bluuebunny/crossref_metadata_2025 huggingface dataset:
Is metronomic vinorelbine (mVRL) able to inhibit both HUVEC and triple-negative breast cancer (TNBC) cells? The proof-of-concept VICTOR-0 study.
Authors: Cerrito Maria Grazia , Pelizzoni Davide , De Giorgi Marco , Digiacomo Nunzio , Lavitrano Marialuisa , Giovannoni Roberto , Bidoli Paolo , Cazzaniga Marina Elena
Published: September 2018

e14014

Background: TNBC represents an important clinical challenge because of poor prognosis. One of the emerging strategy to achieve disease control while reducing toxicity is metronomic chemotherapy (mCHT) which targets the endothelial cells (ECs) and inhibits the tumor growth. mVRL is a promising option in patients (pts) with metastatic breast cancer (MBC), resulting in a median PFS of 7.7 months and median OS of 15.9. To better explain the effect of mVRL we studied the effects of metronomic doses of VRL in in vitro models and compared them with standard doses of the same drug. Methods: Cell viability and cytotoxicity assays were performed on TNBC cancer cells (MDA-MB-231) and Human Umbilical Vein Endothelial Cells (HUVEC). Cell lines were exposed to different concentration (0,01nM-1mM) of VRL for 4 and 96 h. To simulate the metronomic dosing schedule, we replaced the drug-enriched medium every 24h, while to simulate the conventional administration protocol (sCHT) cells were exposed to VRL for 4h, then the medium was changed and replaced with fresh medium without drug every 24 h. The IC50was calculated by non-linear regression fit of the mean values of data obtained in triplicate experiments. Results: A significant anti-proliferative activity was observed on both HUVEC and MDA cells treated with VRL in mCHT as compared to sCHT protocol (see Table). These lower drug concentrations did not have remarkable effects on cell death. Conversely, the higher dose utilized in sCHT produced important cell death in MDA as well as in HUVEC, even if in vivo, the higher dose of drug inducing the largest apoptosis of cancer cells also affectd healthy proliferating cells causing toxicity. Our findings suggest that mCHT inhibited the proliferation of both endothelial and tumour cells and can block cancer progression with minor side effects. Conclusions: This study provides the proof-of-concept that metronomic doses of VRL, but not the standard ones, are able to inhibit, at the same concentration, both the ECs and the TNBC cells. The clinical trial TEMPO-BREAST, which compares metronomic vs standard VRL, is ongoing in MBC pts. [Table: see text]
Paclitaxel once weekly (wP) combined with fixed dose of oral metronomic cyclophosphamide (OMC): A dose-escalating phase I trial.
Authors: Pannier Diane , Adenis Antoine , Tresch-Bruneel Emmanuelle , Bogart Emilie , El Hajbi Farid , Dansin Eric , Kotecki Nuria , Ceugnart Luc , Ryckewaert Thomas , Delaine Stephanie Clisant , Lauridant Philippin Geraldine , Lesoin Anne , Ducornet Sandrine , Vanseymortier Marie , Decoupigny Emilie , Le Deley Marie-Cecile , Penel Nicolas
Published: September 2018

e14015

Background: OMC, as continuous administration of low doses of chemotherapy acts as direct cytotoxic as well as antiangiogenetic agent. wP also induces antiangiogenic effects in mouse models. The aims of this trial were to determine the recommended Phase 2 dose (RP2D) of wP given in combination with OMC, and estimate activity and safety of the combination. Methods: Methods This is a single-center, phase 1 trial. Patients (pts) > 18 years with refractory metastatic cancers were eligible if no standard curative measures existed. Paclitaxel was administered IV weekly (D1, D8, D15; D1 = D28) in combination with a fixed dose of OMC (50mg x2/day). A 3+3 design was used for Dose-Escalation of wP (40 mg/m² to 75 mg/m²), followed by an expansion cohort at RP2D. The primary endpoint was the dose-limiting toxicity (DLT), defined as grade > 3 non-hematological or grade 4 hematological toxicity (NCI-CTCAE v4.0) occurring in the first 28 days, or any toxicity leading to a dose reduction. Results: 28 pts (18 in dose-escalation phase and 10 in expansion cohort) were included between May 2011 and December 2013. The sex ratio was 2:1, the median age was 54.5 (range, 26-67); the most common primary tumors were colorectal cancers (n = 9), sarcomas (n = 4), Head & Neck (n = 3). 16/18 pts enrolled in the dose-escalation phase were evaluable for DLT. DLT occurred in 0/3, 1/6 (neuropathy), 0/3 and 2/4 pts (hematological toxicity) at dose 40, 60, 70 and 75 mg/m² of wP, respectively. The RP2D of wP was 70 mg/m2; 1/10 pts in the expansion phase had an hematological DLT. At RP2D (n = 14), the maximal grade of adverse events (AE), regardless of causality, was Gr2 in 3 pts, Gr3 in 7 pts, Gr4 in 3 pts and Gr5 in 1 pt; the maximal grade of treatment-related AE was Gr1 in 1 pt, Gr2 in 8 pts, Gr3 in 3 pts and Gr4 in 1 pt (no AE in 1 pt). At RP2D, the median PFS was 2.8 mo and Growth Modulation index was ≥1.33 in 4/14 pts (29%). There was 1 objective response (1/14; 7%): 1 pt with lung adenocarcinoma achieved a partial response. Conclusions: The combination of OMC and wP resulted in an acceptable safety profile. Further evaluation of this combination with wP at 70mg/m² could be warranted in a phase 2 trial. Clinical trial information: NCT01374620.
Evaluation of cardiovascular status in clinical trials in breast cancer.
Authors: Oren Ohad , Oren Michal
Published: September 2018

