bluuebunny/crossref_metadata_2025 huggingface dataset:
Increasing physician recognition and management of immune-mediated adverse events (imAEs): Results of a structured learning platform.
Authors: Rasheed Zeshaan , Kim Caius , Vissers Eugene , Asnis-Alibozek Aviva G. , Antonia Scott Joseph
Published: February 2018

211

Background: Immunotherapies have significantly improved cancer outcomes across multiple tumor types, while concurrently introducing new and unique toxicities, requiring timely recognition and intervention. To advance physician knowledge of imAEs, an educational online platform was developed for use by AstraZeneca clinical trial investigators (PIs). Herein, we report the impact of this educational strategy on PIs’ knowledge and confidence in recognizing and managing imAEs. Methods: The web-based learning platform included 8 structured and interactive modules (mode of action, colitis, pneumonitis, rash, hepatitis, endocrinopathy, neurotoxicity and nephritis), each containing 3 lessons reviewing background, pathophysiology and diagnosis of individual imAEs, management strategies and expert videos. Pre- and post-training questions to test knowledge (n = 5) and confidence (n = 2) were offered. The platform launched in May 2016 and remains active. PIs participating in durvalumab and/or tremelimumab clinical trials are eligible for participation. Results: As of Jan 19 2017, 2372 PIs have been invited to participate, 356 accessed the platform, and 294 completed ≥1 lesson (57% mode of action, 62% colitis, 42% pneumonitis, 20% rash, 24% hepatitis, 18% endocrinopathy, 19% neurotoxicity, 15% nephritis). Although an overall high proportion of correctly answered questions was identified at the pre-training stage (73% of 2935 total questions, n = 169 PIs), accuracy increased by a mean of 11% (range -3‒27%) at the post-training stage (84%). In each module, there was ≥1 question (range 1‒3) for which correct answers increased by ≥15% post- vs pre-training. Overall, after learning, confidence levels in recognition and management of imAEs increased by 28% (57 to 85%, p < 0.05; n = 35‒102 PIs) and 28% (51 to 79%, p < 0.05; n = 28‒101 PIs), respectively. Conclusions: The number of PIs completing ≥1 lesson indicates a desire for imAE training. This educational initiative enhanced knowledge, and among PIs with suboptimal confidence pre-training, 1 in 2 reported increased confidence in imAE recognition and management, which may improve patient care and maximize treatment potential.
T cell responses to tumor associated antigens in multiple myeloma patients treated with MV-NIS, an oncolytic measles virus.
Authors: Packiriswamy Nandakumar , Upreti Deepak , Zhou Yumei , Dispenzieri Angela , Peng Kah Whye , Russell Stephen J.
Published: February 2018

218

Background: Evidence from mouse studies shows that Oncolytic viral mode of tumor cell killing can boost the cytotoxic T lymphocyte response against tumor associated antigens (TAA), leading to ‘bystander’ killing of uninfected tumor cells. Methods: To investigate whether oncolytic virotherapy can boost immune responses to tumor antigens in human subjects we studied T cell responses to 10 different TAA reported to have high expression in patients with multiple myeloma (n = 10) before and after intravenous administration of an oncolytic measles virus (MV-NIS). Baseline and 6 week post-therapy PBMC samples were stimulated with peptides specific to each of the selected TAA and their responses to this antigenic stimulation were measured using IFNγ ELISPOT. Results: Despite their prior exposure to multiple immunosuppressive treatment regimens, some of the tested patients had higher T cell responses to some of the TAA even prior to MV-NIS. Baseline T cell responses against MAGEc1 were present in 50% of the patients, and against hTERT and NYESO-1 in 30% of the patients. Furthermore, MV-NIS treatment significantly boosted T cell responses against NYESO-1, MAGEc1, MAGEA1 and MUC1 in 40% of the patients. Interestingly, in one outlier patient who achieved a stringent and durable complete disease remission after MV-NIS therapy, strong baseline T cell responses were present against 8 of the 10 tested TAA but did not change significantly after virotherapy. Based on the T cell responses to the TAA, three distinct phenotypes can be identified. Phenotype 1 was characterized by positive T cell responses to TAA prior and post therapy, Phenotype 2 was characterized by positive T cell responses to TAA only post therapy and phenotype 3 was characterized by negative T cell responses to TAA prior and post therapy. Conclusions: Our data suggests oncolytic measles virotherapy boosted the cytotoxic T lymphocyte response against tumor associated antigens in some of the patients. Identifying patient’s phenotype based on responsiveness to the TAA could be useful marker for identifying the immune responsive state in multiple myeloma patients and identify patients who can be most responsive to oncolytic measles virotherapy. Clinical trial information: NCT00450814.
Synergy of optimized administration sequence and timing of active DC immunotherapy with a PD1 checkpoint inhibitor in a mouse model of renal cell carcinoma.
Authors: Zubkova Olga A. , Agapova Larissa S. , Ovsepyan Armen A. , Ivanova Vilena , Zeynalova Elmira , Lykov Maxim V. , Eremeev Artem V. , Karpov Andrey P. , Ruchko Sergey V. , Nicolette Charles A. , Shuster Alexander M.
Published: February 2018

