bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary findings from part 1 of COMBI-i: A phase III study of anti–PD-1 antibody PDR001 combined with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma.
Authors: Dummer Reinhard , Arance Fernández Ana María , Hansson Johan , Larkin James M. G. , Long Georgina V. , Gasal Eduard , Kaper Mathilde , Upalawanna Allison , Mookerjee Bijoyesh , Atkinson Victoria 
Published: February 2018

189 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with advanced BRAF V600–mutant melanoma; however, many still progress and die from this disease. Thus, new treatment strategies are needed. BRAF and MEK inhibitor combinations (eg, D+T) may reverse immunosuppressive phenotypes induced by oncogenic BRAF and improve sensitivity to checkpoint inhibitors by enhancing HLA and melanocytic antigen expression and tumor antigen–specific T-lymphocyte recognition. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating the anti–PD-1 antibody PDR001 in combination with D+T in treatment-naive pts with BRAF V600–mutant unresectable or metastatic melanoma in 3 parts: 1, safety run-in; 2, biomarker cohort; and 3, randomized, double-blind, placebo-controlled part. Here we report preliminary findings for 9 pts in part 1 dosed with PDR001 400 mg Q4W + D 150 mg BID + T 2 mg QD. Response was assessed at wk 12 and Q8W thereafter. Results: At data cutoff (16 Jul 2017; median follow-up, 2.7 mo), all 9 pts completed the 8-wk dose-limiting toxicity (DLT) period, during which 1 DLT (transaminitis [AST and ALT > 8 × ULN]; n = 1) occurred. Adverse events (AEs) of any grade occurring in > 3 pts included pyrexia (n = 9), headache (n = 6), chills (n = 4), and vomiting (n = 4). Grade 3/4 AEs reported in > 1 pt included hepatitis (n = 3), increased lipase (n = 2), and increased transaminases (n = 2). AEs leading to discontinuation occurred in 2 pts (22%; transaminitis, n = 1; grade 3 hepatitis, n = 1) who permanently discontinued PDR001 but were still receiving D+T at the data cutoff. All 9 pts responded: 3 (33%) achieved a complete response (confirmed, n = 1), and 6 (67%) had partial responses (confirmed, n = 1). Additional safety and efficacy results for these 9 pts, all ongoing at the data cutoff, will be presented. Conclusions: These preliminary results indicate that PDR001 can be combined with D+T with a manageable safety profile and demonstrate promising activity in pts with BRAF V600–mutant melanoma. Clinical trial information: NCT02967692.
Effect of CTLA-4 overexpression on response to ipilimumab in melanoma.
Authors: Nesline Mary , Puzanov Igor , Ernstoff Marc S. , Pabla Sarabjot , Conroy Jeffrey M. , Glenn Sean T. , Papanicolau-Sengos Antonios , Burgher Blake , Giamo Vincent , Andreas Jonathan , Qin Maochun , Lenzo Felicia L. , Gardner Mark , Morrison Carl 
Published: February 2018

190 Background: CD8 positive tumor infiltrating lymphocytes (TILS) are highly associated with immune response and prognosis, and are also under investigation as a marker of response to checkpoint inhibitors. Given lack of predictive biomarkers for ipilimumab, growing number of trials for new indications for combination ipilimumab + nivolumab, and evidence to support therapeutic target overexpression as markers of response, we examined the role of CTLA-4 expression and TILS in response to ipilimumab and combination ipilimumab + nivolumab in melanoma. Methods: Formalin-fixed paraffin embedded melanoma samples taken prior to treatment by ipilimumab (n = 36) or combination ipilimumab + nivolumab (n = 10) were evaluated by a comprehensive immune gene expression profile to establish the relationship between CTLA-4 and CD8 and therapeutic response (RECIST v1.1). Results: Increased CTLA-4 expression was moderately associated with increased TILS (r2= .41, p = .004). This was observed in the monotherapy group (r2= .38, p = .02), and was higher in the smaller combination therapy group, though not statistically significant (r2= .59, p = .06). Higher levels of TILS were observed in responders who achieved clinical benefit from either regimen within 6 months (n = 20). No significant difference was observed between responders (M = 57.1, SD = 30.2) and nonresponders (M = 48.6, SD = 32.9); t(44) = -.895, p = .376. Lower levels of CTLA-4 were observed in responders who achieved clinical benefit from either regimen within 6 months. No significant difference was observed between responders (M = 54, SD = 35) and nonresponders (M = 38.7, SD = 26.8); t(44) = 1.70, p = .09. The ratio of TILS to CTLA-4 expression was higher in responders who achieved clinical benefit within 6 months (n = 20).No significant difference was observed between responders (M = 5.2, SD = 14.0) and nonresponders (M = 1.4, SD = 2.7); t(41) = -1.2, p = .212. Conclusions: While not statistically significant, CTLA-4 expression in melanoma patients treated with either ipilimumab or combination ipilimumab + nivolumab was lower in responders compared to nonresponders. This analysis does not support the concept that over-expression of CTLA-4 is a biomarker of response to anti-CTLA-4 therapy.