e14038

Background: With the expansion of treatment options in oncology, patients are now increasingly exposed to potentially cardio-injurious compounds. Nevertheless, many clinical trials do not assess the cardiac status of participants, from time of enrollment to study completion. Methods: We reviewed the landmark clinical trials of each of the single-agent chemotherapies specified by the NCCN for use in locally advanced/metastatic breast cancer. We analysed the cardiovascular exclusion criteria, baseline cardiac evaluation as well as cardiac surveillance of patients in each study. We then investigated the literature in the years following each index publication, scrutinising for evidence of cardiac toxicity. Results: 14 phase 2/3 studies were analysed. The total number of patients was 2,522. 42.8% (6/14) of the studies excluded patients with clinically-determined cardiovascular disease, 66.6% (4) of which specified normal EF as a pre-requisite for enrollment. 42.8% (6/14) of the studies evaluated the baseline cardiovascular function of participants using EKG or TTE. 35.7% (4/14) of the studies included a more rigorous monitoring that included serial EKGs and/or TTEs. New Heart Failure (HF) occurred in 1.63% (20/1226) and 0.87% (9/1024) of patients in the more- and less- rigorous trials, respectively (P value = 0.11). Subsequent follow-up studies (published a mean of 8.5 years later) disclosed significantly higher incidence of symptomatic HF (range 2.3-28.0%) with 3 (of 4) chemotherapies in the more-rigorous study group (doxorubicin, cyclophosphamide, epirubicin) and 1 (of 10) chemotherapies in the less-rigorous group (docetaxel). Conclusions: The majority of clinical studies in breast cancer do not prospectively assess cardiac status beyond a pure clinical assessment. The discrepancy between the toxicity profile shown by original studies and that detected in subsequent investigations implies that the tools currently used to evaluate the cardiovascular status of enrollees may be insufficiently sensitive in predicting the development of HF. Novel tools (circulating markers, imaging) and longer follow-up periods are needed to ascertain the cardiotoxic profile of new chemotherapies.
Clinical efficacy of icotinib in patients with advanced non-small cell lung cancer harboring EGFR exon 18, 20 and 21 uncommon mutations.
Authors: Xu Chunwei , Wang Wen-xian , Fang Meiyu , Zhuang Wu , Lin Gen , Chen Xiao-hui , Zhu You-cai , Du Kai-qi , Huang Yun-jian , Xu Hai-peng , Chen Yan-ping , Chen Gang , Lv Tangfeng , Song Yong
Published: September 2018

e14050

Background: EGFR gene mutations were discovered in some of NSCLC patients. Two major EGFR mutations include 19del and L858R. These mutations account for more than 90% of all mutations related to EGFR TKIs sensitivity. Icotinib, an EGFR TKI, showed equivalent response rates and better tolerability compared with gefitinib, double blind trial (ICOGEN) with advanced NSCLC previously treated in China. In addition, other uncommon mutations have been identified. The efficacy of icotinib in patients harboring these mutations to icotinib is still unknown. This study investigated the efficacy of icotinib in patients carrying G719X/E709X/G724S in exon 18, S768I/20 insertions/T790M/V769M in exon 20 and L861Q/L833F in exon 21. Methods: Retrospectively analysed 24 cases of 18 exon, 58 cases of 20exon and 17 cases of 21 exon uncommon mutation NSCLC patients until the progress of the disease or the emergence of the side effects and clinical efficacy was observed after months followed-up. Results: 99 patients with G719X/E709X/G724S/S768I/20 insertions/T790M/V769M/ L861Q/L833F mutations were enrolled. The patient response rate and disease control rate were 31.58%, 66.66%, 0, 25.00%, 11.11%, 4.76%, 0%, 23.53%, 0% and 73.68%, 66.66%, 100%, 80.00%, 44.44%, 47.62%, 100%, 64.71%, 100%, respectively. The mPFS were 2.7 months, respectively. Patients with L833F mutation manifested the longest mPFS(4.2 months), followed by those with G724S mutation(3.5 months), S768I and V769M(3.2 months), E709X(3.1 months), G719X(2.8 months), L861Q(2.2 months), exon 20 insertions(1.9 months) and T790M(1.6 months). Patients with complex mutations show a better PFS than those with single mutations(G719X mutations 3.3 months vs 2.6 months, P = 0.029; E709X 7.2 months vs 2.7 months, P = 0.225; S768I mutations 2.2 months vs 3.3months, P = 0.174; T790M 2.45 months vs 2.9 months, P = 0.845; L861Q mutations 2.1 months vs 5.6 months, P = 0.065 ).Conclusions: Icotinib is less effective in patients with uncommon mutations than in those with common mutations. Patients with complex mutations benefited more from icotinib than those with single mutations.
Apatinib for EGFR-TKIs resistant NSCLC patients: Initial clinical experience.
Authors: Zhou Na , Zhang Chuantao , Jiang Man , Hou Helei , Zhao Lantao , Liu Dong , Cong Jing , Zhu Hua , Zhang Xiaochun
Published: September 2018

