bluuebunny/crossref_metadata_2025 huggingface dataset:
Indirect mechanisms of action of a novel IgG1 monoclonal antibody, NEO-201, to enhance immune killing of tumor.
Authors: Arlen Philip M. , Annunziata Christina M. , Fantini Massimo , Morelli M. Pia , Tsang Kwong Y.
Published: February 2020

17

Background: NEO-201 is an IgG1 mAb targeting variants of CEACAM5/6 that demonstrates tumor sensitivity and specificity. Functional analysis revealed that NEO-201 is capable of engaging innate immune effector mechanism including ADCC and CDC to directly kill tumor cells expressing its target. Previous studies demonstrated safety/tolerability in non-human primates, and an on going clinical trial at the NCI is currently exploring its dosing and safety. We have explored indirect mechanisms of its action that may enhance immune tumor killing. NEO-201 has the ability to enhance NK activity by blocking the binding of CEACAM5 on tumor cells to CEACAM1 on NK cells. In addition NEO-201 can target and eliminate regulatory T cells (Tregs). Methods: In vitro functional assays, using various human tumor cell lines as target cells and NK-92 cells (CEACAM1+/CD16−) as effectors, were conducted to assess the ability of NEO-201to enhance antitumor cytotoxicity of NK-92 cells by blocking the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells. In addition, flow cytometry analsyis and CDC assays were performed to evaluate the ability of NEO-201 to target and eliminate human Tregs in vitro. Results: Addition of NEO-201 significantly enhanced NK-92 cell cytotoxicity against highly CEACAM5+/NEO-201+ cells, suggesting that its activity is correlated with the level of CEACAM5+/NEO-201+ tumor cells. Furthermore, NEO-201 targets human Tregs and mediates killing of opsonized T-reg cells via CDC. Conclusions: Previously we have demonstrated the ability of NEO-201 as an IgG1 mab to destroy tumor cells expressing its target directly through both ADCC and CDC. This study suggests that in addition, NEO-201may also mediate immune killing through additional mechanisms including blocking the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells to reverse CEACAM1-dependent inhibition of NK cytotoxicity. In addition, we have shown that NEO-201 is also able to recognize and eliminate human Tregs. Ongoing studies are looking at leveraging this phenomenon by combining NEO-201 with checkpoint inhibitors.
Control of cancer progression by extracorporeal removal of soluble TNF-alpha receptors.
Authors: Josephs Steven , Segal Robert , Panahi Marilyn , Ong Matthew , Kunkel Mark , Jafri Amir , Foster Jonathan D. , Ogilvie Gregory K.
Published: February 2020

20

Background: Tumor necrosis factor (TNF)-alpha is a potent antineoplastic cytokine which exerts tumor destruction in part through vascular disruption. Local administration of TNF-alpha exerts profound anti-cancer effects as observed in studies using isolated limb perfusion. However, systemic administration of this cytokine is associated with vascular leakage and limits clinical use. Methods: One method of stimulating localized effects of TNF-alpha is through removal of its soluble receptors, sTNF-R1 and sTNF-R2 using extracorporeal apheresis; ie, Immunopheresis. In this comparative oncology study, we utilized the proprietary LW-02 device to remove sTNF-Rs in pet dogs with varying types of solid malignancies (Part A; n = 12) or with oral malignant melanoma (Part B; n = 8). Canine patients received between 12-24 apheresis treatments over the course of 4 to 8 weeks. Results: In the over 300 immunopheresis treatments, no device associated adverse effects were reported. Consistent reduction of sTNF-Rs was observed, as measured by decreased plasma levels during treatment as well as elution of sTNF-Rs from the cartridge. Of 17 evaluable dogs who completed treatment, 7 had disease stabilization or regression as confirmed by cRECIST criteria. Conclusions: These data strongly support the clinical translation of the LW-02 device as a potential therapeutic approach for treating solid malignancies/melanoma, either as mono- or as adjuvant therapy.
Regulation of gene expression by DNA methylation with cytotoxic T lymphocytes evaluation in consensus molecular subtypes of colorectal cancer.
Authors: Shen Yuanyuan , Hummel Justin , Trindade Isabel Cristina , Papageorgiou Christos , Shyu Chi-Ren , Mitchem Jonathan B.
Published: February 2020

25

Background: Low cytotoxic T lymphocyte (CTLs) infiltration in colorectal cancer (CRC) tumors is a challenge to treatment with immune checkpoint inhibitors. Consensus molecular subtypes (CMS) classify patients based on tumor attributes, and CMS1 patients include the majority of patients with high CTL infiltration and “inflamed” tumors. Epigenetic modification plays a critical role in gene expression and therapy resistance. Therefore, in this study we compared DNA methylation, gene expression, and CTL infiltration of CMS1 patients to other CMS groups to determine targets for improving immunotherapy in CRC. Methods: RNA-seq (n = 511) and DNA methylation (n = 316) from The Cancer Genome Atlas databases were used to determine gene expression and methylation profiles based on CMSs. CMS1 was used as a reference and compared to other subtypes (CMS2-4). Microenvironment Cell Populations- counter (MCPcounter) was used to determine tumor CTL infiltration. Genes with significantly different expression (p < 0.01, LogFC≥|1.5|) and difference of mean methylation β value ≥|0.25| were integrated for Pearson correlation coefficient analysis with MCPcounter score (r > |0.7|). Results: Comparing CMS1 and CMS2, ARHGAP9, TBX21, and LAG3 were differentially methylated and correlated with CTL scores. ARHGAP9 and TBX21 were decreased and hypomethylated in CMS2. Comparing CMS1 and CMS3, ARHGAP9, TBX21, FMNL1, HLA-DPB1, and STX11 were downregulated in CMS3 and highly correlated with CTL scores. ARHGAP9, FMNL1, HLA-DPB1, and STX11 were hypomethylated in CMS3 and TBX21 was methylated in both, but had a higher methylation ratio in CMS1. Comparing CMS1 and CMS4, TBX21 was the only gene downregulated, hypomethylated, and highly correlated with CTL scores in CMS4 patients. Conclusions: We found six genes differentially expressed, differentially methylated, and highly correlated with CTL infiltration when comparing CMS1 to other CMS groups. Specifically, TBX21 was the only gene highly correlated with CTL scores with differential gene expression and methylation in CMS2-4 when compared to CMS1. Thus, T-bet may be a critical regulator of T cell responses in CRC.
The immunogenomic difference between Asian and non-Asian esophageal squamous cell carcinoma (ESCC) patients: An analysis of the Cancer Genome Atlas (TCGA) cohort.
Authors: Kuo Hung-Yang , Guo Jhe-Cyuan , Hsu Chia-Lang , Huang Ta-Chen , Hsu Chih-Hung
Published: February 2020

