor cells and CAFs. These observations provide a new strategy for the clinical use of genetically modified tumor cells as cancer vaccines.
Evaluating the reversible control of an engineered CAR T cell ON-switch.
Authors: Gilbert Amy , Santoro Stephen , Tse Tiffany , Candelario-Chopra Tara , Gomes Tina , Campos Jose , Spelman Michael , Seacrest Stephaine , Coyle Scott , Rupp Levi , Emtage Peter
Published: September 2018

e14550

Background: CAR T cell therapy holds enormous promise for many cancer types but its application may be limited by serious toxicities. To lower this hurdle, our aim is to engineer tunable cell therapies. One of our approaches includes a “ON-switch” chimeric antigen receptor (Wu et al., Science 2015) that requires the administration of a small molecule acting as a dimerizing agent between one polypeptide chain containing the antigen recognition domain and half of an inducible heterodimerization system and another polypeptide chain containing the second half of the inducible heterodimerization motif, the CD3ζ chain and a costimulatory motif. Using an FDA approved small molecule drug, we evaluate the reversibility of ON-switch CAR T cells in preclinical models. Methods: First, we evaluated the proliferation, cytotoxicity and cytokine production of several ON-switch constructs in human primary T cells. Next, to address the reversibility of the ON-switch (ON→OFF→ON), we performed a series of co-culture experiments where the small molecule drug was added to tumor cells and ON-switch CAR T cells, then washed out, and then re-introduced back into the co-cultures. We compared CAR T cell mediated killing and cytokine production from the On-switch CAR T cells relative to a canonical CAR T control. Results: Our On-switch CAR T cells were shown to proliferate, secrete cytokines as well as mediate dose dependent cytotoxicity in the presence of the small molecule drug. Importantly, in the presence of antigen but in absence of the small molecule drug we did not measure any significant functional activity in our ON-switch CARs. Additonally, following the removal of the small molecule drug over a period several days we did not observe any significant CAR mediated cytotoxicity. Following the subsequent re-addition of the small molecule, we observed further CAR T cell mediated cytotoxicity against tumor cells. Conclusions: These results show that the small molecule inducible On-switch CARs maintain functional activity as well as reversibility allowing for the tunable control of a CAR T cell.
Phase I study of anti-PD1 in combination with low-dose decitabine in patients with advanced and untreated malignancies.
Authors: Wang Chunmeng , Liu Yang , Zhang Wenying , Chen Meixia , Shi Lu , Dong Liang , Li Xiang , Yang Qingming , Nie Jing , Han WeiDong
Published: September 2018

e14555

Background: Anti-PD1 have produced significant antitumor activity in multiply malignancies, however, resistance to anti-PD1 is becoming increasingly apparent in recent years. Low-dose decitabine, a classical DNA hypomethylating agent, was shown to boost effector T cell function and trigger a T cell-mediated response. This phase I study was designed to assess the safety, immunological effects and antitumor activity of this novel combination in patients with advancedanduntreated lymphomas and solid tumors. Methods: Patients were treated with decitabine (10mg/d on day 1-5) and anti-PD1 (2-3mg/kg, day 8) per 3 weeks. Modified salvage regimens (lymphoma: COP; solid tumors: platinum-based chemotherapy) were allowed to be intermittently inserted for patients with aggressive progression. Treatment continued unless disease progression or severe toxicity. Safety was assessed by CTCAEv4.0, and response by standard international criteria. The phenotype and activity of T cells were periodically measured in peripheral blood by flow cytometry. Results: Todate, 11 patients with heavily treated history and refractory bulky lesions have been enrolled, including 8 with lymphomas (7 NHL, 1 HL resistant to anti-PD1) and 3 with metastatic solid tumors (2 gastric cancers, 1 esophageal cancer) failure to anti-PD1. 5 patients (45%) experienced Grade ≥ 3 toxicities, with 1 taken off due to toxicity, and 1 died of asystole during the term of severe cytokine release syndrome (CRS). The common events of leukocytopenia and CRS were prominent features of anti-PD1 plus decitabine. 9 patients were evaluable for response, 1 HL obtained complete response, 3 NHL and 3 solid tumors achieved partial response, and 2 NHL had stable disease with nearly 20% shrinkage. The frequency of interferon-γ-producing CD8+ T cells in the total CD3+ population was largely increased after anti-PD1 plus decitabine infusion. Conclusions: Decitabine augmented the pro-inflammatory effects of anti-PD1 characterized by systemic inflammation response, and further improved antitumor activity of anti-PD1. Clinical trial information: NCT02961101. Clinical trial information: NCT02961101.
Analysis of response rate with anti-PD1/PDL1 antibodies in advanced solid tumors: A meta-analysis of randomized clinical trials (RCT).
Authors: Carretero-González Alberto , Lora David , Ghanem Ismael , Zugazagoitia Jon , Castellano Daniel , Sepúlveda Juan Manuel , Lopez-Martin Jose A. , de Velasco Guillermo , Paz-Ares Luis G.
Published: September 2018