31

Background: AGS-003 is an immunotherapy consisting of autologous dendritic cells electroporated with amplified total tumor RNA plus synthetic CD40L RNA and is currently being tested in combination with standard of care to extend survival of newly diagnosed metastatic renal cell carcinoma (RCC) patients in the Phase 3 ADAPT clinical trial. We set out to establish a model system based on the Renca mouse model to more thoroughly study the AGS-003 mechanism of action and identify optimal combination therapies, including with a PD1 checkpoint inhibitor (aPD1 CPI). Methods: Mouse DC precursors were processed in a similar manner to how human monocytes are processed to manufacture AGS-003. Mature DCs were injected s.c. to treat BALB/c mice in an orthotopic syngeneic RCC model. This model system was utilized to test the efficacy and mechanism of action of the AGS-003-like homologous mouse DCs in combination with a murine monoclonal antibody PD1 CPI (anti-mPD1). Results: Murine DCs with similar properties to AGS-003 in combination with anti-mPD1 and sunitinib, resulted in recruitment and migration of lymphocytes into the tumor microenvironment and an increase in peripheral blood CD8+CD28+CD45RA- memory T cells in vivo. Multiple combination dosing strategies were tested and only one dosing regimen (DCs administered prophylactically followed by aPD1 mAb administered therapeutically) showed a substantial synergistic effect (67 days median OS) while all other DC/aPD1 dosing combinations did not exceed the efficacy of DC monotherapy treatment (44.5-48 days median OS). Control animals treated with PBS had a median OS of 29 days. Conclusions: These data demonstrate the importance of the administration sequence for active immunotherapy and aPD1 CPI combination therapy. Our data suggest that the cellular immune response must be initiated and established prior to administration of the aPD1 CPI/sunitinib combination therapy in order to observe synergy in this RCC mouse model. This model may be useful to explore additional combination therapies and effective treatment regimens with other therapeutic agents to guide future clinical development.
Safety and feasibility of immuno-cryotherapy.
Authors: Raja Junaid , Ghodadra Anish , Gettinger Scott N. , Kluger Harriet M. , Sznol Mario , Schalper Kurt Alex , "Kevin" Kim Hyun S.
Published: February 2018

34

Background: To investigate the safety and feasibility of image guided immuno-cryotherapy in patients with immune checkpoint inhibitor failure. Methods: Consecutive patients with primary or acquired failure to immune checkpoint inhibitor therapy were studied following treatment with concomitant image-guided cryotherapy and immune checkpoint inhibition. In addition to demographic features, type of malignancy, size of targeted metastatic lesion, number of cycles of cryotherapy, systemic immunotherapy, and adverse events in a 90 day post procedural window were extracted. The primary end point was safety and adverse events stratified by the common terminology for adverse events (CTCAE) criteria. As a secondary endpoint, efficacy of the cryotherapy was assessed by iRECIST. Results: Ten patients underwent combined image-guided cryotherapy and checkpoint immunotherapy between 2015 and 2017. Five patients received CTLA 4 blockade with cryotherapy, and 8 patients received PD1 axis blockade and cryotherapy. Six patients had metastatic non-small cell lung cancer and 4 had metastatic melanoma. Immunoprofiling demonstrated one patient each with a mutation in NRAS (G12C), NRAS (Q61R), KRAS (G12C), and ALK; and 2 with aBRAF V600E mutation. Cryotherapy was performed in immunotherapy failure sites, including liver (5) and adrenal glands (3), lymph node and muscle. The median size of targeted lesions was 4.5 cm (standard deviation 3.7cm). There were no grade 3 or higher adverse event, though 6 patients had grade 1 and 2 adverse effects in the periprocedural period which included fatigue, local pain, and poor appetite, isolated cases of diarrhea, colitis, pneumothorax, and procedural site hematoma. Regarding therapeutic response: 5 patients demonstrated partial response, 1 stable response, and 1 progression of disease. Two patients died in the followup period from non-treatment induced causes and 1 is awaiting follow-up. Disease control rate was 85.7%. Conclusions: Immuno-cryotherapy with immune checkpoint therapy in patients with immune checkpoint inhibitor resistance is safe and feasible in metastatic NSCLC and melanoma. There were no grade 3 or above adverse events.
Endoplasmic reticulum stress induced Lox-1+ CD15+ polymorphonuclear myeloid-derived suppressor cells in hepatocellular carcinoma and associated with poor prognsis.
Authors: Li Xing , Wu Xiang-yuan , Jiang Nan , Xing Yan-Fang , Chen Jie , Lin Qu
Published: February 2018

38

Background: A recent study indicated that Lectin-type oxidized LDL receptor-1 (LOX-1) was a distinct surface marker for human polymorphonuclears myeloid-derived suppressor cells (PMN-MDSC). The present study was aimed to investigate the existence LOX-1 PMN-MDSC in hepatocellular carcinoma (HCC) patients, the latent mechanism and their association with clinical parameters. Methods: 30 HCC patients and 30 health control were included. LOX-1+CD15+ PMN-MDSCs were investigated. Results: LOX-1+CD15+ PMN-MDSC were significantly elevated in both WB and PBMC of HCC patients compared with healthy control. LOX-1+CD15+ PMN-MDSC were more abundant in PBMC than WB. Addition of PMN-MDSCs resulted in significantly reduced proliferation and IFN-γ production of T cells with a dosage dependent manner. LOX-1-CD15+ PMNs present no suppressive function. The suppression on T cell proliferation and IFN-γ production was reversed by ROS inhibitor and Arginase inhibitor. ROS level of LOX-1+CD15+ PMN by DCFDA were higher in LOX-1+CD15+ PMN-MDSCs than LOX-1-CD15+ PMNs, as well as the mRNA levels of the NADPH oxidase NOX2. Meanwhile, the expression of arginase I and activity of arginase were also significantly raised in LOX-1+CD15+ PMN-MDSCs. LOX-1+CD15+ PMN-MDSCs displayed significantly higher expression of spliced X-box–binding protein 1 (sXBP1), ATF3 and CCAAT/enhancer binding protein (CHOP) were higher. For HCC patients, LOX-1+CD15+ PMN-MDSCs in WB were positively related to Cancer of the Liver Italian Program (CLIP) score. Conclusions: LOX-1+CD15+ PMN-MDSC were elevated in HCC patients and suppressed T cell proliferation through ROS/Arg I pathway with ER stress as a potential feature. LOX-1+CD15+ PMN-MDSC presented positive association with the prognosis of HCC patients.
Targeting intracellular oncoproteins with single domain antibody for cell therapy of esophageal cancer.
Authors: Gao Bin , Lv Lihui , Xia Zhenkun , Gu Mingzhu , Liu Ying , Guo Zhixia , Liang Meng , Yuan Yunchang ,   ASCO_MAR
Published: February 2018