27

Background: Recently reported global phase 3 trials of immune checkpoint inhibitor (ICI) versus second-line chemotherapy for esophageal cancer revealed that Asian population appear to obtain more benefit from ICI than non-Asian patients even in ESCC subgroups. Whether this observation could be explained by the immunogenomic difference between Asian and non-Asian ESCC remains uncertain. Methods: We retrieved the data of genetic alterations and gene expression profiling from ESCC patients of TCGA dataset, and compared the mutational profiles, immune subtypes, composition of immune cell infiltrates, and T cell-related signatures between Asian and Non-Asian patients with ESCC. Abundance of immune cell infiltrates were estimated by averaging expression values of the corresponding immune cells’ transcriptomic markers defined by Danaher et al. (J Immunother Cancer. 2017; 5:18.). The 6 immune subtypes were adopted from Thorsson et al (Immunity. 2018;48(4):812-830). The T-cell related signatures were determined by averaging the corresponding genes' expression values following previous reports. Results: We retrieved 93 patients with ESCC (Asian: non-Asian= 45: 48) from TCGA database. There is no statistical difference in overall survival between Asian and non-Asian ESCC patients. Higher mutation frequencies of TP53, NFE2L2, ZNF750, and lower mutation frequency of SMARCA4 were seen in Asian patients than in non-Asian patients. As for the immune contexture, we found that the composition of immune cell infiltrate, the distribution of immune subtypes, and a variety of T cell-related gene signatures including the 6-gene interferon-gamma signature, the 10-gene interferon-gamma signature defined by Merck or by Ribas et al, and the 13-gene inflammatory signature defined by Gajewski et al, were not significantly different between Asian and non-Asian groups. Conclusions: Our analysis failed to identify statistically significant difference in the immunogenomics of ESCC tumors between Asian and non-Asian patients in the TCGA cohort. Further immunogenomic studies focusing on patients from Asian countries with high ESCC prevalence are warranted.
Deleterious alterations of DNA damage response and repair (DDR) genes in association with clinical benefit to programmed cell death protein-1 (PD-1)/PD ligand 1 (PD-L1)-based therapy in esophageal squamous cell carcinoma (ESCC).
Authors: Guo Jhe-Cyuan , Lin Chia-Chi , Huang Ta-Chen , Chang Chun-Jung , Kuo Hung-Yang , Hsu Chih-Hung
Published: February 2020

28

Background: Previous studies have indicated genetic alterations (GA) of DDR genes and tumor mutational burden (TMB) as potential markers for anti-PD-1/PD-L1 therapy in several cancer types. The study explored whether GA of DDR genes and TMB are associated with clinical benefit (CB) for ESCC patients receiving anti-PD-1/PD-L1 therapy. Methods: Thirty-five ESCC patients treated with PD-1/PD-L1 blockade antibody, alone or in combination, were enrolled. Tumor response was evaluated per RECIST 1.1, and CB was defined as complete response, partial response or stable disease at least 6 months. Formalin-fixed paraffin-embedded ESCC tissues were analyzed by FoundationOne CDx. All loss-of-function alterations were considered as deleterious according to previous reports (Teo MY, et al: Clin Cancer Res 2017; 23:3610-8 and J Clin Oncol 2018; 36:1685-94). Results: All of 35 enrolled patients was male: 16 and 19 received PD-1/PD-L1 blockade alone and PD-1/PD-L1-based combination therapy, respectively. The response rate was 14%, and the CB rate was 29%. All patients had GA of TP53 (100%), followed by CDKN2A/B (71%), and FGF3, FGF4 plus FGF19 (40%). The median TMB was 4 muts/Mb (range 1-16) and all evaluable ESCC tissues (N=31) were microsatellite stable. Twenty-one (60%) patients had GA of DDR genes, but only 4 (11%) patients had deleterious GA of DDR genes. The clinicopathological characteristics were not significantly different between patients with or without GA of DDR genes or those with or without deleterious GA of DDR genes. Patients harboring deleterious GA of DDR genes trended to have improved response rate (25% vs. 12.9%, P = 0.063), CB rate (50% vs. 22.6%, P = 0.268), and median PFS (4.1 vs. 1.8 mon, P = 0.074). Neither TMB nor all GA of DDR genes was associated with response or CB. Conclusions: Deleterious GA of DDR genes may be associated with therapeutic efficacies of anti-PD-1/PD-L1 therapy in patients with ESCC. (Funded by NHRI-107A1-CACO-01181816, NHRI-108A1-CACO-01191916, MOST-106-2314-B-002-225-MY2, NTU-108L901403, and MOST 108-3017-F-002-004-).
Prognostication model based on genomic expression in the tumor microenvironment of ER-positive, HER2-negative stage III breast cancer via machine learning.
Authors: Abdou Yara , Jerez Jessica , Baird Andrew , Dolan Jillian , Lee Seongwon , Park Shinyoung , Lee Sunyoung S.
Published: February 2020