e14576

Background: Anti-PD1/PDL1 antibodies (mAbs) have been shown to increase overall survival (OS) compared to standard of care (SOC) in solid tumors (mainly melanoma and lung cancer). Despite the efficacy in OS, a significant proportion of patients (pts) will have progressive disease (PD) as best response. Therefore, we have conducted a meta-analysis to study the rates of response comparing these novel antibodies with SOC (chemotherapy or targeted therapy). Methods: We conducted a search of the published RCT in MEDLINE and EMBASE analyzing anti-PD1/PDL1mAbs monotherapy compared to SOC. All studies used RECIST v1.1. Relative risk (RR) with 95% confidence interval (CI) of response rates between groups was estimated. Clinical heterogeneity was explored via subgroup analyses for location of primary tumor, number of previous treatment lines and selected population by PDL1 expression. Results: Eleven studies accounting for 6,396 pts were included (anti-PD1/PDL1 mAbs: 3,333 pts; SOC: 3,063 pts[2,637 pts: chemotherapy, 426 pts: targeted therapy]). Adjusted response rates were (N ,%): Complete Response (CR)(50/3035, 1.65%), Partial Response (PR)(558/3035, 18.39%), Stable Disease (SD)(585/2345, 24.95%) and PD (896/2345, 38.21%); and CR (7/2769, 0.25%), PR (241/2769, 8.70%), SD (744/2083, 35.72%) and PD (744/2083, 35.72%) with anti-PD1/PDL1 mAbs and SOC, respectively. Anti-PD1/PDL1 mAbs improved CR rate (RR 4.70) and PR rate (RR 2.38). There were no differences in the PD rate between groups (RR 1.09; table 1). Subgroup analyses showed a significant improvement in clinical benefit with anti-PD1/PDL1 mAbs for melanoma (RR 1.5; 1.42-1.91 95% CI) and pts treated in the first line setting (RR 1.57; 1.27-1.95 95%CI). Conclusions: Anti-PD1/PDL1 mAbs increase overall response rate compared to SOC without an increase in PD rate. Melanoma and pts treated in first line setting seem to have greater benefit with anti-PD1/PDL1 mAbs. [Table: see text]
Development of a diagnostic PD-L1 immunohistochemical assay for nivolumab therapy in urothelial carcinoma.
Authors: De Los Santos Rose Ann , William Josette , Hanks Debra Ann , Northrup Adam , Jaiswal Dipeshkumar , Jansson Malinka , Phillips Therese , Cleveland Rachel , Satnick Ilana , Pierce Coree , Wynne Bethany , McDonald Hendrick , Carnahan Josette , Reddy Swarnalatha Y. , Phillips Christine , Brooks Dania , Inzunza H. David , Taylor Clive R. , Novotny James , Oroudjev Emin
Published: September 2018

e14585

Background: PD-L1 IHC 28-8 pharmDx is a qualitative assay developed by Agilent Technologies for the Autostainer Link 48 platform and is based on EnVision FLEX visualization technology and monoclonal rabbit anti-PD-L1, clone 28-8 antibody. The assay has been co-developed with the immunotherapeutic agent nivolumab; initially as an aid in assessing PD-L1 expression in non-squamous non-small cell lung cancer (NSCLC) and melanoma patients. Here we describe the efforts to validate this assay for urothelial carcinoma (UC). Methods: IHC staining was performed on Autostainer Link 48 platform using an automated staining protocol stated per the assay’s instruction for use (IFU). Specimens were coverslipped and interpreted for % PD-L1 positive tumor cells. The assay was analytically validated on commercially acquired formalin-fixed, paraffin-embedded (FFPE) human UC invasive tumor specimens at ≥1% and ≥5% PD-L1 positive tumor cells expression levels. Results: A wide range of % PD-L1 positive tumor cells at all staining intensity levels have been detected. Assay in-house precision was validated for inter-operator, inter-instrument, inter-day, inter-run and intra-run as well as inter-observer and intra-observer agreement. Robustness studies evaluated the assay under multiple conditions for target retrieval pH, temperature and incubation time, slide type as well as tissue section thickness. Assay reproducibility was evaluated at three external sites by testing samples for intra-site/inter-day and inter-site agreement measures. Specimens were also evaluated by an observer at each site, with three reads for each observer to assess intra-observer and inter-observer agreement. All validation studies demonstrated agreement estimates above 85% with values for lower bound 95% confidence intervals calculated above 84%. Conclusions: Results of all conducted studies show high robustness and reproducibility of the assay on UC.
Observational study of the efficacy of nivolumab (Nivo) as 2+ line treatment and quality of life (QoL) in advanced refractory non-small cell lung cancer (NSCLC) patients: Interim analysis.
Authors: Laktionov Konstantin K , Arzumanyan Alla L , Bolotina Larisa V , Breder Valeriy Vladimirovich , Buevich Natalia N , Danilova Anastasia , Filippova Elena A , Kornietskaya Anna , Kramchaninov Mikhail M , Kushniruk Eugenia K , Latipova Dilorom Hamidovna , Lipatova Daria A , Moiseenko Fedor Vladimirovich , Nikitina Tatiana P , Orlov Sergey , Orlova Rashida , Protsenko Svetlana , Sarantseva Ksenia A , Stroyakovskiy Daniil , Ionova Tatyana I
Published: September 2018