56

Background: Intracellular oncoproteins such as NY-ESO-1 and WT1 are widely distributed in different cancers and ranked as number 1 and 10 prioritized cancer antigen by international experts. It is difficult to target these antigens due to the intracellular nature by conventional antibodies. Methods: Here we reported the development of antibodies to target intracellular antigens, the same way as TCR does, recognizing MHC complex with peptides derived from intracellular oncoproteins. Phage display libraries were screened out against HLA-A2 assembled with different peptides from both WT1 and NY-ESO-1. Antibodies were tested to bind to corresponding HLA-A2/peptides complex on ELISA and FACS and finally the ability to bind to paraffin samples derived from malignancy cancer patients were confirmed. Results: We have identified several antibodies that specifically recognize the corresponding HLA-A2/peptide. Particularly, 2F4 and 1H1 could bind to RMFPNAPYL of WT1 HLA-A2 monomer on ELASA assay, by contrast the antibody did not bind to 5 other non-related HLA-A2 monomers. Furthermore, on FACS assay, both antibodies bound to WT1 peptide loaded T2 cells that express empty HLA-A2 complex on the surface. 2F4 could be routinely expressed as Fc fusion protein and maintained TCR-like feature and could recognize tumor cell lines expressing both HLA-A2 and WT1 antigen on FACS analysis. Both antibodies bind to HLA-A2/ WT1 with the affinity ranging between 10-8 and 10-9 M by Biacore analysis. Finally, paraffin sections from esophageal cancer patients were stained with antibody specific to HLA-A2/RMF and about 30% of samples shown strong reactions and The antibody to HLA-A2/SLL ( NY-ESO-1) shown a similar results although weaker stains due to the lower affinity of the antibody. Conclusions: Intracellular oncoproteins could be targeted by antibodies recognizing HLA associated with the onco-peptide processed. These antibodies have potential applications on CAR-T cell therapy or the development of bi-specific therapeutics for a number of malignancy tumors.
Hepatotoxicity in advanced cancer patients receiving immune-based cancer treatment.
Authors: Alshawa Anas , Fujii Takeo , Abu Sbeih Hamzah , Blechacz Boris , Bilen Mehmet Asim , Hess Kenneth R. , Suarez-Almazor Maria E. , Hong David S. , Tsimberidou Apostolia Maria , Gong Jing , Stephen Bettzy , Subbiah Vivek , Piha-Paul Sarina Anne , Fu Siqing , Mendoza Tito R. , Thirumurthi Selvi , Meric-Bernstam Funda , Naing Aung , Miller Ethan
Published: February 2018

67

Background: Immune-based cancer treatment (IBCT) is increasingly used to treat a variety of cancers. Despite the promising results, adverse events such as dermatitis, colitis, and hepatitis remain a concern. Hepatitis is usually mild but may be severe, requiring modification or cessation of treatment. Here, we describe several cases of immune-mediated hepatitis. Methods: We identified patients enrolled in clinical trials using IBCT through the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, between January 2010 and July 2015. Charts were reviewed for mention of “autoimmune hepatitis”, “hepatitis” or abnormal transaminases, all of which were attributed to IBCT by the treating physician. Hepatotoxicity was graded based on CTCAE v4.0. Results: We identified 12 cases of immune-related hepatotoxicity out of 290 patients. Three patients (1.03%) had grade 3 elevation of transaminases, designated as “autoimmune hepatitis.” Each required systemic steroids and transaminases returned to baseline within a month. IBCT was temporarily held in 2 cases and was permanently discontinued in the third due to grade 4 myositis rather than hepatitis. One patient (0.3%) had grade 2, and eight patients (2.8%) had grade 1 transaminases elevations that were possibly attributable to immunotherapy, but which resolved spontaneously without alteration in treatment. Other significant reported immune-related toxicities ≥ grade 3 were: dermatitis (n = 4), enterocolitis (n = 3), myasthenia gravis (n = 2), myositis (n = 2), pneumonitis, pleuritis, and pancreatitis (n = 1 each). Conclusions: 1.03% of patients experienced grade 3 elevation of transaminases that were attributable to immune therapy. Hepatic adverse events related to immunotherapy in our study were manageable. Further studies are needed to develop biomarkers to identify patients at risk to develop such toxicities. [Table: see text]
mRNA-nanoparticles to enhance and track dendritic cell migration.
Authors: Grippin Adam , Sayour Elias , Wummer Brandon , Monsalve Adam , Wildes Tyler , Dyson Kyle , Mitchell Duane Anthony
Published: February 2018