3

Background: Stroma in the tumor microenvironment (TME) is known to impact prognosis and responses to therapy. Few mathematical models exist to prognosticate patients, based on mRNA expressivity in the TME. Methods: Clinical outcomes data and mRNA-seq of 98 patients with stage III estrogen receptor (ER) positive (+) and HER2 negative (-) breast cancer were obtained from TCGA. Twenty six gene groups composed of 191 genes (refer to presentation) enriched in cellular and non-cellular elements of TME, mutational burden (MB), and clinical data were analyzed by Kaplan-Meier (KM) analysis and multivariate nonlinear regression assisted by machine learning to achieve confined optimization with model-data minimization among multiple distribution functions. Results: Prognostication was modeled with higher risk score (RS) representing worse prognosis in stage 3 ER+HER2- breast cancer. Fifteen genes (CD8A, CD8B, FCRL3, GZMK, CD3E, CCL5, TP53, ICAM3, CD247, IFNG, IFNGR1, ICAM4, SHH, HLA-DOB, CXCR3) and five genes (LOXL2, PHEX, ACTA2, MEGF9, TNFSF4) out of 191 genes associated with good and poor prognosis were identified. Genomic expression of the fifteen and five gene groups were labeled as G and P, respectively. RS = 9.3185 – 0.3250 × (Age at diagnosis0.0001) – 8.2979 × (P/G−0.0051). Based on RS, patients were clustered into two groups; high and low RS groups, showing two KM curves with P = 0.05, HR = 2.878 (95% CI 1.903 – 3.471), confirming the validity of RS modeling. Analysis of immune profiles in high and low RS groups shows that expression of genes associated with desmoplastic reaction, neutrophils, and immunosuppressive cytokines are higher in high RS groups; and those related to immune system activation are higher in low RS groups (p < 0.05). Conclusions: Machine learning-assisted mathematical modeling of RS and gene analysis identified TME-related genes and gene groups that are strongly associated with worse prognosis in stage 3 ER+HER2- breast cancer. RS could potentially prognosticate patients in the clinic with available genomic profiles.
Activation of memory/effector T cells and association between prognosis and OX40-positive T cells in advanced head and neck cancer patients treated with anti-programmed death-1 antibody.
Authors: Ohmura Hirofumi , Yamaguchi Kyoko , Hanamura Fumiyasu , Kenrou Tanoue , Kawagoe Shiho , Arimizu Kohei , Matsushita Yuzo , Kajitani Tatsuhiro , Tamura Shingo , Shimokawa Hozumi , Uchino Keita , Oda Hisanobu , Shinohara Yudai , Ito Mamoru , Tsuchihashi Kenji , Isobe Taichi , Ariyama Hiroshi , Kusaba Hitoshi , Akashi Koichi , Baba Eishi
Published: February 2020

35

Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances anti-tumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 and has shown efficacy for platinum-refractory recurrent or advanced head and neck cancer (HNC). However, subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for HNC and specifically associated with the prognosis have not been clarified. Methods: Peripheral blood mononuclear cells of 15 HNC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). We performed comprehensive analysis of the proportion of immune cell subsets by flow cytometry, including the expression of coinhibitory and costimulatory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), B and T lymphocyte attenuator (BTLA), CD28, OX40, inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were also analyzed. Results: Median progression free survival (PFS) of the whole patients was 96 days (95% CI 70–308). After a single course of nivolumab, patients showed a significant increase in activated central memory and effector subsets of CD4+/CD8+ T cells and activated helper T1 cells (p = 0.0039, 0.0078, 0.0273, 0.0391, 0.0391). A trend of increase of activated effector memory CD4+/CD8+ T cell was observed (p = 0.4961, 0.3594). At the time of PD, effector regulatory T cells, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells and BTLA positive CD4+/CD8+ T cells significantly increased. Significant positive correlations were found between PFS and the proportion of OX40 positive CD4+/CD8+ T cells before nivolumab therapy (p = 0.0239, 0.0134). Conclusions: Nivolumab therapy enhances activation of central memory and effector subsets of CD4+/CD8+ T cells. The expression level of OX40 on T cells was correlated with efficacy of nivolumab therapy in HNC patients.
Preclinical evaluation of anti-ROR1 CAR T cells employing a ROR1 binding SCFV derived from the clinical stage mab cirmtuzumab.
Authors: Prussak Charles E. , Oh Christopher , Velez Lujan Juliana , Lam Sharon , Zhang Jieyu , Fernandez Jayde , Sinha Navyaa , Pham Jessica , Shi Haoming , Shin Caitlin , Kaufman Gunnar F. , Widhopf II George F. , Cohen Ezra E.W. , Kipps Thomas J. ,   University of California, San Diego Moores Cancer Center
Published: February 2020