e14059

Background: The 3rd generation TKI is still not available for Chinese NSCLC patients with EGFR-mutant who develop acquired resistance following treatment with 1st EGFR tyrosine kinase inhibitors (EGFR-TKIs). Apatinib, a novel small molecule TKI targeted VEGFR2, recommended as third-line treatment for metastatic gastric cancer patients, might be used as an alternative strategy for these patients. This study is an initial clinical experience about Apatinib for EGFR-mutant NSCLC patients with 1stTKI resistance. Methods: Eight patients pathological diagnosed as adenocarcinoma with EGFR mutant were enrolled between January, 2016 and January, 2017. All patients had undergone TKI treatment and disease progression. They had an ECOG performance status (PS) of 0–1. 250 mg-500mg/day of Apatinib was continuously administered for two months, during which we observed the curative effect and adverse events closely. Informed consent was obtained from each patient before enrollment. Results: Computed tomography (CT) scan evaluation revealed that partial response (PR) occurred in 25% (2/8) patients and other 75% (6/8) showed stable disease (SD). There was no progressive disease (PD) occurred. Hypertension is one of the most frequent adverse reactions, which appeared in 50% (4/8) patients who were getting to be normal under antihypertensive agent. Others like hand-foot syndrome, anergy and temple elevated urine protein also appeared and could be better controlled. Conclusions: Apatinib is a safe and effective oral targeted drug on EGFR-mutant NSCLC patients with TKI resistance. It could provide a new therapy strategy for them before taking osimertinib. To further investigate the role of Apatinib in drug resistant EGFR-mutant NSCLC, large sample and additional clinical trials are needed. Table1. Clinicopathologic Characteristics of Patients. [Table: see text]
Dose-exposure-response relationship between AZD6738 and peripheral monocytes.
Authors: Pierce Andrew , Berges Alienor , Cheung S Y Amy , Standifer Nathan , Ross Graham , Smith Simon , Hollingsworth Simon J , Krebs Matthew , Postel-Vinay Sophie , Bang Yung-Jue , El-Khoueiry Anthony B. , Abida Wassim , Sundar Raghav , Carter Louise , Castanon-Alvarez Eduardo , Im Seock-Ah , Lopez Juanita Suzanne , Yap Timothy Anthony , Harrington Kevin , Soria Jean-Charles
Published: September 2018

e14063

Background: AZD6738 is a potent, selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) serine/threonine-specific protein kinase with good selectivity against other phosphatidylinositol 3-kinase-related kinase (PIKK) family members. To support dose/schedule guidance through mathematical modelling of clinical pharmacokinetic/pharmacodynamic relationships, we sought to determine quantitative pharmacodynamic effects of AZD6738 in peripheral blood with respect to drug exposure. Methods: We assessed peripheral blood cell subpopulations in clinical studies of AZD6738 used either as a monotherapy, a combination with the PARP-1 inhibitor olaparib and in combination with the PD-L1 inhibitor durvalumab through both blood analyser and flow cytometry characterization. Peripheral pharmacokinetics of AZD6738 were also assessed. Results: Levels of peripheral monocytes were suppressed in a dose-dependent manner for the duration of AZD6738 dosing resulting in a decrease of up to 80% within the first 7 consecutive days of AZD6738 treatment; these results were consistent across studies. Upon cessation of an AZD6738 dosing interval monocyte levels return to baseline values within 14 days; in combination with durvalumab there is a trend for the rebound in monocyte counts to surpass baseline levels by up to 20%. Monocyte suppression is specific to AZD6738 and not found with either single agent olaparib or single agent durvalumab, possibly attributable to defective base excision repair in monocytes and lack of PARP-1. Monocytes were found to be the most sensitive cell type to AZD6738 treatment compared with neutrophils, platelets, haemoglobin or lymphocytes. Conclusions: This drug effect of AZD6738 is consistent with natural clearance of peripheral monocytes under suppression of monocyte precursor proliferation in the bone marrow, suggestive of a change in the equilibrium between production and elimination of peripheral monocytes. Used as a surrogate marker of target inhibition, a mathematical model of the AZD6738/monocyte dose-exposure-response relationship is described and has been used to inform AZD6738 Phase 2 dose and schedule.
A new model for estimating glomerular filtration rate in patients with cancer.
Authors: Janowitz Tobias , Williams Edward Hywel , Marshall Andrea , Ainsworth Nicola , Thomas Peter B , Sammut Stephen John , Shepherd Scott Thomas Colville , White Jeff D. , Mark Patrick , Lynch Andy , Jodrell Duncan Ian , Tavaré Simon , Earl Helena Margaret
Published: September 2018

e14074

Background: The glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing, however, the best method to estimate GFR in patients with cancer is unknown. We identify the most accurate and least biased method. Methods: Data on age, sex, height, weight, serum creatinine, and results for GFR from 51Cr-EDTA excretion measurements (51Cr-EDTA GFR) were obtained from Caucasian patients aged 18 years or older with histologically confirmed cancer diagnoses at the University of Cambridge Hospital NHS Trust, UK. We developed a new multivariable linear model for GFR using statistical regression analysis. 51Cr-EDTA GFR was compared to the estimated GFR (eGFR) from seven published and our new model using an internal validation data set and root-mean-squared-error (RMSE) and median residuals. A comparison of carboplatin dosing accuracy based on an absolute percentage error more than 20% (APE > 20%) was undertaken. Results: Between August 2006 and January 2013 data from 2,471 patients were obtained. The new model improved the eGFR accuracy (RMSE 15.00ml/min (95% CI 14.12-16.00)) compared to all published models. Body surface area (BSA) adjusted CKD-EPI was the most accurate published models for eGFR (RMSE 16.30ml/min (95% CI 15.34-17.38)) for the internal validation set. Importantly, the new model reduced the fraction of patients with a carboplatin dose APE > 20% to 14.17% in contrast to 18.62% for BSA adjusted CKD-EPI and 25.51% for the Cockcroft-Gault model. The results were externally validated. Conclusions: In a large data set, from patients with cancer, a new model improves eGFR and carboplatin dose calculations, when compared to BSA adjusted CKD-EPI, the model we identified as the best published model for determination of eGFR in patients with cancer.
Clinical development of 4SC-202, a combined epigenetic inhibitor of HDAC class I and LSD1, to overcome anti-PD-1 refractoriness and increase efficacy of checkpoint inhibition.
Authors: Hermann Frank
Published: September 2018