72

Background: Despite aggressive clinical interventions, glioblastoma (GBM) remains almost universally fatal. In a pilot, randomized, and blinded clinical trial, we recently demonstrated that administration of RNA-loaded dendritic cell (DC) vaccines was associated with significantly improved progression-free and overall survival in patients with GBM (Mitchell et al, Nature 2015). Furthermore, clinical outcomes correlated with migration of Indium-111-labeled DCs to vaccine-site draining lymph nodes (LNs) measured by SPECT/CT imaging. While these studies demonstrated that DC migration may be an important clinical biomarker for response to DC vaccination, the complexity and regulatory requirements associated with nuclear labeling to track DC migration limits widespread application of this technique. We have therefore developed RNA-loaded magnetic nanoparticles (RNA-NPs) to enhance DC migration to LNs and track that migration with a widely available imaging modality (i.e. MRI). Methods: Cationic liposomes were loaded with iron oxide nanoparticles with or without cholesterol modification. The resulting nanoparticles were complexed with RNA and used to transfect DCs ex vivo. RNA-NP-loaded DsRed+ DCs were then injected intradermally into mice and tracked noninvasively with T2-weighted 11T MRI before excision and quantification with flow cytometry. Results: In vitro experiments demonstrate that iron oxide loading does not reduce RNA-NP-mediated transfection of DCs. Additionally, replacement of cationic lipids with cholesterol increased RNA-NP transfection of the DC2.4 cell line and enhanced the T cell stimulatory capacity of treated bone marrow-derived dendritic cells (BMDCs). Compared to electroporation, RNA-NPs enhanced DC migration to lymph nodes and reduced T2 MRI intensity in DC-bearing lymph nodes. Conclusions: This data suggests that iron oxide-loaded RNA-NPs enable noninvasive cell tracking with MRI and enhance DC migration to lymph nodes. We have further shown that inclusion of cholesterol in RNA-NPs augments the stimulatory capacity of transfected DCs. Future work will consider effects of RNA-NPs on antitumor immune responses and the utility of MRI-detected DC migration as a biomarker of vaccine efficacy.
Immunologic efficacy of E39 & E39' vaccination in a phase I/IIa trial in ovarian and endometrial cancer patients.
Authors: Brown Tommy A , Peace Kaitlin M. , Myers John W , Vreeland Timothy J , Hale Diane F , Jackson Doreen O , Greene Julia M , Berry John S , Clifton Guy T , Herbert Garth S , Peoples George Earl
Published: February 2018

75

Background: The treatment options for cancer are ever-evolving & now include vaccines targeting tumor-specific immunogenic peptides to induce tumor cytolysis. Folate binding protein (FBP) is a tumor-associated antigen (TAA) highly expressed in most endometrial & ovarian cancers (Ca), shielded from the normal immune system. The most promising FBP peptides are E39 & an attenuated form, E39' (aka J65). In our most recent phase I/IIa trial we evaluated an E39+GM-CSF inoculation series at 3 doses (VG) vs controls (CG) as well as booster vaccination with E39 or E39' after the initial inoculation series. Here we present the immunologic data from this phase I/IIa trial. Methods: Patients (pts) with ovarian or endometrial Ca who were disease-free after standard of care therapy but at risk for recurrence were enrolled. HLA-A2+ pts were vaccinated in a 3+3 dose escalation of 100mcg, 500mcg, & 1000mcg. The remaining pts received 1000mcg inoculations. Vaccine was given every 3-4 weeks for a total of 6 inoculums. Pts were then offered to participate in booster vaccination with 9 pts randomized to receive E39 & 9 pts E39'. FBP expression level was measured on the resected disease. Overall immunologic response & by subgroups was measured by delayed type hypersensitivity (DTH) & ELISPOT in the VG. Results: A total of 29 pts were vaccinated. Mean DTH prior to the initial dose of E39 was 5.74mm & after final dose was 10.33mm (p = 0.018). Mean overall ELISPOT change over time through 18 months was +69.1 when compared to baseline (p = 0.675). At 18 months, mean ELISPOT increased by 97.1 in 1000mcg vs -57.0 in < 1000mcg dosed pts (p = 0.047) & by +255.33 in pts with > average initial DTH vs -0.75 in < average initial DTH (p = 0.004) when compared to baseline. Immunological analyses were not significantly different between FBP hi/lo expression or E39 vs E39’ booster (p > 0.05). Conclusions: E39 demonstrated significant overall immunogenicity on in vivo testing as measured by DTH. Ex vivo analysis (ELISPOT) suggests that E39 is more immunogenically efficacious in pts with > average initial DTH & those who are optimally dosed (1000mcg). FBP expression level & E39 vs E39’ use in booster inoculations did not significantly impact in vivo or ex vivo immunogenicity. Clinical trial information: NCT01580696.
Identification of microRNAs that target PD-L1 in mismatch repair-deficient colorectal cancer.
Authors: Ashizawa Mai , Okayama Hirokazu , Ishigame Teruhide , Mimura Kousaku , Kono Koji
Published: February 2018

85

Background: Programmed cell death 1 (PD-1) / PD-ligand 1 (PD-L1) immune checkpoint blockade has emerged as a promising therapeutic strategy in various types of cancer. Here we report that certain microRNAs (miRNAs) are involved in immunosuppressive microenvironment by directly targeting PD-L1 in mismatch repair deficient (dMMR) colorectal cancer (CRC). Methods: We identified candidate miRNAs by using RNA-sequence analyses for mRNA and miRNA expression obtained from The Cancer Genome Atlas (TCGA) Colon Adenocarcinoma combined with miRNA target prediction programs. HCT116 and SW837 CRC cell lines were transfected with miRNA mimics and inhibitors, and PD-L1 expression was examined by qRT-PCR, western blotting and flow cytometry. The CRC cell lines were co-cultured with activated T cells and then cytotoxicity for T cells were evaluated. Results: Using miRNA expression profiles of 260 tumors obtained through TCGA Colon Adenocarcinoma, 47 miRNA probes were found to be inversely correlated with PD-L1 expression. Among them, 19 mature miRNAs were down-regulated in dMMR tumors. Furthermore, eight in silico miRNA-target prediction programs were utilized to identify candidate miRNAs that target the 3’UTR of PD-L1 mRNA. We found that forced miRNA expression decreased PD-L1 expression in protein (total and surface) and mRNA levels, and they also dramatically decreased IFN-induced cell surface PD-L1 expression by 32% in CRC cell lines. Furthermore, we found that forced miRNA expression decreased PD-L1 associated apoptotic cell death in co-cultured activated T cells. Conclusions: Our findings suggest that PD-L1 expression is at least in part regulated by miRNAs and may also suggest potential miRNAs to serve as biomarkers and therapeutic targets for cancer immunotherapy.
Aspartyl (Asparaginyl) β-Hydroxylase AABH as a serum biomarker for colorectal cancer.
Authors: Moshiri Mahmood , Moshiri Kiarash , Farbod Yasamin , Moshiri Arsha , Sekhavati Mohammad Hadi
Published: February 2018