Development of gene expression signatures characterizing the tumor-immune interaction.
Authors: Danaher Patrick , Warren Sarah , Cesano Alessandra 
Published: February 2018

205 Background: The efficacy of anti-tumor immunity depends on diverse factors, including not just abundance of immune cell populations but also activities of those populations and of tumor cells. Many of these processes are onerous to assay, but all are reflected in a tumor’s gene expression profile. Using a novel method, we develop gene expression signatures measuring a variety of biological processes underlying the tumor-immune interaction. These signatures fall into categories including antigen availability, structural barriers to immune infiltration, inhibitory signaling by both immune and tumor cells, inhibitory metabolism, pro-immune signaling, killing of tumor cells, tumor receptiveness to immune signaling, and tumor proliferation and death. Methods: We develop a method to train signatures of biological processed by synthesizing biological knowledge and large gene expression datasets. For a given process, we use literature searches and expert knowledge to derive lists of candidate genes. We then evaluate the co-expression of these candidate genes in data from The Cancer Genome Atlas (TCGA), discarding genes whose co-expression patterns are incompatible with their measuring their putative biological process. This approach safeguards the interpretability of our signatures: we only report signatures whose genes show evidence for measuring the desired biology. Finally, we further exploit co-expression patterns to obtain optimal weights for each signature gene. Results: We attempted to train signatures of over 30 biological processes involved in immune oncology. Of these, 17 candidate gene sets displayed sufficient evidence for measuring their putative biology. We show these signatures provide granular but intelligible descriptions of both immunotherapy datasets and single samples. We find they improve power in differential expression analyses and in training of predictors of drug response. Conclusions: The signatures we derive convert gene expression data into measurements of biological processes central to immune oncology, and they improve statistical power and interpretation of results in immunotherapy studies. Our training procedure ensures these signatures measure their intended biology.
A phase 1 study of p53MVA vaccine in combination with pembrolizumab.
Authors: Chung Vincent M. , Kos Ferdynand , Hardwick Nicola , Yuan Yuan , Chao Joseph , Li Mengsha , Zurcher Kathryn , Frankel Paul Henry , Li Daneng , Waisman James Ross , Diamond Don J. 