e14593

Background: Therapy with immune checkpoint inhibitors (ICI) changed the paradigm of treatment in many solid tumors including NSCLC. Recently several ICI were approved for NSCLC second and first line. By now data on Nivo benefits/risks in NSCLC is quite limited. The aim of this study was to evaluate clinical and patient-reported outcomes on Nivo in second plus line within the expanded access program in NSCLC. We report interim analysis on response rates, safety and QoL. Methods: Adult pts with advanced refractory NSCLC received Nivo 3 mg/kg q2w. Tumor response was assessed using RECIST v. 1.1., adverse events (AEs) with NCI CTCAE v3.0. and QoL by RAND SF-36. Group comparisons were made using Wilcoxon test. Results: From July of 2015 to January of 2017, 157 pts were enrolled in 7 centers in RF. Median follow-up time was 14 weeks. Clinical characteristics: 66% – males; median age – 62 (29−80); ECOG PS 0-1/2-3 – 81%/19%; former/current smokers – 73%; non squamous NSCLC – 64%; ≥2 lines of previous systemic treatment – 51%. We observed 1.5 increase of Integral QoL index in 53% of pts at 4 weeks; significant improvement was observed for emotional functioning (33.3 vs 50.0; p < 0.05). Efficacy was evaluated in 56 pts: PR – 6/56, SD – 35/56, PD – 15/56. Clinical improvement was noticed in 36 pts. Early deaths from cancer occurred in 9 pts; early deaths not related to cancer – 2 pts. 18 pts discontinued Nivo prematurely ( < 8 weeks) because of rapid clinical worsening. 72 pts were not evaluated for response on cut-off. More pts with quick worsening as compared with responders were with non squamous NSCLC (75% vs 50%) and had brain mets (20% vs 0%). Among responders 33% were with PS > 1 and were > 65 y.o; pts in this group had no brain mets. AEs were registered in 40 pts (median of Nivo treatment – 6 weeks); among them 11 with grade 3-4 AEs. Conclusions: Early data from this study supports thata large number of pts benefits fromNivo treatment. Nivo is well tolerated by this population, with 7% of grade 3 or 4 toxicities. Nivo treatment is accompanied with significant QoL improvement in 53% pts.
Immunotherapy releated cardiomyopathy.
Authors: Sonmez Ozlem , Sever Ozlem Nuray , Oyan Basak , Demir Osman Gokhan
Published: September 2018

e14601

Background: Side effects of immunotherapies also differ from classical cytoxic chemotherapy agents such as effects. Cardiomyopathy is a relatively rare complication. Studies have shown that the risk of developing myocarditis is higher when the ipilimumab / nivolumab combination is used than when the single agent nivolumab is used. ImmunoCheckpoint inhibitors are associated with an increase in immunologic response and immunosuppressives such as corticosteroids, TNF-alpha antagonists and mycophenolate acetate are used in treatment.In this study, we aimed to report cardiac toxicity in patients who treated with immune checkpoint inhibitors. Methods: Forty patients who were treated with immunocheckpoint inhibitors were screened retrospectively at two centers in Turkey between August 2015 and January 2017 . Results: Twenty-eight of the patients were male (70%), 12 were female (30%); The median age was 61 (32-81) years. 23 (57.5%) patients received nivolumab and 16 (40 %) patients received pembrolizumab and 1(2.5%) patient received pembrolizumab/ipilimumab combination. Seven of the cases had immuno-related side effects (17.5%).In two of our patients, after the second cure of the treatment, diffuse edema and shortness of breath due to heart failure was detected. Echocardiography revealed a low ejection fraction. Methylprednisolone was started by cessation of treatment. One week after the symptoms improved rapidly and control ejection fractions normalized. One of these patients was diagnosed with malignant melanoma and the other with RCC , they using pembrolizumab and nivolumab respectively. Conclusions: In conclusion, side effects that may occur may lead to fatal outcomes, while immunotherapy, which is increasingly used in oncology practice, may result in satisfactory success in treatment. Patients and their relatives should be adequately informed about side effects caused by these agents, complaints should be carefully evaluated and treatment should be started without spending time.
Dosing immunotherapy combinations: Analysis of 3,526 patients in cancer clinical trials.
Authors: Nikanjam Mina , Patel Harsh , Kurzrock Razelle
Published: September 2018