e14096

Background: Checkpoint inhibitor (CI) like anti-PD(L)-1 antibodies are a breakthrough innovation, but a high unmet medical need remains for a large proportion of patients not responding. Low mutational load, microsatellite stability and a non-inflamed tumor microenvironment have been described as negative predictive factors. A promising approach to increase the benefit from anti-PD(L)-1 treatment is to alter the tumor microenvironment to a more immune-inflamed phenotype by combination assets. Epigenetic modulation has been reported as one key determining factor in shaping the immune microenvironment and compounds altering these processes, like histone deacetylases (HDAC) inhibitor in particular offer a promising approach. Methods: We report preclinical results from the small molecule compound 4SC-202, an orally available clinical stage epigenetic inhibitor, specifically targeting HDAC class I and lysine-specific demethylase LSD1. Results: 4SC-202 has shown the ability to elicit a variety of immune modulating effects on tumors and their microenvironment by enhancing the expression of tumor associated antigens as well as MHC and co-stimulatory molecules. Combination treatment of 4SC-202 with CI in syngenic mouse models showed a strong synergistic effect leading to enhanced tumor reduction when compared to 4SC-202 or checkpoint inhibitor treatment alone. Importantly, 4SC-202 strongly increased the number of tumoricidal cytotoxic T cells (CTL) without affecting the viability of activated T cells. Conclusions: Anti-PD(L)-1 refractory/non-responding patients remain a population with a high unmet medical need, increasing in number over time. Advanced melanoma is the model tumor for immunotherapy in general and CI in particular. Based on the strong preclinical rationale, we hypothesize that the addition of 4SC-202 to anti-PD-1 treatment may lead to increased immunogenicity of the tumor, an inflamed tumor microenvironment and subsequent clinical benefit in anti-PD-1 refractory/non-responding melanoma patients. The “SENSITIZE” study is intended to proof this concept in a phase Ib/II clinical trial.
Serum microRNAs to predict the response to nivolumab in patients with esophageal squamous cell carcinoma.
Authors: Sudo Kazuki , Kato Ken , Matsuzaki Juntaro , Kawauchi Junpei , Takizawa Satoko , Miyamoto Takahiro , Shoji Hirokazu , Iwasa Satoru , Honma Yoshitaka , Takashima Atsuo , Hamaguchi Tetsuya , Takeshita Fumitaka , Sakamoto Hiromi , Boku Narikazu , Ochiya Takahiro
Published: September 2018

e14511

Background: A phase II study demonstrated that nivolumab (Nivo), a PD-1 inhibitor, had a meaningful activity for patients with esophageal squamous cell carcinoma. Although several biomarkers, including PD-L1 expression levels in tumor tissue, are explored to predict the efficacy of Nivo, further investigation is needed. Here we evaluated whether serum levels of microRNA (miRNA) could be a candidate of predictive markers. Methods: Among 65 patients who participated in the phase II study (JapicCTINo.142422) and received Nivo 3 mg/kg IV Q2W, 19 patients were treated at our institution. Patients were classified into responder and non-responder by investigators based on modified ir-RECIST. Serum samples were stored before and during treatment in the National Cancer Center Biobank. Comprehensive miRNA microarray analyses were performed using a 3D-Gene Human miRNA Oligo Chip (Toray Industries, Inc.), which was designed to detect 2565 miRNA expression levels. miRNA were compared between responders and non-responders using Fisher’s linear discriminant analysis, and then we calculated the area under curve (AUC) values of receiver operating characteristic curve. We explored the miRNA that showed AUC values of more than 0.8 and difference by 0.5 in the average log2 value of miRNA levels (log2miRNA) between responders and non-responders, and investigated their relation to progression-free survival using Kaplan-Meier curves and log-rank tests. Results: Among 19 patients, 5 responded (CR/PR, 1/4) to Nivo. We identified 3 miRNAs in the serum before treatment that were related to response to Nivo with AUC of 0.84 (log2miRNA of non-responder/responder: 13.16/12.47), 0.90 (8.65/10.20) and 0.81 (7.18/6.57), respectively. In the serum after the first treatment, 5 miRNAs were related to response to Nivo with AUC of 0.93 (11.93/11.09), 0.93 (11.87/11.13), 0.85 (7.92/8.53), 0.92 (6.61/5.82) and 0.93 (7.77/ 7.09), respectively. Among these 8 miRNAs, 4 miRNAs were significantly associated with progression-free survival. Conclusions: We identified miRNA candidates that could predict the response to Nivo. Further validation is warranted to confirm the results of our explorative research.
Tumor cell-free DNA copy number instability compared to CA19-9 as an early predictor of response to systemic therapy in pancreatic ductal adenocarcinoma (PDAC).
Authors: Kundranda Madappa N. , Koenig Alexander , Beck Julia , Bornemann-Kolatzki Kirsten , Coats Jessica , Bergelin Jana , Waypa Jordan , Mitchell William Marvin , Urnovitz Howard , SchÃ¼tz Ekkehard , Dragovich Tomislav , Ellenrieder Volker , Weiss Glen J.
Published: September 2018

e14524

Background: Humoral tumor markers are used clinically for real-time assessment of therapeutic efficacy. In pancreatic ductal adenocarcinoma (PDAC) the predominant marker is CA19-9, which is not expressed by 10 to 30% of patients depending on race. We compared plasma cell-free DNA (cfDNA) copy number based assay with changes in serum CA19-9 levels and radiological responses to predict responses to systemic therapy. Methods: In a laboratory blinded, prospective multicenter pilot study, 40 non-resectable PDAC patients, treated with (m)FOLFIRINOX, CAPIRI, or gemcitabine +/- nab-paclitaxel) are currently enrolled. CA19-9 was determined in the local center’s laboratory. Tumor cfDNA was measured with a copy-number instability (CNI) scoring assay, determined by next generation sequencing in a centralized laboratory. The CNI score assesses the amount of cfDNA with somatic macro-alterations originating from malignant neoplasms. The difference of the values before commencing therapy (baseline) and prior to cycle 2 (either rising or falling) was calculated as a predictor of standardized radiological evaluation of chemotherapeutic efficacy. Results: 37 patients (3 drop-outs) had data for baseline and cycle 2, of which CA19-9 was elevated and evaluable in 29 patients. The direction from baseline to cycle 2 of CA19-9 and CNI scores were in agreement in 18/29 patients. 9 of 11 cases with discordant CNI score and CA19-9 had treatment response data, and CNI correlated with 7/9 (78%); in contrast 7/9 had rising CA19-9, when response was stable disease or better (22% concordance). In the 27 patients with available imaging, CNI predicted better (n = 18) than CA19-9 (n = 10) (p = 0.03 Fisher’s exact). Conclusions: This comparative study on cfDNA versus CA19-9 suggest that cfDNA CNI quantitation is a potentially more reliable blood based marker for early real-time assessment of efficacy in systemic PDAC therapy than CA19-9, compared to standard of care imaging. The better prediction after the first cycle might be due to the very short in vivo half-life of cfDNA ( < 1hr) compared to about one week for CA19-9. These results justify a larger prospective validation trial.
Evaluation of CD73 in lung cancer.
Authors: Yu Hui , Amar Maya , Rivard Christopher J , Ellison Kim , Rozeboom Leslie , Suda Kenichi , Brovsky Kristine , Hirsch Fred R.
Published: September 2018