41

Background: Chimeric antigen receptor (CAR)-modified T cells (CAR-T) were generated targeting cells expressing ROR1, which is present on many malignant cancers and has been associated with cancer stemness and chemo-resistance. The ROR1 CAR utilizes the humanized single-chain fragment variable (scFv) binding domain of UC-961 (cirmtuzumab), which exhibits high affinity and specificity for human ROR1 and has demonstrated an excellent safety profile in Phase 1 studies. Methods: CAR constructs with varying spacer regions and intracellular co-stimulatory domains, using the scFV of cirmtuzumab, were constructed and used to generate CAR-T cells from healthy donors. These ROR1 CAR-T cells were tested for cytotoxicity against lymphoid cancer cells in vitro and in vivo studies that employed immune-deficient mice engrafted with labeled human leukemia cells MEC1 or MEC1-ROR1, which had been transfected to stably express ROR1. Results: The 2nd generation and 3rd generation CAR-T-cells with analogous spacer regions were comparably potent and selectively cytotoxic for cells bearing the ROR1 target antigen. But the 2nd generation CARs demonstrated greater potency in vitro even at low effector to target ratios. For the in vivo studies, mice received a single injection of ROR1 CAR-T cells or activated T cells from the same donor as a control. The ROR1 CAR-T cells rapidly cleared the leukemic cells from the animals, whereas animals receiving control T cells or no therapy quickly succumbed to progressive disease within 3 weeks. The administered CAR-T products remained highly active following administration and could be detected for ≥ 3 months without evidence for T cell exhaustion. Conclusions: The generated CAR-T cells utilizing constructs with the Fv of cirmtuzumab, a humanized mAb highly specific for ROR1, onco-embryonic surface antigen, effectively and selectively killed neoplastic cells bearing ROR1 both in vitro and in vivo. As ROR1 expression and signaling has been associated with cancer stemness and chemo-resistance utilizing ROR1 CAR-T therapy to target cancer cells might mitigate tumor escape. These data strongly support the rationale for continued development of our ROR1 CAR-T.
Aspartyl (asparaginyl) β-hydroxylase (AABH), a serum biomarker for lung cancer.
Authors: Moshiri Kiarash
Published: February 2020

45

Background: There are no serum biomarkers currently approved for the detection of lung cancer, a leading cause of cancer associated mortality world wide. More than 180,000 cases of lung cancer will be diagnosed in the United States in 2020 by other means such as by X-ray and CT scanning methods, which have inherently lower sensitivity and higher cost when compared generally to serological methods. While the five year survival for lung cancer is 15%, a survival rate of 50% can be achieved when detection is made early in individuals with localized cancer. Current detection methods, however, enable such detection in only about 18% of cases overall. Methods: A prospective serum biomarker Aspartyl (Asparaginyl) ß Hydroxylase (AABH), has been previously found to be elevated by immunohistochemical staining (IHC) in a broad range of cancers, including lung cancer. AABH was detected in > 99% of tumor specimens tested (n > 1000) but absent in adjacent tissue. The present study introduces a double monoclonal sandwich ELISA which provides detection and comparative quantification of AABH in serum of lung cancer patients vs. normal, and high-risk controls such as cigarette smokers without cancer. This is relevant since 87% of lung cancers are attributable to cigarette smoking, and associative parallels can be seen with recent reductions in rates of smoking. Results: Increased levels of serum AABH were found in 99% of patients with lung cancer (n = 192). Serum AABH was found to be undetectable in individuals not known to have cancer (n = 129, specificity = 93%). In patients with lung cancer, AABH was detectable at all stages. In a population of 50 smokers not known to have cancer, the mean serum AABH level was 0 ng/ml with 90% specificity. Conclusions: The AABH serum ELISA therefore has great promise as an additional diagnostic tool for lung cancer having the practicality and cost effectiveness of conventional serological screening. Elevated serum AABH in conjunction with CT scanning may greatly facilitate earlier diagnosis of lung cancer at a stage in which cure rates are significantly higher and thus may contribute to increased patient survival.
Neutrophil to lymphocyte ratio, PD-L1 expression, and survival in patients with advanced non-small cell lung cancer receiving first-line immune checkpoint inhibitor therapy.
Authors: Li Mingjia , Zhao Songzhu , Spakowicz Daniel , Burkart Jarred Thomas , Patel Sandip H. , Husain Marium , He Kai , Bertino Erin Marie , Shields Peter G. , Wei Lai , Presley Carolyn J , Otterson Gregory Alan , Owen Dwight Hall
Published: February 2020

46

Background: Neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with various types of cancer, including those who are treated with immune checkpoint inhibitors (ICI). We evaluated NLR at baseline and during early phase of treatment for patients with advanced non-small cell lung cancer (NSCLC) who received ICI to evaluate its prognostic value in first line ICI therapy and its relationship to programmed death-ligand 1 (PD-L1) expression. Methods: We retrospectively evaluated patients with advanced NSCLC who received ICI as first line therapy from 2016 to 2018. NLR was calculated as ratio of absolute neutrophil/lymphocyte counts and was consider elevated if ≥5. PD-L1 expression by immunohistochemistry was performed as standard of care with 22C3 antibody. Kaplan Meier analysis was used for survival. Wilcoxon-Mann-Whitney test was used to evaluate PD-L1 expression between groups. All Calculation was performed using SAS V9.4. Results: A total of 78 patients were included in this study; 28 received pembrolizumab monotherapy, 45 received pembrolizumab, carboplatin, and pemetrexed, and 5 received other pembrolizumab combinations. Patients with baseline NLR < 5 before initiating ICI had median estimated OS of 46.1 months (79.4% patient still alive and 95% CI not reached) compare to median OS of 10.7 months (95% CI lower limit 6.4 and upper limit not reached) for patients with NLR ≥5, P < 0.001. Similar association between NLR and OS can be seen when NLR were repeated immediate before the cycle 2 with P = 0.001. We observed an association between baseline NLR and PD-L1 expression. The median PD-L1 tumor proportion score (TPS) was 60% (Interquartile Range 1-80) for patients with baseline NLR < 5 vs 20% (IQR 0-60) for patients with NLR ≥5, P = 0.037. Conclusions: We confirmed the prognostic value of NLR for patients with advanced NSCLC at baseline and during early treatment in patients with NSCLC receiving first line ICI treatment. We also found an association between elevated NLR and lower PD-L1 expression. Future study with larger cohort is still needed to further delineate these relationships.
Association of immune microenvironment to response in treatment-naïve non-small cell lung cancer (NSCLC) samples with follow-up second-line immunotherapy data.
Authors: Cumberbatch Marie , Elliott Nathan , Warren Sarah , Kim Woo Ho , Womack Christopher , Bhagat Milan , Colarossi Lorenzo , Memeo Lorenzo
Published: February 2020