e14620

Background: Immunotherapy combinations are used to improve outcomes in metastatic cancer, but knowledge of appropriate starting doses for novel combinations is lacking. Methods: Phase I-III adult combination clinical trials (≥1 drug was immunotherapy; anti-PD1, PDL1, or CTLA4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014-2016, ASH/ESMO 2014-2015 abstracts). The safe dose used in each combination was divided by the single agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage. Results: 84 studies (N=3,526 patients, 60 combinations) were analyzed (see Table). Eight studies had unacceptable safety: ipilimumab with cytoxan, vemurafenib, dacarbazine, dabrafenib/trametinib, or carboplatin/etoposide; nivolumab or pembrolizumab with pazopanib; and tremelimumab with sunitinib. Lowest additive dose percentages evaluated in these studies were: 160, 175, 175, 217, 300, 167, 175, and 167%; it is unclear if lower doses would have been tolerable. Combinations with ipilimumab had lower additive dose percentages. Response rates (median [interquartile range]) were higher for 3 than 2 drug combinations (53% [33%-63%] (N = 23 studies) vs. 23% [14%-39%]) (N = 60 studies) with similar rates seen for targeted, cytotoxic, or dual immunotherapy combinations. Conclusions: In 63% of studies not including ipilimumab, full doses of combinations could be given. Triplet combinations had median response rates of 53 vs. 23% for doublets (p<0.001). These findings can help inform safe starting doses for novel immunotherapy combinations in clinical trials and practice. [Table: see text]
Comparison of an FAP-targeted, CD137 activating DARPin drug candidate with a non-targeted, CD137 activating antibody in a human PBMC transplanted HT-29 mouse tumor model.
Authors: Hepp Julia , Link Alexander , Fiedler Ulrike , Reichen Christian , Metz Clara , Titz Alexander , Tosevski Ivana , Juglair Laurent , Schildknecht Patricia , Kaufmann Yvonne , Fontaine Simon , Bessey Ralph , Arany Zita , Zitt Christof , Dawson Keith M. , Steiner Daniel , Snell Dan , Levitsky Victor , Stumpp Michael T.
Published: September 2018

e14626

Background: Urelumab (BMS-663513) is a humanized monoclonal antibody binding to CD137 which, upon Fc-clustering, leads to activation of T-cells. Urelumab is currently in Phase 2 clinical development and has been reported to cause significant hepatotoxicities (around 15% Grade ≥2 ALT and AST elevation) when given as infusion every 3 weeks at doses ≥0.3 mg/kg. Currently ongoing clinical trials report decreased systemic toxicity but limited efficacy at lower doses of urelumab. We hypothesized that more effective triggering of CD137 without associated systemic toxicity may be achieved by targeting a CD137 agonistic engager without Fc to fibroblast activation protein (FAP) which is abundantly expressed in the stroma of many solid tumors. To achieve this, a targeted molecule belonging to the DARPin family of binding proteins was composed of one FAP- and two CD137-binding domains in a “beads on a string” format and tested in a mouse model with human PBMCs. Methods: Human PBMCs were used to reconstitute the immune system in NOG mice implanted subcutaneously with HT-29 human colon cancer cells. Mice were monitored for survival, body weight, and tumor size during the treatment phase of two weeks. Results: None of the mice in the control group died and no significant body weight loss was observed. Six of ten (60%) mice in the CD137 antibody group showed strong signs of graft vs. host disease and either died or reached the termination criterion of ≥20% body weight loss and were sacrificed. One of 30 (3%) mice died in the DARPin drug candidate groups but none of the animals showed body weight loss of ≥20% (p < 0.001, Log-rank test). Tumor growth inhibition was comparable for all treatment groups (around 20-30% at Day 18, p < 0.05 vs. control, Mann Whitney Test). Conclusions: This study confirms the hypothesis that systemic toxicities caused by the urelumab mode of action can be circumvented by FAP-targeting of a CD137 agonistic DARPin drug candidate while achieving comparable tumor growth inhibition. Consequently, higher clinical doses of tumor stroma-targeted agonistic DARPin drug candidates might be possible, and may result in stronger tumor growth inhibition.
Phase I study of oncolytic virus (OV) MG1 maraba/MAGE-A3 (MG1MA3), with and without transgenic MAGE-A3 adenovirus vaccine (AdMA3) in incurable advanced/metastatic MAGE-A3-expressing solid tumours: CCTG IND.214.
Authors: Jonker Derek J. , Hotte Sebastien J. , Abdul Razak Albiruni Ryan , Renouf Daniel John , Lichty Brian , Bell John C. , Powers Jean , Breitbach Caroline J , Stojdl David F , Stephenson Kyle B , Bramson Jonathan L , Hummel Jeff , Lemay Chantal G , Cutz Jean-Claude , Wells Julie , Eady Robin , Sun Xiaoqun , Tu Dongsheng , Dancey Janet
Published: September 2018