86

Background: Colorectal Cancer (CRC) is the third most common type of cancer diagnosed in the US and Canada. WHO, Canadian Cancer Society (CCS), the National Comprehensive Cancer Network (NCCN) and American Cancer Society (ACS) recommend that men and women begin CRC screening at age 50 or younger if at high risk. Recommended screening procedures: Annual occult fecal blood test (OFBT), a colonoscopy every 5 years, OFBT and colonoscopy every 5 years, or a colonoscopy every 10 years. According to The Surveillance, Epidemiology, and End Results (SEER) Program, only 39% of CRC are diagnosed in stage I, 36% are diagnosed in Stage II, 19% are diagnosed with metastasis. The corresponding 5-year survival rates are 89.8%, 67.7%, and 10.3%. Neither the CCS nor the ACS recommends a blood test be done as part of screening. This is due to the fact that, until now, there has not been a blood test with adequate sensitivity or specificity for screening. Methods: In this study we discovered that Aspartyl (Asparaginyl) β-Hydroxylase (AABH) measurement in serum can be used as an screening test for CRC. AABH has been detected by immunohistochemical staining (IHC) on the cell surface of different cancers including CRC. It has been detected by IHC in > 97% of tumor specimens tested (n > 200) but has not been found in tissue samples from normal individuals. Results: This observation and the observation that AABH is found in the serum of patients with cancer, but not in n0n cancer patients, led us to develop a Sandwich ELISA Assay to measure AABH in serum. In the current study we have quantified AABH levels in CRC patients and compared it with normal individual. Increased levels of AABH were found in the serum of 91.5% of patients with CRC in all different stages of Cancer (n = 60). In normal individuals, AABH was essentially undetectable in serum (n = 30). AABH was identified in serum from patients with CRC irrespective of cancer stage. All serum AABH levels for stages I, II, III and IV were more than 3.3 ng/mL. Conclusions: Thus, our data indicate that by measuring AABH in the serum, we should be able to detect CC at an earlier stage than it is currently detected, resulting to a much better 5-year survival for CC.
Autologous tumor lysate-pulsed dendritic cell vaccination therapy after resection of stage IIA (T2N0, T3N0) esophageal cancer: An analysis of immunological responses.
Authors: Sato Yasuyoshi , Yagi Koichi , Mori Kazuhiko , Matsushita Hirokazu , Kakimi Kazuhiro , Seto Yasuyuki
Published: February 2018

96

Background: Immunotherapy using active immunization of tumor associated antigens has been expected to improve the prognosis of malignant tumor patients. We conducted phase I trial to investigate safety and efficacy of autologous tumor lysate-pulsed dendritic cell (DC) vaccination therapy after resection for esophageal cancer. We already reported the clinical results for enrolled 11 patients. All patients completed the protocol therapy and no treatment-related adverse events more than grade 3 was observed (primary endpoint), and recurrence rate within 2 years was 18% (n = 2). In this study, we further analyzed the immune responses in vaccinated patients. Methods: Patients with stage IIA (T2N0 or T3N0, UICC TNM classification 6th edition) esophageal cancer after curative (R0) resection were eligible. Tumor lysate we used for DC vaccines potentially contains mutated proteins (neoantigens) derived from somatic mutations. Patients received DC vaccines (more than 5.0×106 cells) 6 times every 2 weeks. We evaluated neutrophil-to-lymphocyte ratio (NLR) in each patient from CRF data. We identified candidate neoantigens by next generation sequencing and MHC class I binding prediction algorism. We screened the immune responses against those neoantigens using HLA transgenic mice and healthy human PBMCs. Results: Absolute lymphocyte counts, absolute neutrophil counts and NLR were not specifically different between patients with or without recurrence. For specific immune responses, we observed the reactivity in 6 out of 59 candidate neoepitopes identified from two patients in HLA transgenic mouse system. Two out of 6 peptides displayed reactivity in human healthy PBMCs. Conclusions: We analyzed immune responses to predicted candidate neoantigens. We are now investigating immune landscape in the tumor using RNA sequencing data and its relevance to the antigen responses. Clinical trial information: UMIN000002837.
A phase 1b investigation of safety/efficacy of nivolumab and ABI-009 (nab-rapamycin) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS) and Ewing sarcoma.
Authors: Gordon Erlinda Maria , Chua-Alcala Victoria S. , Kim Katherine , Quon Doris M , Chawla Sant P
Published: February 2018