e14525

Background: Immunotherapy has shown promising results in multiple forms of cancer including lung cancer patients. Treatment targeting alternative immune checkpoints may demonstrate value for specific cancers or in combination therapy with other immunotherapies or chemotherapeutic agents. While adenosine has physiological importance in preventing excess inflammatory reactions and inhibiting autoimmunity, it is generated through an enzymatic cascade in the tumor microenvironment whereby AMP is ultimately dephosphorylated to adenosine by CD73 on tumor cells. Previous studies have shown that increased tumor CD73 expression correlated with increased metastasis, worse prognosis and chemotherapy resistance. Methods: Genomic data from the CCLE and TCGA database were evaluated for CD73 expression in lung cancer. The specificity of an anti-CD73 antibody (Cell Signaling) was confirmed by Western blotting in lung cancer cell lines. Immunohistochemistry (IHC) was performed for FFPE lung cancer cell lines and a NSCLC patient cohort. CD73 expression data was correlated with patient demographic data including outcomes. Results: CD73 mRNA was expressed in lung cancer cell lines (70/126, 55.6%) and did not correlate with other immune checkpoint ligands including PD-L1, GAL-9, and B7H4 in NSCLC. Review of the TCGA database identified CD73 expression is highest in thyroid carcinoma and significant in lung cancer. The prevalence of CD73 protein expression by IHC in NSCLC cell lines was 84.8% (39/46) and 15.4% (6/39) in SCLC cell lines. We also evaluated CD73 protein expression in a NSCLC cohort with a prevalence of 32.1% (36/112), with no significant correlation to patient clinical characteristics or outcomes. Conclusions: We evaluated the expression of the immune checkpoint, CD73, in lung cancer cell lines and tissues. Both genomic data and protein expression by IHC demonstrated CD73 was significantly expressed. However, there was no correlation with other immune biomarkers or patient demographics or outcomes. CD73 is a new target for immunotherapy and current clinical studies with CD73 inhibitors may prove beneficial to lung cancer patients.
Feasibility of cancer vaccine therapy using dendritic cells generated from induced pluripotent stem cells expressing carcinoembryonic antigen.
Authors: Ojima Toshiyasu , Kitadani Junya , Iwamoto Hiromitsu , Nakamori Mikihito , Nakamura Masaki , Yamaue Hiroki
Published: September 2018

e14538

Background: We investigated whether genetically modified human dendritic cells (DCs) derived from induced induced pluripotent stem cells (hiPSDCs) expressing carcinoembryonic antigen (CEA) could induce the CEA specific cytotoxic T lymphcytes (CTLs) against cancer cell lines endogenously expressing CEA in vitro model using healthy volunteers. Furthermore, we established in vivo tumor model using the CEA transgenic mice (TGM) as a preclinical experiment. Methods: Human model; we differentiated hiPSDCs from iPSCs of three healthy donors and transduced the CEA cDNA into DCs. Mouse model; we differentiated miPSDCs in CEA TGM and transduced the CEA cDNA into DCs. Results: Human model; the surface marker expression, cytokine secretion, and migratory capacity of hiPSDCs were equivalent to human monocytes derived-DCs (hMoDCs). After 3 cycles of stimulation to autologous peripheral blood mononuclear cells (PBMCs) by genetically modified hiPSDCs, the cytotoxic assay was performed using a 51Cr release assay. The CTLs induced by hiPSDCs-CEA exhibited CEA specific cytotoxic activity against the target cells expressing. Mouse model; in the CEA transgenic mice model, the CTLs generated in mice immunized with miPSDCs-CEA showed CEA specific cytotoxic activity against MC38-CEA. Moreover, in the subcutaneous tumor model, vaccination with miPSDCs-CEA achieved significantly high growth inhibitory effect for the MC38-CEA. No adverse events were observed. Conclusions: This vaccine therapy using genetically modified iPSDCs is promising for clinical application for patients with gastrointestinal cancer patients.
Defining an allogeneic CAR-T approach by shRNA-mediated knockdown of the T-cell receptor.
Authors: Suhy David , Garcia Patty , Strings-Ufombah Vanessa , Suhy Natalie , Roelvink Peter , Kilfoil Georgina
Published: September 2018