e14637

Background: OVs display oncolytic activity and boost adaptive cell immunity. MG1MA3 is a Maraba virus modified to express tumour antigen MAGE-A3. MG1MA3, both alone and after immune priming with a MAGE-A3 modified adenovirus (AdMA3) may trigger anti-tumour T-cell responses. Methods: N = 41 patients (pts) with MAGE-A3 expressing solid tumours were evaluated in 3 groups (A) Dose escalation of MG1MA3 iv d1+4, q8w (n = 9); (B) Single fixed dose AdMA3 1e10 pfu IM d1 (n = 6); (C) AdMA3 priming d(-14) followed by dose escalated MG1MA3 (d1+4, q8w) (n = 25). Arm A and C had a 3+3 design. Pre + post treatment blood and tissue biopsies were evaluated for viral and immune markers. Endpoints included MTD/MFD, RP2DL, safety, tolerability, pharmacokinetics, viral delivery and replication. Results: Dose limiting toxicities (hypoxia/dyspnea, vomiting, headache) occurred in 4 pts (2 each Arm A +C). RP2DL for arm C was AdMA3 1e10 pfu IM d(-14) then MG1MA3 1e11 pfu iv d1+4. Common treatment related toxicities on Arm C occurring hours to a few days after MG1MA3 included diarrhea, nausea, vomiting, anorexia, chills, fatigue, fever, flu-like symptoms, hypophosphatemia, headache, and hypotension. Preliminary tumour gene expression results reveal induction of pro-inflammatory genes, including chemokines (CCL2, CCL5, CX3CL1, CXCL10), acute phase response proteins (IL-6, TNF), antigen presenting cell (APC) activation markers (CD80, HLA-A, HLA-B), markers of APC and Natural Killer cell infiltration (CD56, CD68, TLR3), as well as a co-incident decrease in the suppressive cytokine TGF-β. MG1MA3 replication was observed in some pts, inferred by detection of circulating genomes on days 4, 8 and 15 after clearance of the input dose. Induction of anti-tumour immune responses (CD8 T cells and antibodies vs MAGE-A3) was demonstrated in 3 of 6 Arm C pts evaluated to date. In one patient, over 1% of circulating CD8 T cells were directed against MAGE-A3. Conclusions: AdMA3 prime followed by MG1MA3 OV boost is feasible with a defined RP2DL, and capable of inducing potent anti-tumour immune response. Alternate schedules will be evaluated. Clinical trial information: NCT02285816.
The efficacy and safety of apatinib in patients with metastatic colorectal cancer refractory to standard therapies.
Authors: Lv Wangxia , Yuan Meiqin , Yang Yunshan , Shi Zhong , Zhong Haijun
Published: September 2018

e15003

Background: Colorectal cancer is the third most frequent cancer and the fourth most frequent cause of cancer-related death worldwide.25% of patients with colorectal cancer have metastatic disease which leads a clinically significant detrimental effect on prognosis. After failure of standard treatments, regorafinib will be recommended to patients, but it has not been approved in China now. Apatinib is a novel, small-molecule tyrosine kinase inhibitor of VEGFR-2 which has shown a survival benefit in gastric cancer in a Phase III trial. This study is an initial clinical experience about the efficacy and safety of apatinib in patients with metastatic colorectal cancer refractory to standard therapies. Methods: Patients with refractory metastatic colorectal cancer received apatinib 500mg once daily. A treatment cycle was defined as 28 days (4 weeks). Response was assessed using RECIST 1.1 criteria. Toxicity was recorded using CTCAE version 4.0. Results: Between August 2015 to October 2016, seventeen patients were enrolled. One patient had PR (5.9%),twelve patients had SD (70.6%), and four had PD (23.6%). The ORR was 5.9% and DCR was 76.5%. The median PFS was 125 days (4.0months, 95%,CI = 1.1-6.9). The grade3/4 adverse events were hypertension (2/17;11.8%), proteinuria (2/17;11.8%), Hand-foot syndrome (2/17;11.8%), leukopenia(1/17;5.9%), neutropenia(1/17;5.9%), hyperbilirubinemia(1/17;5.9%), and diarrhea(1/17;5.9%),respectively.There were no treatment-related deaths. Conclusions:Apatinib is active for the treatment of refractory metastatic colorectal cancer with a manageable tolerability profile. Further investigations of apatinib in mCRC are needed.
Comparative effectiveness and safety of monoclonal antibodies (bevacizumab, cetuximab and panitumumab) in the treatment of metastatic colorectal cancer: Systematic review and metanalysis.
Authors: Silva Wania Cristina , Abreu Lima Ellias Magalhaes , Araújo Vânia Eloísa , Santos Jéssica Barreto Ribeiro , Silva Michael Ruberson Ribeiro , Acúrcio Francisco Assis , Cherchiglia Mariangela Leal , Andrade Eli Iola Gurgel
Published: September 2018