49

Background: Archival specimens collected months or years prior to starting immunotherapy are often used to identify patients for second line immune checkpoint inhibitor (ICI) treatment. PD-L1 expression and the immune microenvironment in these patients may have altered over time following multiple lines of failed standard of care (SOC) treatments. Methods: Formalin fixed paraffin embedded (FFPE) tumor samples, taken during resection performed as first line surgical treatment from a cohort of NSCLC patients (n = 18), were evaluated by Nanostring using the IO360 gene expression panel, and by immunohistochemistry (IHC) for CD3, CD8, PD-L1, CD68 and CD163. The resultant immune profiles were correlated with the clinical follow-up data for radiotherapy, SOC chemotherapy, and second line immunotherapy with the aim of understanding whether immune signatures predictive of response to ICI therapy may be identified in such samples. Results: Of the 18 cases, clinical follow-up data indicated objective response to ICI therapy for 4 patients, with the mean time from initial diagnosis to ICI treatment being 2.8 years (range: 0.4 to 8.5 years). Although pathologist PD-L1 IHC scores were not predictive of response, IHC image analysis data revealed significant increases in CD3 (2.3-fold) and CD8 (2.7-fold) T cell numbers in the responder population. In addition, although CD68+ macrophage frequencies did not differ significantly between responder and non-responder populations, reduced M2-like CD163+ macrophage/monocyte numbers were evident for responders. While the Tumor Inflammation Signature was not predictive of response, several gene expression signatures were significantly associated with response including increased abundance of CD8 T cells, cytotoxic cells, cytotoxicity, MHC class II antigen presentation and Melanoma-Associated Antigens (MAGE). Conclusions: Despite these patients having received various lines of radiotherapy and SOC chemotherapy prior to receiving immunotherapy, immune profiles associated with response to second line immunotherapy were detected in surgical first line resection samples.
Real-world safety of pemetrexed, carboplatin, and pembrolizumab in U.S. NSCLC patients.
Authors: Muehlenbein Catherine , Kim Sangmi , Ryabko Ekaterina , Oton Ana , Agg Himani , Smolyakova Natalia , Kim Jong Seok
Published: February 2020

50

Background: A Phase 3 KEYNOTE-189 clinical trial showed improved clinical benefit with acceptable toxicity of pemetrexed combined with pembrolizumab and platinum (Gandhi, 2018). However, the safety data with this combination has not been evaluated in a real-world setting with large number of patients with non-squamous non-small cell lung cancer (NSQ NSCLC). Methods: Flatiron Health’s electronic health record-derived data were used to identify advanced NSQ NSCLC patients (≥18 y) who received pemetrexed, pembrolizumab, and carboplatin (≤6 cycles; Pem+Pembro+Carb) as initial treatment from May 2017 to Oct 2018. Endpoints were overall occurrence of select laboratory adverse events (AEs; any Grade and Grade ≥3), which were described by treatment phase (Pem/Pembro cycles < 5 vs ≥5) and pre-specified subgroups. Results: The study included 1088 patients (median age = 68 y; male, 57%). In patients with maintenance (Pem/Pembro ≥5) cohort (N = 462), the median number of treatment cycles was 9 for Pembro and 6 for Pem. The occurrence rates of neutrophil count decrease and platelet count decrease were numerically higher in the induction phase, whereas those of chronic kidney disease (CKD) showed an opposite trend (Table). Grade ≥3 CKD occurrence rate was higher in patients with mild renal impairment (5.1% vs 2.6%) and elderly (≥75 y) patients (7.5% vs 3.3%). Conclusions: Considering the heterogeneity and vulnerability of real-world population, the laboratory AE occurrence rate with Pem+Pembro+Carb in this study was comparable with those reported in KEYNOTE-189. Various trends were observed for the respective AEs by treatment phase. [Table: see text]
A real-world analysis of non-small cell lung cancer patients treated with pembrolizumab or pembrolizumab in combination with pemetrexed and platinum.
Authors: Agg Himani , Winfree Katherine B. , Zhu Yajun Emily , Muehlenbein Catherine
Published: February 2020

53

Background: Pembrolizumab (Pembro) is used in first-line treatment of patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) as monotherapy and in combination with pemetrexed and platinum agent (Pembro+Pem+Plat). Pembro monotherapy is approved for patients whose tumors express PD-L1 Tumor Proportion Score (TPS) ≥ 1% while triplet therapy is approved regardless of PD-L1 TPS. These 2 regimens have not been compared in a head-to-head trial, and real world (RW) treatment pattern data are lacking. This study used RW data to describe patients who received Pembro or Pembro+Pem+Plat and associated overall survival (OS). Methods: This retrospective observational study selected adult patients with diagnosis of advanced NSQ NSCLC who started first-line treatment with Pembro or Pembro+Pem+Plat between Mar. 2015- Aug. 2018 in Flatiron Health’s electronic health record-derived database. Patient characteristics were summarized descriptively, and the Kaplan-Meier survival method was used (unadjusted). Results: A total of 1137 patients received Pembro (median age 72 years) and 1068 patients received Pembro+Pem+Plat (median age 67 years). Patient characteristics are shown in the Table. Median OS was 11.9 months for the Pembro cohort and 14.3 months for the Pembro+Pem+Plat cohort. Median OS by PD-L1 TPS was TPS < 1%: 8.8 months for Pembro and 9.5 months for Pembro+Pem+Plat, TPS 1-49%: 8.9 months for Pembro and not reached (NR) for Pembro+Pem+Plat, and TPS ≥50%: 13.4 months for Pembro and NR for Pembro+Pem+Plat. Conclusions: These RW data seem to suggest baseline differences between the population with Pembro and Pembro+Pem+Plat with regard to age, PS, disease stage, as well as PD-L1 status. Those baseline differences may play a role in the clinicians’ choice of the two treatment options for the NSCLC patients. [Table: see text]
Efficacy and toxicities of immune checkpoint inhibitors (ICIs) in advanced melanoma: A single institution experience.
Authors: Welaya Karim , Baran Andrea M. , Lekkala Manidhar Reddy , Sahasrabudhe Deepak M.
Published: February 2020