TPS45

Background: Immune checkpoint inhibitors that promote sustained T cell activation may have synergistic activity with an mTOR inhibitor. Objectives: (1) To investigate the maximum tolerated dose of ABI-009, an mTOR inhibitor, when given sequentially with nivolumab, a PD-1 inhibitor, in advanced UPS, LPS, CS, OS and Ewing sarcoma; (2) To investigate the disease control rate (DCR), progression free survival (PFS), recurrence-free survival (RFS) and overall survival using nivolumab/ABI-009 combination therapy in advanced UPS, LPS, CS, OS and Ewing sarcoma; (3) To correlate disease control rate (DCR) based on Immune-related Response Criteria (irRECIST) with that based on RECIST v1.1, and to correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: Forty to fifty previously treated patients with UPS, LPS, CS, OS or Ewing sarcoma will be enrolled. This is a phase 1b study using a defined dose of nivolumab 240 mg and escalating doses of ABI-009 56,75,100 mg/m2 given i.v. I. Dose Escalation Phase 1 Part of Study: The study will employ the standard “cohort of three” design. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. II. Expansion Phase 1b Part of Study: An additional 22-28 patients will receive ABI-009 at the MTD and defined doses of nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients in the expansion phase of the study may continue treatment until significant disease progression or unacceptable toxicity occurs. Statistical Considerations: Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. Clinical trial information: NCT03190174.
Phase I trial evaluating genetically modified autologous T cells (ACTengine IMA201) expressing a T-cell receptor recognizing a cancer/germline antigen in patients with squamous NSCLC or HNSCC.
Authors: Blumenschein George R. , Bourgogne Agathe , Reinhardt Carsten , Ma Hong , Walter Steffen , Weinschenk Toni , Kebriaei Partow , Hwu Patrick , Singh Harpreet
Published: February 2018

TPS78

Background: Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy. T-cell receptor (TCR) engineered ACT approach has contributed to success in solid tumors. ACTengine IMA201 is a product based on autologous T cells engineered to express a naturally occurring TCR specific to a cancer-germline peptide. The target peptide has been characterized in depth by Immatics’ proprietary antigen discovery platform, XPRESIDENT showing exceptional specificity, copy number and expression homogeneity. XPRESIDENT has applied two independent methodologies to confirm the selectivity of tumor target: i) ultra-sensitive quantitative immunopeptidome analyses by mass spectrometry and ii) quantitative mRNA expression analyses by RNASeq. Immatics´ TCR discovery platform is optimized to identify TCRs with low micromolar affinity, specific recognition of tumor cell lines and lack of recognition of healthy normal cells. Methods: This study is an open-label first-in-human dose-escalating phase I trial investigating safety, tolerability and clinical activity in end-stage solid tumor patients. Key eligibility criteria include: recurrent or refractory squamous non-small cell lung cancer or head and neck squamous cell cancer, HLA-A*02:01 phenotype, qPCR biomarker positive from a tumor biopsy, prior established lines of therapy, RECIST v1.1 measurable lesions and ECOG score 0 or 1. At baseline, patients will undergo leukapheresis to collect mononuclear cells (PBMC). The activated PBMC will be transduced with a lentiviral vector for manufacturing of IMA201. IMA201 is infused after a pre-conditioning (lymphodepletion) followed by LD-IL2. The primary objective is to assess safety and to identify the maximum tolerated dose. Secondary endpoints include overall response rate (RECIST and irRC), PFS and OS. The translational objectives include: i) the persistence and functionality of IMA201 in vivo, ii) correlative biomarkers for clinical success, and iii) target expression levels in the tumor. Enrollment to the study is currently ongoing. Clinical trial information: NCT03247309 .
Aspartyl (Asparaginyl) ß hydroxylase (AABH) as a serum bio-marker for prostate cancer to identify prostate cancer, regardless of PSA level.
Authors: Moshiri Mahmood , Moshiri Kiarash , Moshiri Arsha , Monhemi Hassan , Sekhavati Mohammad Hadi
Published: February 2018

10

Background: Background: Prostate Specific Antigen (PSA) is a molecular marker of prostate cancer (PC). I most countries, standard of care suggests annual PSA testing in all men over 50 years of age; and for men at high risk, the test is recommended from 40 years of age. Due to low Specificity and low sensitivity of the PSA test, a large number of unnecessary biopsies occur every year. This low specificity can be due to the fact that PSA is found in both benign and malignant lesions of Prostate tissue. To date measurement of the percentage of free PSA, have resulted an small improvements in specificity of PSA testing. Thus, the development of a simple blood test to detect prostate cancer that exhibits higher specificity compared to PSA could have the potential of reducing biopsies performed due to false positive screening results and improve the quality of medical care. Methods: We have investigated the utility of aspartyl (asparaginyl) β-hydroxylase (AABH) as a prostate cancer biomarker. AABH has been detected by immunohistochemical staining (IHC) in a broad range of cancers including Prostate Adenocarcinoma through out the world. AABH have been detected by IHC in more than 97% of tumor specimens tested (n > 200) while absent in normal and non cancer tissue. We have developed a sandwich ELISA test for the detection of AABH in serum samples. Preliminary results showed an accuracy of 91- 94% for detecting cancer patients from non-cancer patients in different types of Cancer. Here we have utilized this assay to detect AABH levels in the sera of patients diagnosed with Prostate cancer (biopsy proven, pre-treatment samples), compared to non-cancer individuals. Results: AABH was detected above a threshold level of 1.2 ng/mL in 91% of the sera of PC patients (n = 60), in all different stages and grades of Prostate Cancer. All non-cancer individuals (n = 30) had AABH values below the threshold. Further study of direct comparison of AABH to PSA levels (n = 4,000) is underway. Conclusions: Our data suggest that measurement of serum AABH levels may help to detect Prostate Cancer in early stage and potentially reduce the number of prostate biopsies performed due to increased high serum PSA.
Prostate 8 study: A pilot randomized controlled trial (RCT) of a web-based lifestyle intervention versus control group among men with prostate cancer.
Authors: Kenfield Stacey A. , Van Blarigan Erin , Ameli Niloufar , Lavaki Emil , Monroy Cynthia , Tantum Lucy K. , Newton Robert Usher , Zhang Li , Cooperberg Matthew R. , Carroll Peter , Chan June M.
Published: February 2018