e15008

Background: Biological agents have presented variable results in the treatment of metastatic colorectal cancer. This study aim to evaluate the effectiveness and safety of the monoclonal antibodies bevacizumab, cetuximab and panitumumab associated or not to chemotherapy in this scenario. Methods: A systematic review and metanaysis was performed based on observational cohort studies published in the following databases: MEDLINE/ Pubmed, LILACS, COCHRANE Library and EMBASE, up to march 2016. The effectiveness outcomes assessed in this trial were overall survival (OS), progression free survival (PFS), pos-progression survival (PPS), response rate based on RECIST criteria and metastasectomy rate. The safety outcome assessed was adverse events. Review Manager 5.3 software was used to perform the data metanalysis and the Newcastle-Ottawa scale evaluated the methodological quality of the observational trials included. Results: 16 trials were included in this metanalysis, 11 evaluating effectiveness and 8 assessing safety. Their methodological quality were considered moderate according to the Newcastle-Ottawa Scale. Basically, this study compared bevacizumab based therapies with no bevacizumab based therapies, once there was no enough data regarding cetuximab and panitumumab. Overall, the group treated with bevacizumab based therapies did better than those in the no bevacizumab group, with OS mean difference (MD) of 4,41 (95% CI 1.75 to 7.07; p = 0.001; I² = 86%) and PFS MD of 3.19 (95% CI 0.42 to 5.96; p = 0,02 I² = 96%). The PPS MD was also statistically significant (MD = 5.90; 95% CI 2.59 to 9.21; p = 0,0005; I² = 82%). When safety was the outcome concerned, the group treated with bevacizumab had more hypertension and gastrointestinal perforation. There was no statistical difference between the groups regarding others side effects. Conclusions: This study showed a potential benefit in using bevacizumab as a part of the treatment of mCRC. Bevacizumab improved PFS, OS and PPS and these differences were statistically significant. However, the drug also increased treatment related toxicities.
Compassionate use program with FDT-TPI (trifluridine-tipiracil) in pre-treated metastatic colorectal cancer patients: Spanish real world data.
Authors: Garcia-Alfonso Pilar , Ruiz Ana , Carrato Alfredo , Vieitez Jose M , Gravalos Cristina , Pericay Carles , Benavides Manuel , Delgado Mayte , Argiles Guillem , Garcia-Carbonero Rocio
Published: September 2018

e15019

Background: Trifluridine/tipiracil (FTD-TPI) is comprised of an antineoplastic nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil. Compassionate use programs (CUPs) provide a treatment option for patients with unmet medical needs and an early opportunity to obtain data on efficacy, safety and use in a real-world setting. Methods: Patients were registered and approved to receive 2 cycles of trifluridine/tipiracil treatment, which could be renewed as necessary, we analysed baseline characteristics, safety results and exposure to the treatment with trifluridine/tipiracil (FTD-TPI) in the Spanish CUP. Results: A total 636 were registered in Spain and 538 received treatment with trifluridine/tipiracil. Median age was 64 years, of which 25% were older than 70 years old and 60% were male, 67% of pts were ECOG PS 1. Oral trifluridine/tipiracil was initiated at 35 mg/m2 bid. Most pts had received 2, 3, or ≥4 lines of prior treatment for metastatic disease (27%, 28%, and 38%, respectively); and 4% unknown. 275 (47%) patients had KRAS mutated and 209 (36%) had KRAS wild type. 35% received adjuvant chemotherapy and 20% of the patients were treated with regorafenib in previous lines. The main reasons for not initiating treatment included cancellation of request due to worsening condition and progressive disease. Treatment was generally well tolerated. A total of 173 AEs were reported in the Spanish CUP, the majority were myelosuppressive AEs; febrile neutropenia (grade ≥3) was reported in 6 pts (1.3%), grade _ > 3 neutropenia was reported in 56 (33%), grade 4 neutropenia in 16 (9%). Grade 3 anemia was reported in 8 (15% of the total AEs reported).The majority of pts 306 (56%) were allocated 3-4 cycle of treatment, 95(17.3%) 5-6 cycles, and 30(5. 5%) between 7-8 cycles. Conclusions: Thisreal-world data analysis is consistent with those reported in phase 3 trials of trifluridine/tipiracil (FDT-TP)in pretreated mCRC. The efficacy analyses of this population is planned.
The effect of bundle of warmth care for patients with advanced colorectal cancer undergoing chemotherapy on reduction of oxaliplatin-related peripheral sensory neuropathy.
Authors: Lin Jin-Xiang , Chen Zhan-hong , Chen Xiang-Wei , Fan Zu-Yan , Huang Xiu-Yan , Li Xing
Published: September 2018