59

Background: Historically, the prognosis of advanced melanoma has been poor. Recent landmark studies (KEYNOTE-006, CheckMate 066, CheckMate 037 and CheckMate 067) have shown significant improvement in outcomes of patients with advanced melanoma treated with ICIs. In a single institution retrospective study, we evaluated the efficacy and toxicities of ICIs in patients with advanced melanoma treated in real-world clinical practice. Methods: We included patients who received pembrolizumab (PEMBRO), nivolumab (NIVO), or ipilimumab plus nivolumab (IPI/NIVO) at the University of Rochester Medical Center from June 2015 to December 2018. Patient- and cancer-related characteristics were collected and compared between treatment groups. Outcomes including duration of treatment, response rates, and adverse events (AEs) were captured. Progression free survival (PFS) and overall survival (OS) were summarized using the Kaplan-Meier method. Results: We included 89 patients (55 received PEMBRO, 20 received NIVO, and 14 received IPI/NIVO); median age at ICI initiation was 68 years (range, 28-92) and 29% had Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥2. Forty-five patients (51%) had ≥2 co-morbidities. Nine patients (10%) had autoimmune diseases prior to initiating ICIs and 34 patients (38%) had brain metastasis. ICIs were given as first line in 71 patients (80%). Compared to those who received PEMBRO or NIVO, patients who received IPI/NIVO were younger (median age was 61 vs.71 vs. 70, p=0.003) and had better ECOG PS (ECOG PS ≥2 was 0% vs. 40% vs. 33%, p=0.007). Table shows the outcomes for the three groups. Conclusions: Patients with advanced melanoma treated with ICIs derived similar response rates to those seen in published landmark studies. However, median OS was shorter (range was 38 months to not reached in published studies). [Table: see text]
A phase I/IIa clinical trial investigating the therapeutic cancer vaccine UV1 in combination with ipilimumab in patients with malignant melanoma: Four-year survival update.
Authors: Ellingsen Espen Basmo , Aamdal Elin , Inderberg Else Marit , Rasch Wenche , Brunsvig Paal , Aamdal Steinar , Hovig Eivind , Nyakas Marta , Guren Tormod Kyrre , Gaudernack Gustav
Published: February 2020

62

Background: Combining checkpoint blockade with a cancer vaccine may induce broader immune responses, leading to better clinical outcomes. UV1 targets the enzyme telomerase (hTERT) which is expressed in almost all cancer types and is essential for the immortality of cancer cells and a hallmark of cancer. UV1 consists of three synthetic long peptides and vaccination induces Th1 responses in most patients irrespective of HLA type. This trial explores the synergistic effect of CTLA-4 blockade and hTERT vaccination, allowing unchecked expansion of hTERT-specific T cell clones. Increased number of tumor-specific T cells is associated with a favorable clinical outcome in patients with metastatic melanoma. We investigated the safety, immunological and clinical responses of UV1 vaccine and ipilimumab in this group of patients. Methods: In a phase I/IIa, single-center trial (NCT02275416) patients with metastatic melanoma received treatment with UV1 (300 µg) + GM-CSF (75 µg) as an adjuvant, combined with ipilimumab (3 mg/kg). Safety was assessed according to CTCAE v. 4.0, and tumor responses according to RECIST v.1.1. Immune responses against UV1 peptides were monitored in peripheral mononuclear blood cells by using 3H-thymidine proliferation and IFN-γ ELISPOT assays. Tumor mutational burden (TMB) estimations were based on whole-exome sequencing. Results: 12 patients were treated from Feb to Nov 2015. Treatment was generally well tolerated. Adverse events mainly included injection site reactions and diarrhea. Immune responses occurred very early and 10/11 evaluable patients showed an immune response. Three patients obtained a partial response, and one patient a complete response. 3-year overall survival (OS) was 67%. 4-year survival outcome will be presented along with baseline characteristics and TMB estimations. Conclusions: Combining UV1 and ipilimumab is safe and induces clinical responses in melanoma. The high proportion of immunological responders and early induction of detectable immune responses suggest synergism. OS compares favorably to historical controls. Clinical trial information: NCT02275416.
Multi-institutional, prospective, randomized, double-blind, placebo-controlled phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine to prevent recurrence in high-risk melanoma patients: A subgroup analysis.
Authors: Chick Robert Connor , Faries Mark B. , Hale Diane F. , Kemp Bohan Phillip M. , Hickerson Annelies , Vreeland Timothy J. , Myers John William , Cindass Jessica L. , Brown Tommy A. , Hyngstrom John Robert , Jakub James W. , Sussman Jeffrey J. , Berger Adam C. , Shaheen Montaser F. , Clifton G. Travis , Wagner Thomas , Peoples George Earl
Published: February 2020