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Background: Lifestyle behaviors may reduce risk of prostate cancer progression. Guidelines and tools to support lifestyle modification are needed to improve prostate cancer care. Methods: We conducted a 12-week RCT among 73 men with clinical stage T1-T3a prostate cancer to determine if a lifestyle intervention that included a responsive website, Fitbits, and text messaging helps men adopt 8 healthy lifestyle behaviors (vigorous activity, not smoking, and 6 diet factors) compared to a control group. Eligible men had no contra-indications to aerobic exercise, Internet access, and engaged in ≤4 of the targeted 8 habits at baseline. We explored the efficacy of the intervention (n = 32) vs. control (n = 32) on behavior change via a lifestyle survey, 7 days of ActiGraph GT3X+ accelerometer data, and the Prostate 8 (P8) score (8 self-reported behaviors assigned 0 or 1 point, range 0-8). Results: Baseline characteristics were similar between arms. The median baseline P8 score was 3 in each arm. 12-week assessments were 88% complete (intervention, 94%; control, 82%). Intervention arm participants’ wore their Fitbits a median of 82 days (98%, IQR: 72-83), replied to a median of 71% of texts (N = 60, IQR: 57-89%), and visited the website a median of 3 days [IQR: 2-5] and over 3 visits [IQR: 2-5]. Baseline moderate and vigorous activity were self-reported as 3.7 hrs/wk and 12 min/wk (intervention) and 5.3 hrs/wk and 18 min/wk (control). 1 person was a smoker at baseline. Median [IQR] absolute change in the P8 score from baseline to 12 wks was 2.0 [1.0, 3.0] (intervention) and 0.0 [-1.0, 1.0] (control) (p = 0.0005); and the change between groups was statistically significant for cooked tomatoes, cruciferous vegetables, fish, processed meat, but not significant for healthy sources of vegetable fat (high at baseline) or vigorous activity. Accelerometer data indicated no significant differences in change in physical activity between arms. Conclusions: This novel intervention was feasible and acceptable. These data suggest that the intervention was effective for promoting healthier dietary changes; further research is warranted to examine how to facilitate improvements in physical activity. Clinical trial information: NCT02470936.
Stereotactic body radiotherapy (SBRT) versus high dose rate (HDR) brachytherapy (BT) boost for high-risk (HR) prostate cancer.
Authors: Gonzalez-Motta Alejandro , Roach Mack
Published: February 2018

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Background: Declining use of BT has prompted questions regarding the use of SBRT in HR patients. A systematic literature review was conducted to assess toxicity, and biochemical outcomes following SBRT or HDR BT boost in HR patients. Methods: A search was carried out on the PubMed and Embase databases, for studies published between 2007 and 2017, including HR patients treated with SBRT or HDR boost. Results: We identified 11250 articles, with 6 SBRT and 41 HDR boost studies eligible. The median follow-up was 3.5-5.5 and 2.6-10.3 years in SBRT and HDR boost studies, respectively. The five-year bDFS was 41%–96% in HDR and 69%–98% in SBRT boost studies. Toxicity was reported using the Radiation Therapy Oncology Group (RTOG) scale or the Common Terminology Criteria for Adverse Events (CTCAE) scale and/or validated patient reported Quality of Life (QoL) outcomes. Single SBRT and HDR studies reported 1 year IPSS scores < 7, with 2 SBRT reports of excellent outcomes by the EPIC scale. Acute grade 2 (G2) genitourinary (GU) toxicity ranged from 24-46% and 0.4-33% in SBRT and HDR boost studies, respectively. Late G2 GU toxicity occurred in 2.3-25% and 0-22% following SBRT and the HDR boost, respectively. Late grade 3 (G3) GU toxicity was reported in 0-2.3% and 0-10% with SBRT and HDR boost, respectively. Late G3 GU was reported in 0.8% (2/226) and 4% (114/2763) following SBRT and HDR boost, respectively. Acute G2 gastrointestinal (GI) was noted in 8-19% and 0-19% of SBRT and HDR boost studies, respectively. Late G3 GI was reported in 0-10% and 0-4.6% of SBRT and HDR boost studies, respectively. Late G3 GI was reported in 2% (5/226) and 0.6% (18/2829) of SBRT and HDR boost studies, respectively. Conclusions: SBRT boost may be associated with higher acute G2 but lower late G3 GU toxicity but was not shown by QoL reports, and could be due to selection bias, learning curves or other factors. Randomized trials and validated QoL instruments are needed to accurately compare SBRT to HDR boost.
Is expanded radiographic criteria for clinically positive lymph nodes associated with outcome in pathologically node positive prostate cancer?
Authors: Reichard Chad A. , Gregg Justin , Bathala Tharakeswara , Achim Mary F. , Davis John W. , Chapin Brian Francis
Published: February 2018

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Background: Patients with pN1 prostate cancer (PCa) have heterogeneous outcomes largely dependent on variables only known post-treatment. Traditionally, the size criteria for clinically positive pelvic adenopathy is axial diameter of 10mm. We employed expanded radiographic criteria (ERC) to evaluate for association with differences in outcome differences. Methods: 187 men treated with RP BPLND for PCa from 2001-2013 were identified as pN1. Imaging studies were re-reviewed by a single radiologist (TB) for nodes that were considered positive if they were 8mm or greater in size OR if they were 6mm or greater in size AND either rounded, asymmetrical OR heterogeneously enhancing. This yielded a group of 34 cN1 patients by ERC. Time to biochemical recurrence (BCR) was compared between cN0 and cN1 patients by K-M method. Cox proportional hazards modeling was used to determine association of baseline PSA, node status, adjuvant therapy, Gleason score, positive margins, and ECR with time to BCR and overall survival (OS). Results: Median age (61 v 59 p = 0.3), baseline PSA (8.7 v 11.1 p = 0.2), and positive margin rate (33% vs 32% p = 0.9) did not differ between cN0 and cN1 patients. Median number of positive LNs was higher in the cN1 group (2.7 v 1.8) p = 0.03. Median biochemical recurrence free survival did not differ between groups (3.3 vs 1.8 years p = 0.3) (Fig1). Only Gleason score was associated with shorter BCR free survival HR 1.3 (95%CI 1.0-1.62, p = 0.047). cN1 disease with expanded radiographic criteria did not predict BCR (HR 1.03, 95CI 0.62-171, p = 0.9) or ACM (HR 0.46, 95CI, 0.1-2.12, p = 0.3). Conclusions: Expanded radiographic criteria for clinically positive lymph nodes was not associated with BCR-free survival or OS in a group of pN1 PCa patients. Further study is required to determine if cN1 status based on expanded clinical criteria or more sensitive imaging methods is associated with outcome differences.
Secondary malignancies following low-dose-rate brachytherapy for prostate cancer in a single institution.
Authors: Obayashi Kotaro , Kimura Go , Kuribayashi Shigehiko , Shibayama Keita , Sano Masayuki , Tanabe Kuniaki , Akatsuka Jun , Hayashi Tatsuro , Toyama Yuka , Hamasaki Tsutomu , Maebayashi Katsuya , Kumita Shinichiro , Kondo Yukihiro
Published: February 2018