e15031

Background: FOLFOX is the one of the most selected chemotherapy regimens for advanced colorectal carcinoma (aCC) patients, which includes oxaliplatin, 5-fu and leucovorin. However, oxaliplatin often causes chemotherapy-induced peripheral sensory neuropathy (CIPN) which is a common treatment-related adverse effect and affects long- term quality of life. The aim of the study is to observe the effect of warmth intervention on patients with advanced colorectal cancer undergoing chemotherapy. Methods: A total of 60 aCC patients were recruited. They were randomized into an intervention group (30 patients) and a control group (30 patients). The intervention group accepted the bundle of warmth care which included wearing cotton gloves and socks, washing hands and taking a bath with warm water, soaking hands and feet before sleep with warm water, reducing exposure to cold and avoiding cold food. The control group was treated with conventional health education which including how to reduce exposure to cold. CTCAE-4.0 was used to evaluate patient, s peripheral sensory neuropathy at baseline, 3 months, 6 months and 6 months after chemotherapy terminate. Results: At baseline, there was no peripheral sensory neuropathy in two groups. In 3 months, incidence of peripheral sensory neuropathy of intervention group and control group were 26.67%(Ⅰ:20.00%,Ⅱ:6.67%) VS 83.34% (Ⅰ:46.67%,Ⅱ:30.00%,Ⅲ:6.67%)(χ2= 22.289,p = 0.000). In 6 months, incidence of peripheral sensory neuropathy of two group were 36.67% (Ⅰ: 26.67%,Ⅱ: 10.00%) VS 93.34%(Ⅰ:46.67%,Ⅱ:30.00%,Ⅲ:16.67%) (χ2= 23.398,p = 0.000). 6 months after chemotherapy terminate, incidence of peripheral sensory nerve damage of two group were 13.33%(Ⅰ:10.00%,Ⅱ:3.33%) VS 33.34%(Ⅰ:6.67%,Ⅱ:10.00%,Ⅲ:6.67%) (χ2= 4.283,p = 0.233). Conclusions: Bundle of warmth care reduced oxaliplatin-related peripheral sensory neuropathy on patients with advanced colorectal cancer undergoing chemotherapy.
An individual patient data (IPD) meta-analysis of the impact of thrombocytosis (?plts) on overall survival (OS) whilst using an intermittent chemotherapy (iCTx) strategy in advanced colorectal cancer (aCRC).
Authors: Adams Richard , Goey Kaitlyn , Chibaudel Benoist , Koopman Miriam , Punt Cornelis J. A. , Arnold Dirk , Hinke Axel , Hegewisch-Becker Susanna , De Gramont Aimery , Labianca Roberto , Tveit Kjell Magne , Wasan Harpreet Singh , Diaz-Rubio Eduardo , Kaplan Richard S. , Maughan Tim , Brown Louise C , Fisher David ,   ARCAD Group
Published: September 2018

e15044

Background: iCTx in pts with aCRC offers potential for improvement in QoL. The COIN trial is the largest study to compare iCTx v. continuous strategies in aCRC, a pre-specified subgroup analysis of 16 baseline factors was undertaken among pts with stable or responding disease after 3 mths of first-line therapy to see if the relative treatment effect differed by subgroup. Baseline ⇡plts alone identified a group of pts with significantly worse OS when an iCTx strategy was applied. Here we seek to validate this finding in other intermittent strategy trials. Methods: Published RCTs of iCTx in aCRC were identified via literature review. Eligible trials could allow one or more re-introductions of “full” initial regimen either upon progression or after a set period of time. Outcome and platelet data were requested and collated into a central database. The COIN trial was declared the discovery dataset and other eligible trials the validating datasets. Two co-primary hypotheses were agreed based upon the COIN trial results: Hypothesis 1: In pts with baseline ⇡plts, any planned complete stop of all therapyis detrimental to OS when compared to any maintenance strategy. Hypothesis 2: In pts with baseline ⇡plts, any planned stop of oxaliplatin(Ox) therapy is detrimental to OS when compared to any equivalent strategy where Ox is maintained. Unadjusted IPD meta-analysis was performed according to a pre-specified statistical plan. Results: All trials had broadly similar inclusion criteria . Incidence of ⇡plts range 17-32%. ⇡plts was a poor prognostic marker. Combining IPD from all trials, iCTx was not detrimental to OS. Hypothesis 1 included AIO-0207, CAIRO3, COIN B, OPTIMOX 2 and GISCAD with 1622 pts, HR for interaction of ⇡plts with treatment strategy 0.97 (0.66-1.40), p = 0.78. Hypothesis 2 included TTD MACRO, NORDIC VII and OPTIMOX I, with 1268 pts, HR for interaction 1.36 (0.71-2.62), p = 0.18. Conclusions: These IPD meta-analyses do not validate COIN trial findings that showed reduced OS in pts with baseline ⇡plts who are given a planned treatment break. Sensitivity analyses will be presented, including impact of RAS mut status.
Impact of metastasectomy in the multimodality approach for BRAFV600E metastatic colorectal cancer (mCRC): The Mayo Clinic experience.
Authors: Johnson Benny , Jin Zhaohui , Truty Mark J. , Smoot Rory L. , Kendrick Michael L. , Nagorney David M. , Grothey Axel
Published: September 2018