Published: February 2018

206 Background: Mutations in the p53 gene are present in a majority of solid tumors, resulting in the accumulation of oncogenic and potentially immunogenic p53 protein within tumor cells. We have developed a genetically engineered Modified Vaccinia Ankara (MVA) virus to express wild type p53 transgene (p53MVA) as an immunotherapeutic strategy. We observed robust p53-specific CD8+ T cell responses which were further enhanced by anti-PD-1 treatment. This phase 1 study evaluates the safety and tolerability of the p53MVA vaccine in combination with pembrolizumab. Methods: Patients with non-small cell lung, head and neck squamous cell (HNSCC), hepatocellular (HCC), renal cell, melanoma, bladder, soft tissue sarcoma, triple-negative breast (TNBC), pancreatic (PDAC) and MSI high colorectal cancer failing or intolerant to standard treatment were eligible. Confirmation of p53 involvement by immunohistochemistry or mutational analysis was required for eligibility. A 3-at-risk rolling design was employed and patients received 5.6 x 108 pfu p53MVA for 3 doses in combination with 200 mg pembrolizumab for 7 doses every 3 weeks. Blood draws for immunological monitoring were obtained pre-treatment and up to week 19. Results: Two patients (TNBC and HNSCC) showed clinical benefit associated with durable p53-specific CD8+ T cell responses with gene expression pathway scores of T cell function and associated immune response categories elevated for more than 6 months. The TNBC patient had complete regression of cutaneous metastases and stable disease for > 6 months. Two patients (TNBC and PDAC) were on study for 35 and 9 weeks respectively; however, p53-specific T cells were not generated. Four patients (HCC, PDAC and 2 with TNBC) had rapidly progressive disease. Conclusions: Targeting p53 antigen associated with cancer using a viral vaccine p53MVA in combination with PD-1 blockade represents a novel immunotherapeutic approach capable of stimulating systemic immune responses and associated clinical benefit. Clinical trial information: NCT02432963.
Radiation therapy and immune-related side effects in patients treated with PD-1 inhibitors.
Authors: Abdallah Nadine , Patel Suketu Nagin , Nagasaka Misako , Kim Seongho , Kim Harold E. , Sukari Ammar 
Published: February 2018

207 Background: Checkpoint inhibitors exert their antitumor effects by producing a heightened immune state, and inadvertently give rise to immune-mediated toxicities, including pneumonitis and hypothyroidism. We investigated whether these side effects were more common in patients who were treated with both PD-1 inhibitors and radiation. Methods: Our institution’s pharmacy database was used to collect data on patients who received ≥ 1 dose of PD-1 inhibitors, with or without radiation before August 31, 2016. Adverse effects of hypothyroidism, and pneumonitis were recorded and graded based on CTCAEv4. A logistic regression analysis was performed between radiation and hypothyroidism among patients with Hodgkin’s lymphoma (HL) and head and neck squamous cell carcinoma (HNSCC) and between radiation therapy (RT) and pneumonitis in lung cancer patients. Results: 231 patients received at least one dose of PD-1 inhibitors prior to data cut-off. Median age was 65 (24-92). There were 125 patients (54%) with lung cancer, 18 (8%) with HL and 9 (4%) with HNSCC. 115 patients received radiation. HL and HNSCC patients had higher odds to experience hypothyroidism (adjusted p = 0.023) but this did not seem to be due to RT exposure [HR:0.156, 95% CI 0.008-1.122, p = 0.110]. Lung cancer patients with thoracic radiation had higher odds to experience pneumonitis [HR:2.206, 95% CI 0.451-15.931] although this was not statistically significant (p = 0.358). Conclusions: There was no association between RT and hypothyroidism. Our results suggested a possible increased risk of pneumonitis with thoracic radiation among lung cancer patients treated with PD-1 inhibitors, although statistically insignificant. Larger prospective studies are needed to further delineate this effect.
Cancer immunotherapy using trabectedin and nivolumab in advanced soft tissue sarcoma: A retrospective analysis.