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Background: A novel vaccine strategy may prevent recurrence in high-risk melanoma patients (pts). The TLPLDC vaccine uses yeast cell wall particles (YCWP) to load tumor lysate into autologous dendritic cells (DC). In this phase IIb trial of TLPLDC vs. placebo in resected stage III/IV pts, TLPLDC increased 24 month (mo) disease free survival (DFS) in the per treatment (PT) population. Here, we present a 24mo DFS subgroup analysis and estimated overall 36mo DFS. Methods: Disease-free pts were randomized 2:1 to the TLPLDC vaccine vs. unloaded YCWP+DC at 0, 1, 2, 6, 12, and 18mo. The protocol was amended to allow concurrent adjuvant checkpoint inhibitor (CPI) therapy once approved. The pre-specified PT population included only pts completing the primary vaccine/placebo series (PVS) at 6 mo. Kaplan-Meier estimates of DFS were used to compare treatment arms by stage (III or IV) and CPI therapy (yes/no) in the ITT and PT populations. Results: 144 pts were randomized (103 TLPLDC, 41 placebo); 98 pts (66 TLPLDC, 32 placebo) completed the PVS. There were no clinicopathologic differences between treatment groups. There was no difference in 24mo DFS in stage III pts (n = 112), but in stage IV pts (n = 32), the 24mo DFS was 44% vs 0% (TLPLDC vs placebo) (p = 0.41) in ITT and 73.3% vs. 0% (HR 0.14, p = 0.002) in PT. Stage IV pts were more likely to receive CPI than stage III pts (50% vs. 30%, p = 0.003). There was no difference in 24mo DFS for pts who did not receive CPI (n = 102), but in pts who received CPI (n = 42), the 24mo DFS was 49.3% vs. 31.3% (p = 0.71) in ITT and 68.8% vs. 41.7% (HR 0.46, p = 0.28) in PT, showing a trend toward improved DFS in pts who completed the PVS and received CPI (n = 31). Overall, the 36mo estimated DFS was 34.2% vs. 21.6% (p = 0.89) for ITT and 56.9% vs. 27.9% (p = 0.021) for PT. Conclusions: The TLPLDC vaccine improved DFS in patients completing the PVS at 24 and 36 mos, particularly in the resected stage IV subset. The apparent synergistic effect with TLPLDC + CPI will be confirmed in a phase III study evaluating adjuvant TLPLDC + CPI vs. CPI alone in resected stage IV melanoma pts. Clinical trial information: NCT02301611.
Plasma PD-L1 levels according to histologic grade and IDH status in patients with gliomas.
Authors: Cabezas-Camarero Santiago , García-Barberán Vanesa , Pérez-Alfayate Rebeca , Gandía María L. , Díaz-Millán Isabel , Pérez-Segura Pedro
Published: February 2020

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Background: Plasma immune biomarkers such as soluble plasma PD-L1 (sPD-L1) may serve as surrogates of the immune condition of cancer patients and be potential markers of response to different immunotherapy modalities. Very few data exist regarding sPD-L1 in patients with primary brain tumors. Our aim was to study the levels of sPD-L1 in patients with gliomas according to histologic grade and IDH mutation status. Methods: Patients (pts) with grade II to IV gliomas were prospectively enrolled. Single-time-point plasma samples were obtained prior to adjuvant radiotherapy +/- chemotherapy. sPD-L1 determined using ELISA with a rabbit polyclonal anti-PDL1/CD274 antibody as capture reagent. Results: Between February 2017 and August 2019, 44 patients (pts) with gliomas and 12 healthy controls (HC) were enrolled. N=11 grade II, n=9 grade III, n=24 grade IV; n=26 IDHwt, n=18 IDHmut. Higher sPD-L1 levels in glioma pts compared to HC (60.8 vs 47.8 ng/ml, p=0.05). Higher sPD-L1 levels in grade II vs grades III-IV (73.3 vs 60 ng/ml, p=0.09). Higher sPD-L1 in IDHmut grades II-III vs IDHwt grades II-III + IDHmut/wt grade IV (73 vs 59 ng/ml, p=0.07). Non-significantly higher sPD-L1 in grades II-III vs grade IV (73 vs 59 ng/ml, p=0.46). No difference in sPD-L1 in IDHmut vs IDHwt (63.3 vs 59.1 ng/ml, p=0.496), nor in IDHwt vs HC (59.1 vs 47.8 ng/ml, p=0.109). Trend to significance in IDHmut vs HC (63.3 vs 47.8, p=0.062). Conclusions: sPD-L1 levels were significantly higher in glioma pts compared to HC. A trend was seen towards higher sPD-L1 levels in lower-grade (grades II, III) IDHmut gliomas. These findings may indicate a different systemic immune profile for currently defined glioma groups based on histologic grade and IDH status and merit confirmation in a larger sample.
Targeting the immunosuppressive tumor microenvironment: Synergistic effect of low-dose IL12 in combination with dual immune checkpoint inhibition in a preclinical model of ovarian cancer.
Authors: Pavicic Paul G. , Rayman Patricia A. , Al-Sudani Hussein , Diaz-Montero C. Marcela , Mahdi Haider
Published: February 2020