e14551

Background: An allogeneic approach for CAR T-Cell therapy can significantly streamline manufacturing, provide more accessible options to patients as well as enhance safety by reducing the possibility of graft-versus-host-disease. The T-Cell Receptor (TCR) is comprised of multiple subunits and functions to activate T-cells by a signal transduction cascade that is initiated upon antigen binding. Eliminating expression of the endogenous TCR on modified CAR-T-Cells may eliminate the ability to recognize major and minor histocompatibility antigens in the recipient. This study assessed if simultaneous expression of multiple short hairpin RNAs that knockdown levels of individual TCR subunits could result in the loss of TCR expression and TCR-mediated T-Cell activation. Methods: Recombinant DNA producing short hairpin RNAs against the TCR complex was transfected into T-cells. Cell surface TCR was analyzed by FACS. Following CD3 activation or co-culture with B-cells, T-Cell activation was quantified by measuring the levels of IL-2 by ELISA and QPCR. Results: When expressed individually, each shRNA inhibited it’s cognate TCR subunit by up to 93% of the endogenous levels. However, upon simultaneous expression of the shRNAs against the different subunits from the same vector, we observed a near complete depletion of the TCR complex from the cell surface ( > 99%) as measured by FACS analyses. Furthermore, TCR functionality was inhibited when treated cells were stimulated with either CD3 or in B cell co-cultures with Staphylococcal enterotoxins. IL-2 secretion was inhibited to undetectable levels by ELISA by the multi-shRNA treatment and > 98% by qPCR. Conclusions: Though knockdown of any single component of TCR never exceeded 93%, simultaneous knockdown of several TCR subunits abrogated surface TCR and downstream activation suggesting that disruption of stoichiometric expression the subunits prevented TCR formation. The small size of the shRNA expression cassette ( < 2 Kb) permits co-expression from the same lentiviral vector as the CAR. Altogether, these data point to a viable strategy towards generating a single vector approach for the production of allogeneic T-Cells for immunotherapies against certain cancers.
Anti-PD-1 therapy in patients with end-stage renal disease on dialysis: A single-center case series.
Authors: Park Soo , Daniels Gregory A.
Published: September 2018

e14553

Background: Anti-PD-1 monoclonal antibodies (PD1) have clinical activity in several solid tumors. However, experience treating dialysis pts with PD1 is limited. Dosage adjustments are not recommended for renal impairment but PK studies did not include pts with ESRD on dialysis. Two case reports have described objective responses and a tolerable AE profile. We sought to explore the safety and efficacy of PD1 in such pts. Methods: In this single-center case series, we identified 4 pts with ESRD on dialysis who were treated with PD1 between 10/2014 to 11/2016. Data regarding clinical history, PD1 dosing, dialysis regimen, treatment (tx) response, and toxicity were collected. Results: Four pts were evaluable for data collection. Two pts had metastatic renal cell carcinoma (mRCC) and 2 others had unresectable cutaneous squamous cell carcinoma (cuSCC). Age at tx ranged from 66 to 71; all 4 pts were male. Number of doses ranged from 4 to 8. Two pts with mRCC received nivo 3 mg/kg q2wk after dialysis. Two pts with cuSCC received pembro 2 mg/kg q3wk after dialysis; dosing was extended to q4wk for 1 pt due to persistent grade (G) 2 fatigue. Three pts were on hemodialysis 3 times a wk and 1 pt was on peritoneal dialysis. Time to progression was 3 months for 1 mRCC pt and could not be determined for the other mRCC pt who had a PR but died from possible tx-related causes. Two cuSCC pts are still receiving pembro with PR at time of analysis. Immune-related AEs were seen in all 4 pts, including 2 incidences of G2 fatigue and 1 incidence each of G2 rash and G3 pneumonitis.One pt developed acute encephalitis after 4 doses of nivo that improved with steroids but was ultimately fatal. Conclusions: This single-center case series highlights the efficacy and AE profile of PD1 for pts with ESRD on dialysis. While this is a small series, there was significant anti-tumor activity in this group of pts. Despite the reported favorable AE profile of PD1, one pt had a serious and mortal AE that may have been related to tx. This should be considered in future studies. High molecular weight of PD1 suggests these agents are not removed by dialysis but we were limited by lack of PK data. Our experience adds to the 2 cases in the literature. Further studies are warranted in larger cohorts.
Increased risk of liver toxicity secondary to nivolumab therapy in the treatment of cancer.
Authors: Zarrabi Kevin , Wu Shenhong
Published: September 2018

e14559

Background: Nivolumab, a humanized immunotherapy targeting PD-1, is approved for the treatment of a number of solid and liquid cancers and is associated with liver toxicity. This meta-analysis was conducted to determine the overall risk of hepatotoxicity with nivolumab therapy in cancer patients. Methods: An analysis from all phase I, II, and II clinical trials up to December 2016 examining the role of nivolumab in a variety of cancers was conducted. Eligible trials included those in which patients received nivolumab. Data on all-grade and high-grade (grade 3 and 4) elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were extracted from the safety profiles of each clinical trial. Incidence and relative risk (RR) were calculated using random - or fixed - effect models with 95% confidence intervals. Results: The data from 27 eligible trials were included for analysis. A total of 5,287 patients were evaluated (Nivolumab: n = 3515, Control: n = 1772). The incidences of all-grade and high-grade elevations in AST were 5.4% (95% CI: 3.2% - 9.1%) and 1.60% (95% CI: 0.9% - 3.0%), respectively. The incidences of all-grade and high-grade elevations in ALT were 4.9% (95% CI: 2.9% - 8.2%) and 1.5% (95% CI: 0.9% - 3.1%), respectively. Elevations of both laboratory markers were significantly increased when compared to control (P < 0.001). Nivolumab increased the RR of AST/ALT elevations; RR of all-grade AST elevations was 1.58 (95% CI: 1.1 - 2.2), all-grade ALT elevations was 1.62 (95% CI: 1.2 - 2.3). Subgroup analysis of all-grade AST elevations revealed melanoma patients exhibited a significantly higher rate compared to other solid tumors with an incidence of 8.7% (95% CI: 4.3 - 18.2%). All-grade ALT elevations in melanoma patients revealed the same incidence rate. Of note, renal cell carcinoma patients exhibited a particularly low incidence of all-grade transaminitis with AST 1.6% (95% CI: 0.6 - 11.1%) and ALT 1.8% (95% CI: 0.6 - 14.6%). Conclusions: Nivolumab is associated with significantly increased risk of all-grade and high-grade elevations in AST and ALT. Therapy should include careful monitoring of hepatotoxicity.
Correlation between PD-L1 expression level and clinical benefit in 204 patients across malignancies at a single institution.
Authors: Byrd Kenneth , Nagahawatte Panduka , Martin Michael Gary , Stein Matthew K , Patel Kruti , Schwartzberg Lee Steven , Vanderwalde Ari M.
Published: September 2018