Authors: Gordon Erlinda Maria , Sankhala Kamalesh Kumar , Stumpf Nathan , Ravicz Joshua , Arasheben Suzan , Leong Bryan , Kang Grace , Kim Seth , Tseng William W. , Chawla Sant P 
Published: February 2018

40 Background: To restore innate tumor surveillance that is lost in cancer patients, a tumoricidal agent may have synergistic activity with an immune checkpoint inhibitor. Herein, we report on a retrospective analysis of our clinical experience using trabectedin, an alkylating agent, and nivolumab, a PD-1 inhibitor in advanced soft tissue sarcoma. Methods: Twenty previously treated STS patients received trabectedin (1.5 mg/m2 continuous intravenous infusion, CIV, for 24 hours) every 3 weeks, and nivolumab (3 mg/kg IV over 30 minutes) every 2 weeks. Safety/toxicity was analyzed using the NIH/NCI CTCAE v.4.03. Tumor responses were assessed by RECIST v1.1 and immune-related response criteria (irRECIST). Results: Histologic subtypes in 20 patients include undifferentiated pleomorphic sarcoma (UPS; n = 7), leiomyosarcoma (n = 5), synovial sarcoma (n = 2), myxoid liposarcoma (n = 4) and chondrosarcoma (n = 2). All patients had metastatic disease and a median of 4 lines of prior chemotherapy. Safety analysis (n = 20): Grade 3 treatment emergent adverse events include anemia (n = 2), fatigue (n = 1), decreased platelet count (n = 1), decreased granulocyte count (n = 1) and increased creatine kinase (n = 1). Efficacy analysis (n = 17): Seventeen patients were followed for at least 6 months and their results are reported here. There were 4 partial responses (UPS = 1, myxoid liposarcoma = 1, chondrosarcoma = 1, leiomyosarcoma = 1), 7 stable disease, and 6 progressive disease, with best overall response rate of 23.5%, median progression free survival (PFS) of > 11.6 months (range: 2.3- > 16.9 months), median overall survival (OS) of > 14.2 months (4.5- > 24.0 months), 6 month PFS rate of 64.7%, and 6 month OS rate of 94.1%. In a Phase 3 study, the median PFS was 4.2 months using trabectedin alone (Demetri et al., 2015). Conclusions: Taken together, the data suggest that paired administration of trabectedin and nivolumab is safe, and that this chemo-/immuno-therapy approach has synergistic activity.
The outcome of checkpoint inhibitor therapy in patients with cancer and solid organ transplant: A systematic review of the literature.
Authors: Hassan Noha Abdelwahab , Abudayyeh Ala , Shah Mohsin , Johnson Daniel Hartman , Suarez-Almazor Maria E. , Diab Adi 
Published: February 2018

41 Background: Solid organ transplant recipients have been excluded from Checkpoint inhibitors (CPI) clinical trials because of the concern of allo-immunity and possible organ rejection. Methods: We searched 5 databases through September 2017. Studies describing the use of CPI to treat cancer in solid organ transplant Patients (pts), and provided detailed description of each case were included. Results: Sixteen publications met inclusion criteria, reporting on 19 cases. Median age of pts was 59 (14-77) yrs and 74% were male. Cancer types included melanoma (n=11), cutaneous squamous cell carcinoma (ca) (n=3), non-small cell lung ca and hepatocellular ca (n=2 each), and duodenal ca (n=1). Median time to start CPI after organ transplant was 11 (1-25) yrs. Nivolumab (nivo) was used in 53%, ipilimumab (ipi) in 26%, and pembrolizumab (pem) in 21%. Most pts were maintained on low dose prednisone (≤ 10 mg), mTOR inhibitors, and other immunosuppressives prior to initiating CPI. Graft rejection occurred in 10 of 19 pts (7/12 kidney, 2/5 liver, and 1/2 heart transplants), 90% after receiving anti PD-1, and CPI was discontinued. Median time to rejection was 21 (5-60) days, and obtained biopsies were suggestive of a T-cell mediated rejection process. Only a cardiac transplant recipient with a bioposy proven cellular rejection after nivo, had improved ejection fraction after pulse steroids. Aside from rejection no other immune related adverse events (irAEs) reported. Nivo re-challenge was recommended for a kidney recipient 12 weeks after the rejection process, and the pt had partial tumor response but remained on hemodialysis. Of the 9 pts who had no rejection, 4 had irAEs (hepatitis, colitis, pneumonitis, and dermatitis), including 3 who required high-dose steroids with subsequent improvement, and the remaining 5 pts did not experience any irAEs. Clinical benefit rate was 57% of all pts. Two pts with liver transplants died within 1 month of nivo treatment secondary to acute liver rejection, and 2 others died because of progressive cancer. Conclusions: CPI seem to be associated with high rate of rejection. Multi-institutional collaborative studies are warranted to enhance our understanding of the pathogenesis and plan optiomal therapy that maintain graft tolerance without dampening antitumor clinical benefits.