e15045

Background: BRAF V600E mutations are present in 7% of mCRC patients (pts) and portend a poor prognosis. Data guiding initial treatment decisions are limited. This study investigates the management approach and clinical impact of utilizing metastasectomy for pts with BRAF V600E mCRC. Methods: By using prospective clinical and molecular data from Mayo Clinic, pts with BRAF V600E mCRC were analyzed for clinical characteristics, treatment and survival outcomes. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: 164 pts with BRAF V600E mCRC were identified between 6/1999-8/2015. Complete follow up data were available for 52 pts. Median age of 65 years, 61% female, ECOG PS ≤ 1, 71% of pts had right sided tumors and 28% presented with liver limited metastasis. Only 7% (4/52) received FOLFOXIRI/BEV (average of 8 cycles). Peripheral neuropathy, pending BRAF status , and prior progression on FOLFOX, were the most common reasons documented for avoiding FOLFOXIRI/BEV. FOLFOX/BEV was the most common 1st line regimen used (32% of pts). Median overall survival (mOS) for all 52 pts was 25 months (mo) with median progression free survival (PFS) of 9.3 mo, reflecting worse survival when compared to BRAF wild-type control patients treated at Mayo Clinic (249 pts, mOS: 43 mo). With median follow up of 18.3 mo, 21 pts who underwent metastasectomy had improved OS (29.1mo vs. 22.7mo, HR = 0.33; CI: 0.12-0.78; p = 0.01) and PFS (13.6mo vs. 6.2mo, HR = 0.53, CI: 0.28-0.97; p = 0.03) when compared to the non-metastasectomy cohort, respectively. In multivariate analysis, metastasectomy remained statistically significant for improved survival outcomes (HR 0.52; 95% CI 0.07-1.02; p = 0.02). Median relapse-free survival after metastasectomy was 9.7 mo (95% CI, 5.5 mo-19.5 mo). Only 2 pts remain disease free at the time of last follow up, with 1 pt without recurrent disease for greater than 2 years (28.9 mo). Conclusions: The use of multimodality therapy incorporating metastasectomy for BRAF V600E mCRC is a critical component for enhanced survival outcomes.
Characteristics of Turkish colorectal cancer patients and bevacizumab preference.
Authors: Cicin Irfan , Gumus Mahmut , Uncu Dogan , Ozkan Metin , Kilickap Saadettin , Elkiran Tamer E. , Isikdogan Abdurrahman , Karaoglu Aziz , Oksuzoglu Berna , Ozdemir Feyyaz , Turna Hande , Kara Oguz , Ozyilkan Ozgur , Guducu Merve , Erdogan Alper , Uslu Ruchan
Published: September 2018

e15055

Background: The aim of this registry was to collect demographic, diagnostic, treatment, and outcome information about Turkish patients with colorectal cancer (CRC). Methods: It was designed as a multicenter, cross-sectional, non-interventional study conducted on new and previously diagnosed CRC cases applied to 28 medical oncology outpatient clinics between 2012 and 2015. A total of 7547 male (n = 4314) and female (n = 3233) patients > 18 years were included. Results: The mean age at diagnosis was 57.7±12.4 years. There was no familial or other primary cancer history in majority of patients. 22.9% of patients (n = 1579) were diagnosed at Stage 4. In 73,7% of patients (n = 5492), tumor was left-sided. Lymphovascular invasion was determined in 34.3% of patients, 87.6% had surgery. Liver-only metastasis rate was 53.1%. KRAS was tested in 717 of 1579 mCRC patients and mutation was positive in 39.3% of cases (n = 282). BRAF and KRAS tests were performed at 3.5% (n = 83) and 49.2% (n = 1158) for first line, whereas at 5.5% (n = 54) and 63.9% (n = 630) for second line metastatic treatments, respectively. In 25,5% of stage 4 bevacizumab users, bevacizumab was used both for first and second line treatment (n = 83). In KRAS mutant stage 4 patients bevacizumab was used 67% of first line (n = 185), and 40.2% of second line treatments (n = 51). In KRAS wild stage 4 patients bevacizumab was used 46,8% of first line (n = 197), and 24,5% of second line treatments (n = 58). Conclusions: In this study we found that 22.9% of Turkish colorectal patients were diagnosed at Stage 4. 45% of stage 4 patients were tested for KRAS and mutatian rate was 39.3%. BRAF testing rate was low in Turkish centers. Bevacizumab was a preferred agent both for KRAS mutant and WT patients.