e14573

Background: The utility of PD-L1 expression levels in predicting response to anti-PD-1 agents in many malignancies is uncertain. In this study, we describe outcomes of patients treated with anti-PD-1 agents by PD-L1 expression level. Methods: Molecular profiling of tumors in patients with newly diagnosed metastatic cancer was performed at West Cancer Center starting late 2014. Most profiling was performed by Caris, which in addition to NGS also reports PD-L1 expression (IHC, reported as percent expressed). Patients were included in this retrospective analysis if they were treated with an anti-PD-1 antibody and had available results from PD-L1 testing between 11/2014 and 11/2016. Time to treatment failure (TTF) was defined as time from first dose to documented progression, intolerance or death. Those without treatment failure were censored at the date of last contact. Pending formal retrospective RECIST review, clinical benefit rate (CBR) is reported. Results: 204 patients with reported PD-L1 expression started treatment with anti-PD-1 agents. Of these, 125 had non-small cell lung cancer, 31 had melanoma, 12 had renal cell carcinoma, and the remainder had other malignancies. 110 patients (54%) had PD-L1 expression level of 0%, 22 patients (11%) between 1-4%, 37 patients (18%) between 5-49%, and 35 patients (17%) >50%. Median TTF and CBR by PD-L1 overall and by malignancy are shown in the table below. Conclusions: Higher PD-L1 expression does appear to be associated with increased clinical benefit rate and time to treatment failure, though the highest levels of PD-L1 did not follow this pattern. Based on these surrogate endpoints, there appears to be substantial benefit with PD-1 inhibitor treatment even with 0% PD-L1 expression. Objective response rate will be presented. [Table: see text]
Neoadjuvant chemoradiotherapy to induce the expression of programmed death-ligand 1 of tumor cells and the infiltration of CD8+ lymphocytes in patients with rectal adenocarcinoma.
Authors: Nakagawa Akio , Yamashita Kimihiro , Hasegawa Hiroshi , Yamamoto Masashi , Kanaji Shingo , Matsuda Yoshiko , Matsuda Takeru , Oshikiri Taro , Nakamura Tetsu , Sumi Yasuo , Suzuki Satoshi , Kakeji Yoshihiro
Published: September 2018

e14577

Background: In recent years, immune checkpoint inhibitors have attracted attention and a lot of studies on PD-L1 (Programmed death-ligand 1) have been reported, but their anti-tumor effects are limited to colorectal cancer in which the expression of PD-L1 is infrequent. On the other hand, radiation therapy has been suggested to be closely related to the antitumor effect derived from the immune response. So we report the histological and clinicopathological examination about the relationship between the expression of PD-L1 and CD8 and irradiation in rectal cancer cases in which operation was performed after preoperative chemoradiotherapy (neoadjuvant chemoradiotherapy, NACRT) to clarify the indication for immune checkpoint inhibitors. Methods: Immunohistochemical staining of PD-L1, CD8 as immune related factors was performed on 34 cases in which operation was performed after NACRT(UFT/LV:300mg/m2/day and 75mg/body/day, respectively +RT(45Gy)) was done for locally advanced rectal cancer from January 2005 to December 2014, and we evaluated their preoperative biopsy specimens and resected specimens to examine the relationship between their evaluations and clinicopathological factors. Results: The 5-year survival rate and relapse-free survival rate of 34 patients were 84.4% and 65.5%, respectively, and there were 4 pathological CR cases. In 30 patients excluding CR cases, the expression of PD-L1 in tumor cells was enhanced or emerged in 5 cases(16.7%) and the infiltration of CD8+TIL(tumor infiltrating lymphocyte) was also enhanced in 13 cases(43.7%) after NACRT. Also, patients with PD-L1 expression had significantly poor prognosis (p = 0.0023) than others, and the prognosis tended to be further poor in CD8+TIL noninvasive cases. Conclusions: NACRT for locally advanced rectal cancer induced PD-L1 expression in tumor cells and also induced the infiltration of CD8+TIL.
Immune related adverse events (irAEs): A unique profile based on tumor type.
Authors: Sharma Nitika , Atluri Prashanti , Stroud Chipman Robert Geoffrey , Walker Paul R. , Cherukuri Sulochana Devi , Cherry Cynthia R. , Gibbs Paul , Parent Teresa , Hardin Jessica
Published: September 2018