Efficacy and safety of CetuGEX in recurrent/metastatic squamous cell carcinoma of the head and neck (RM-HNSCC): Results from the randomized phase II RESGEX study.
Authors: Keilholz Ulrich , Kawecki Andrzej , Dietz Andreas , Zurawski Bogdan , Schenker Michael , Kukielka-Budny Bozena , Schafhausen Philippe , Mihailov Anca C. , Ochenduszko Sebastian , Imarisio Ilaria , Mihutiu Simona , Oprean Cristina-Marinela , Folprecht Gunnar , Turcu Alina , Rottey Sylvie , Debourdeau Philippe , Lavernia Javier , Dietrich Bruno , Zurlo Alfredo , Fayette Jerome 
Published: February 2018

59 Background: Standard treatment for RM-HNSCC is a combination of cisplatin (P), 5-FU (F), and the epidermal growth factor receptor (EGFR) blocking monoclonal antibody cetuximab. CetuGEX is a new monoclonal antibody sharing the identical EGFR-binding domain with cetuximab, but a modified Fc part by a proprietary glycosylation method to optimize antibody dependent cellular cytotoxicity (ADCC). Methods: Patients with RM-HNSCC without relevant comorbidities were randomized to receive up to 6 cycles of P 100 mg/m2, F 4 x 1000 mg/m2/24hrs and CetuGEX vs. cetuximab. Initial dose of cetuximab was 400mg/m2, followed by weekly 250 mg/m2. CetuGEX was given as 990 mg, followed by weekly 720 mg. After end of combination treatment, patients received single agent antibody maintenance until disease progression or intolerable toxicity. Stratification factors included FcγRIIIa status, primary tumor site, EGFR pretreatment vs. naïve, and recurrent vs. metastatic disease. Primary endpoint was progression-free survival (PFS) by immune related response criteria (irRC). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR) and overall survival (OS) as well as safety and QoL. Results: During Jan 2014 and Feb 2016, 240 patients were accrued in 34 European centers, of which 123 received cetuximab and 117 CetuGEX. The median follow-up was 15 month until May 2017. No difference was observed for the primary endpoint of PFS by irRC [median 27.7 (CetuGEX) and 26.4 (cetuximab) weeks; HR 1.003; 95%-CI 0.738 – 1.363; p = 0.98]. No advantage of CetuGEX over cetuximab was observed for all other secondary efficacy endpoints and subgroup analyses by stratification factors. Infusion related reactions (IRR) were higher for CetuGEX (38.8%) than for cetuximab (5.7%) (Pearson chi2= 37.08; p < 0.0001), but without sequelae. Conclusions: The RESGEX study is the first head-to-head comparison of an ADCC-optimized to a conventional EGFR-directed antibody. The study failed to show superior efficacy of CetuGEX over cetuximab. Both compounds appear to have the same efficacy and a similar safety profile. Glycosylation changes in the Fc part induced more IRRs. Clinical trial information: NCT02052960.
Development of a fully human t-cell engaging bispecific antibody for the treatment of multiple myeloma.