7

Background: Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer with ~22,000 women diagnosed annually in the US. The impact of immune checkpoint inhibition (ICI) in the treatment of solid tumors has been significant. However, the response rates for OC are low ranging from 11-15%. It is critical to explore strategies to enhance the efficacy of ICI immunotherapy in OC. Targeting immunosuppressive factors and cells within the tumor microenvironment (TME) represents a feasible approach. The use of IL12 is attractive because induces potent antitumor activity by targeting myeloid cells and lymphocytes. However its clinical application has been hindered by its potential systemic toxicity. Here we explore the use of low dose intraperitoneal IL12 to enhance the antitumor activity of dual ICI in OC. Methods: Mice bearing ID8-VEGF tumors implanted intraperitoneally received either anti-PD1 alone or dual ICI treatment of anti-PD1 plus anti-CTLA4 with or without low dose IL12. Ascites accumulation was used as surrogate for tumor progression and determined by assessing weight increase. Blood and ascites were analyzed by flow cytometry for frequency of PMN-MDSC, M-MDSC, and activated T cells. Results: Low dose IL12 alone induced a significant delay in ascites accumulation when compared to untreated controls or mice treated with PD1 monotherapy or dual ICI. Addition of IL12 to dual ICI resulted in significant tumor regression and extended survival benefit compared to dual ICI alone. A synergistic effect of IL12 was not observed when combined with PD1 monotherapy. Antitumor responses associated with a marked decrease in the frequency of M-MDSC in blood and a decrease in both PMN- and M-MDSC in ascites. Decrease in MDSC associated with elevated levels of activated T cells. Conclusions: Low dose IL12 can induce regression of ID8-VEGF tumors. However, durable responses were only observed when IL12 was added to dual ICI. This suggests that IL12 can induce changes in the TME, particularly on MDSC, that can potentiate the antitumor activity of dual ICI. Our findings also suggest a crucial role of CTLA4 blockade perhaps via Treg targeting.
Effect of plinabulin, a novel late-clinical stage immunotherapeutic agent on the adaptive and innate immune system.
Authors: Mohanlal Ramon W. , Huang Lan
Published: February 2020

8

Background: Plinabulin (Plin) is a small molecule Dendritic Cell modulator, which in the presence of antigen, increases T-cell proliferation in an antigen-dependent manner marrow. The addition of Plin to Docetaxel (Doc) improved mOS with 4.6 months vs Docetaxel monotherapy, and prolonged DoR with more than 1 year (p < 0.05), which is indicative of an immune-mediated mechanism of action (Mohanlal, ASCO-SITC 2017). Neutrophils are our first line of innate immune defense against foreign invaders. We previously reported that Plinabulin prevents chemotherapy (Chemo) Induced Neutropenia (CIN) in patients receiving Doc or TAC throughout the cycle (Doc, Doxorubicin, Cyclophosphamide) (Blayney ASH 2018, St Gallen 2019). Here we analyzed the onset time of neutrophil increase following Plin administration. In addition, we analyzed the impact of Plin on plasma haptoglobin, which is an acute phase protein with anti-inflammatory effects together with immune-enhancing effects and is an integral part of innate immunity (Kristiansen Nature 2001). Methods: Absolute neutrophil count (ANC) and haptoglobin data were analyzed from Phase 2 study BPI-2358-106 (NCT03294577) with 10 (n = 15), 20 (n = 15) and 30 mg/m2 (n = 12) Plin in Breast Cancer patients receiving TAC. Plin was administered on Day 1. ANC and Haptoglobin were analyzed by a Central Laboratory (Covance), from blood draws at predose, and post-dose Plin at Day 2,3,6,7,8,9,10,11,12,13 and 15, and changes relative to predose value were evaluated. Results: Plin dose-dependently increased ANC within 1 day (P < 0.001) and Haptoglobin within 3 days (P < 0.03) of dosing. Mean haptoglobin (P < 0.0005) and ANC (P < 0.001) levels increased with ~two-fold vs baseline levels. ANC levels remained increased for approximately 1 week and haptoglobin levels for > 3 weeks. Conclusions: Based on Plinabulin’s ability to stimulate the innate system, together with its previously reported evidence as a potent activator of the adaptive immune system (Mohanlal, ASCO-SITC 2017), it is concluded that Plinabulin is a potent stimulator of the adaptive and innate immune system. Clinical trial information: NCT03294577.
Immune-related adverse events (irAE) to cancer immune checkpoint inhibitors (CPI) and survival outcomes: To rechallenge or not—An Appalachian experience.
Authors: Albandar Heidar , Safi Salah Ud Din , Fuqua Jacob Lane , Merrill Samuel , Ma Patrick C.
Published: February 2020

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Background: The adoption of immunotherapy has led to a paradigm shift in the treatment of many advanced stage malignancies. Patients with durable long term survival under cancer immunotherapy have begun to emerge. Circulating memory immune T and B-cells play a key role in the anamnestic response to future similar antigen exposure and may contribute to durable cancer immunotherapy response and benefits in patients with irAE. We hypothesized that there is increased median overall survival (mOS) in patients who had irAE under CPI therapy. Methods: We conducted a retrospective analysis with an IRB-approved study protocol of adults treated between 2011-2019 at the West Virginia University Cancer Institute, with a histopathologic diagnosis of melanoma or lung cancer, who had received CPI therapy. We collected data on demographics, histology, stage at diagnosis, immunotherapy type used, irAE and its grade, and days from immunotherapy initiation to death. Patients were stratified by irAE status and CPI rechallenge status following irAE. Results: Demographics were similar between the irAE and non-irAE groups within both cancer types. A total of 229 lung and 114 melanoma cancer patients had received CPI. Overall, there were 105/343 (30.6%) cases of irAE found of any grades: 27.5% of lung and 37.7% of melanoma patients developed irAE. The mOS for the non-irAE cohort group was 299 days, which was significantly worse than the irAE cohort (mOS not met, Log-rank, p < 0.0001). Within the irAE cohort, there was no significant survival difference between the non-rechallenged and rechallenged groups (Log-rank p = 0.6150). Conclusions: Our findings identified significantly improved survival outcomes among lung cancer/melanoma patients treated with CPI who developed irAE, including those who were rechallenged after irAE, compared to those who had no irAE. Patients who were CPI-rechallenged after irAE had comparable survival outcomes compared to those without rechallenge. Further multi-center validation studies and prospective studies are warranted to further confirm these findings and help guide clinical management in patients who experience CPI irAE.