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Background: Low-dose-rate brachytherapy (BT) is the internal radiation therapy for non-metastatic prostate cancer by implanting radioactive isotope Iodine 125 into the prostate. The carcinogenetic effect of radiation for the treatment of cancer has been proven during the last decades. However, few studies have been reported about brachytherapy-induced secondary malignancies. In this study, we assessed the BT-induced secondary malignancies in our institution. Methods: We reviewed 487 patients treated with low-dose-rate BT from 2006 to 2016 in our hospital. We checked the occurrence of metachronous malignancies (MM) in all the patients and examined the features of MM including the number, organ sites, histology, period from BT to the occurrence, and analyzed whether the features meet the criteria of radiation-induced malignancies. We also examined the relationship between the BT-related radiation doses and the occurrence of MM. We adopted the criteria of radiation-induced cancer proposed by Sakai et al in 1981; different pathological feature from the organ of origin, the follow-up duration after radiation therapy (over 5 years), and whether the lesion is located in the irradiated field. Results: After a median follow-up period of 57 months (range 10-125 months), 23 MM occurred, which were bladder cancer in 4 cases (0.8%), esophageal in 2 (0.4%), gastric in 5 (1.0%), colon in 4 (0.8%), rectal in 3 (0.6%), pancreatic in 1 (0.2%), lung in 3 (0.6%), and brain in 1 (0.2%). Time from initial treatment to MM was 36 months (range 1-85 months). None of the cases had experienced biochemical recurrence. Average radiation dose to the urethra and the rectum including UD90, UD5, U200, R100, R150 showed no significant difference compared to the patients without occurrence of MM. According to the Sakai’s criteria, one bladder and one rectal cancer were judged as radiation-induced secondary malignancies (0.2%). Conclusions: The risk of secondary malignancies in patients undergoing BT was very low. Further studies with longer follow-up are required because it has been only about 10 years since low-dose-rate brachytherapy started in Japan.
Is PI-RADS 3/total lesion ratio associated with clinically-significant prostate cancer in patients with equivocal-risk lesions on multi-parametric MRI?
Authors: Ghabili Kamyar , Swallow Matthew , Suarez-Sarmiento Alfredo , Syed Jamil , Leapman Michael , Weinreb Jeffrey , Sprenkle Preston
Published: February 2018

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Background: Prostate imaging reporting and data system (PI-RADS) category 3 (P3) provides an equivocal assessment of prostate cancer (PCa). We aimed to investigate imaging parameters including the ratio of P3-to-total regions of interest (ROI) that may assist in identifying P3 lesions harboring clinically-significant PCa (csPCa). Methods: We retrospectively queried our institutional MRI-ultrasound fusion biopsy database to identify patients without a prior diagnosis of PCa and with at least one P3 lesion on multi-parametric MRI (mpMRI) who underwent fusion biopsy during Feb 2015-Oct 2017. mpMRI findings were assessed, including prostate and P3 volumes, number of ROIs, and P3-to-total ROIs ratio (P3 lesion volume/total ROIs volumes). Logistic regression and area under the curve (AUC) were used to assess the ability of clinical and mpMRI characteristics to predict csPCa, defined as any grade group (GG)≥2 cancer or GG 1 cancer in > 2 cores or > 50% of any positive core from targeted biopsy of the P3 lesion. Results: Of 127 men with at least one P3 lesion, 29 (22.8%) had csPCa on the biopsy of P3 lesions. Patients with csPCa in P3 lesions had smaller prostate volumes (42.1mL vs 56mL, p = 0.003), lower P3/total ROIs ratios (0.46 vs 1.00, p < 0.001), and higher numbers of total ROIs (2 vs 1, p = 0.004). Compared with patients who had a P3/total ROIs ratio > 0.58, men with ratios < 0.58 were more likely to be diagnosed with csPCa in a P3 lesion (57.1% vs 9%, p < 0.001). Using a threshold of 0.58, P3/total ROIs ratio was 76.1% sensitive and 80.6% specific for csPCa in a P3 lesion. On multivariate analysis, smaller prostate volume (OR1.04, 95%CI 1.01-1.07, p = 0.01) and lower P3/total ROIs ratio (OR1.04, 95%CI 1.02-1.07, p = 0.003) were associated with an increased risk of csPCa in P3 lesions. P3/total ROIs ratio (AUC 0.73) and prostate volume (AUC 0.70) were superior to PSA density (AUC 0.65) for the prediction of csPCa in P3 lesions. Conclusions: Our data indicated that prostate volume and P3/total ROIs ratio outperformed PSA density in and were associated with detecting csPCa in P3 lesions. P3/total ROIs ratio could be used to avoid 80.6% of unnecessary biopsies of a P3 lesion in men with multiple ROIs.