Authors: Buelow Ben , Choudhry Priya , Clarke Starlynn , Dang Kevin , Davison Laura , Force Aldred Shelley , Harris Katherine , Pham Duy , Pratap Payal , Rangaswamy Udaya , Schellenberger Ute , Shah Nina , Trinklein Nathan , Ugamraj Harshad , Wiita Arun , Van Schooten Wim 
Published: February 2018

60 Background: T-cell engaging bispecific antibody (T-BsAb) therapies are highly efficacious and well suited for targets with low expression on tumor cells. Recently, T-BsAbs with high activation of CD3 have been shown to overstimulate T cells, leading to toxicity and decreased efficacy. Teneobio has developed a fully human BCMA-specific T-BsAb using a low-activating αCD3 that is highly effective in vitro and in vivo against MM but stimulates minimal cytokine release. Methods: UniRats were immunized with either CD3 or BCMA antigens and antigen-specific UniAbs were identified by Ab repertoire sequencing and high-throughput gene assembly, expression, and screening. Antigen-specific VH sequences with the desired target affinity were selected using recombinant proteins and cells. In vitro efficacy studies included T-cell activation by cytokine- and tumor cell kill by calcein-release assays. In vivo efficacy of the molecules was evaluated in NSG mice harboring myeloma cells and human PBMCs. Results: BCMA-specific UniAbs bound plasma cells with sub-nM affinity. Strong and weak T cell agonists were identified that bound human T cells with high and low affinities respectively. T-BsAbs with a strong and a weak αCD3 demonstrated T-cell activation and tumor-cell cytotoxicity in vitro; T-BsAbs with a weak αCD3 showed markedly reduced cytokine production even at doses that showed maximum tumor cell lysis. In vivo, BCMAxCD3 T-BsAbs reduced tumor load and increased survival when co-administered with human PBMCs as compared to controls. Conclusions: Our results suggest that T-BsAbs with low-activating αCD3 arms may have a favorable toxicity profile while maintaining efficacy in the treatment of MM.
CetuGEX and cetuximab in recurrent/metastatic squamous cell carcinoma of the head and neck (RM-HNSCC): PK/PD results from the phase II RESGEX study.
Authors: Baumeister Hans , Zurlo Alfredo , Fayette Jerome , Dietrich Bruno , Keilholz Ulrich 
Published: February 2018

61 Background: Standard treatment for RM-HNSCC is a combination of cisplatin (P), 5-FU (F), and the EGFR blocking monoclonal antibody (mAb) cetuximab (C). The mAb CetuGEX (CG) shares with cetuximab the identical EGFR-binding domain, but harbors a defucosylated glycan at the Fc part to increase antibody dependent cellular cytotoxicity (ADCC) by improved binding at the Fcγ receptors IIIa (FcγRIIIa). Methods: 240 pts with RM-HNSCC were randomized in 34 European centers, of which 123 received C and 117 CG, in combination with P (100 mg/m2) and F (4 x 1000 mg/m2/24hrs) for the first 6 cycles. Initial dose of C was 400mg/m2, followed by weekly 250 mg/m2. CG was administered once 990 mg, followed by weekly infusions of 720 mg. After completion of combination treatment, pts received single agent mAb maintenance until disease progression or intolerable toxicity. The tumor tissues were analyzed for EGFR and p16 expression by IHC staining. Blood samples were withdrawn to analyze the FcγRIIIa phenotypes V/V, V/F and F/F and the FcγRIIa phenotypes R/R, H/R and R/R of each patient. The cellular immune status was analyzed in a subset of about 20 pts per arm before 1st and 5th infusion and 28 days after last infusion (Safety Visit) by flow cytometry. Serum CG concentrations were measured before and after the first ten infusions and for a subset of about 20 pts 5 h, 7 h, 24 h, 48 h, 72 h, and 168 h after the first and 10th infusion. The occurrence of anti-drug antibodies (ADA) was determined before 1st, 2nd, 4th and 10th infusion of CG and at the Safety Visit. Efficacy and safety parameters will be looked at in relation to the biomarkers. Results: While most analyses did not show any difference between CG and C, the subgroup of p16+ pts (N=32) is characterized by a significantly longer overall survival (HR 0.52; 95%-CI 0.29 – 0.86; p=0.009) than that of p16- pts, which remains significant under CG (17 pts; HR 0.43; 95%-CI 0.18 – 0.88; p=0.02) but not C treatment (15 pts), probably due to differences in pts immune status. Conclusion: The RESGEX study is the first head-to-head comparison of an ADCC-optimized to a conventional anti-EGFR mAb. The biomarker assessment may help to understand differences between the two mAbs. Clinical trial information: NCT02052960.