e14606

Background: Immune checkpoint blockade(ICB) has revolutionized the treatment of a growing number of malignancies. Real world administration of oncolytics is often associated with increased adverse event rates versus what is demonstrated in clinical trials. Whether the tumor biology, site of disease burden or underlying organ dysfunction dictates the differing immune side effect profile in various malignancies remains to be understood. Methods: The incidence of grade 2-4 irAE was abstracted from medical records of all patients (pts) treated with ICB (ipilimumab and/or nivolumab) from 2011 to 2016 at a single institution. Results: Of the 126 pts reviewed, 82 pts had metastatic lung cancer, 31 pts had unresectable or metastatic melanoma, 13 pts had metastatic renal cancer(RCC). In the melanoma cohort, concurrent or sequential PD-1 and CTLA4 blockade was used in 10/31 pts. All of the lung cancer and RCC patients received anti-PD-1 alone. In the patients with lung cancer: pneumonitis was identified in 24%, SIRS in 16%, thrombosis in 11%, cerebritis in 9%, colitis in 4%, hepatitis in 4%, thyroiditis in 5%. In RCC, 8% pts experienced pneumonitis and 8% had thyroiditis. In the melanoma population, colitis was identified in 19%, SIRS in 10%, pneumonitis in 3%, thrombosis in 6%, adrenalitis in 6%, hepatitis in 3%. Colitis was seen in 2/13(15%) pts who got ipilimumab alone and 4/10(40%) pts who got both ipilimumab and nivolumab. Conclusions: Pneumonitis, SIRS and cerebritisappear to be the most prevalent irAEs in lung cancer as compared to melanoma or RCC. The incidence of pneumonitis was higher in RCC compared to melanoma. Colitis appears to have a higher incidence in melanoma, the incidence of which further increases when CTLA4 inhibitors are used in conjunction with anti-PD-1. The majority of the RCC patients tolerated ICB with no major irAEs. With the expanding use of ICB in advanced malignancies, increased awareness of these clinically significant and potentially serious irAEs is indispensable. Future trials designed to distinguish the incidence of irAEs in relation to specific tumor types would be informative. [Table: see text]
Preclinical studies of SB 11285, a novel STING agonist for immuno-oncology.
Authors: Challa Sreerupa Valli , Zhou Shenghua , Sheri Anjaneyulu , Padmanabhan Seetharamaiyer , Meher Geeta , Gimi Rayomand , Schmidt Diane , Cleary Dillon , Afdhal Nezam , Iyer Radhakrishnan
Published: September 2018

e14616

Background: The activation of innate and adaptive immunity via Stimulator of Interferon Genes (STING) signaling is a potentially transformative immuno-therapeutic strategy in cancer. We report here in vivo efficacy and safety studies of SB 11285. Methods: Tumor Growth Inhibition (TGI) and Tumor Growth Delay (TGD) studies in syngeneic mouse models were initiated when mean tumor volume (MTV) reached 100mm3: A20 Lymphoma: (10 animals/Group); (A) Saline; (B) 100µg SB 11285, intratumoral (i.t.), days 3,4,6,8,10; (C) 100mg/kg Cyclophosphamide, intraperitoneal (i.p), days 1,2; and (D) combination of cyclophosphamide+SB 11285. CT26 Colon Carcinoma experimental design is shown in Table. Re-challenge study was initiated in tumor-free animals in A20 lymphoma model on day 73, and monitored for an additional 45 days. Presence of activated immune cells intumor tissues was evaluated by immuno-histochemistry. Cytokine response was evaluated in serum after a single i.p. injection of SB 11285 at 10mg/kg. Maximum Tolerated Dose (MTD) in mice was determined by daily i.p. injection of SB 11285 for 10 days. Results: A20 model: % TGI in the treatment groups were—A, 0; B, 86; C, 98, and D, 93; % TGD, day 70: A, 0; B, 64; C, 156; D, 288. In D, day 73, 90% of animals remained tumor-free. CT26 model: Table 1 shows MTV on day 19 and %TGD on day 43; Re-challenge study. All animals from the SB 11285-treated groups remained completely tumor-free on day 45 compared to control group (MTV,1666 mm3); Immuno-histochemistry of SB 11285-treated groups, revealed the infiltration of CD8+T and NK cells into tumor and surrounding tissues; Cytokine analysis did not show systemic inflammatory response; MTD of SB 11285 was 16 mg/kg/day. Conclusions: SB 11285, a novel STING agonist, showed very potent, and highly durable immune response-mediated anti-tumor activity. SB 11285 was well tolerated, safe, and is being advanced to IND-enabling studies. [Table: see text]
Programmed death (PD)-ligand 1 (L1) expression and mismatch repair (MMR) deficiency across tumor types: Candidates for checkpoint inhibitor based immunotherapy.
Authors: Kim Seung Tae , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki , Lee Su Jin , Kim Kyoung-Mee , Lee Jeeyun
Published: September 2018

e14622

Background: The identification of biomarkers associated with response to therapeutic agents has changed the paradigm of cancer treatment into the precision medicine by identification of right targets across cancer types. PD-L1 expression and mutational or neoatigen burden (Mismatch repair (MMR) deficiency) have been actively studied as the predictive biomarkers for the response to immune checkpoint inhibitors. Methods: We have conducted the PD-L1 and hMLH1/MSH2 expression (MMR deficiency) as part of a clinical practice for 430 patients with advanced gastrointestinal (GI) cancer, genitourinary (GU) cancer or rare cancers between June 2012 and March 2016. Herein, we evaluated potential candidates who could be targeted to further immune checkpoint inhibitors. Results: In 430 patients, 414 (96.2%) patients were available to evaluate the status of PD-L1 expression by immunohistochemistry (IHC). Irrespective of tumor-types, overall 26.8% (111 of 414) exhibited expression of PD-L1 in tumor tissues. The PD-L1 expression was examined as follows; 33.5% in HCC, 31.0% in CRC, 27.3% in GC, 25.5% in melanoma, 18.8% in BTC, 16.7% in pancreatic cancer, 15.8% in sarcoma and 13.0% in GU cancer. Among the 394 patients available for MLH1/MSH2 expression, only 18 patients (4.5%) had the MMR-deficient tumors with complete loss of MLH1/MSH2 expression. The MMR-deficiency was observed as follows; 7.9% in GC, 6.7% in HCC, 4.0% in CRC, and 2.7% in sarcoma. On 382 patients evaluable for the status of both PD-L1 and MLH1/MSH2 expression, there was no the significant association between the PD-L1 expression and MLH1/MSH2 loss (p = 0.267) Conclusions: These data may provide useful information and background for future research for immune checkpoint inhibitor across tumor-types. As a single selection biomarker for immune checkpoint inhibitor in various tumor-types, neither the PD-L1 expression nor the MMR deficiency is optimal application in clinical trials.