[This corrects the article DOI: 10.1016/j.gore.2020.100648.].

6017 Background: Vigil is an autologous tumor cell vaccine constructed from autologous harvested tumor tissue transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin thereby creating TGFβ expression control. Methods: A randomized double-blind placebo-controlled trial of Vigil vs. placebo was performed in advanced stage frontline OC patients. Relapse-free survival (RFS) and safety were endpoints. Patients who achieved complete clinical response were randomized [1:1 to placebo (control group, CG) or Vigil (Vigil group, VG)] after completion of frontline surgery and chemotherapy. All patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses. Results: Ninety-two patients were randomized with 91 patients in the per-protocol population (PP), (VG n=46; CG n=45). 62 patients were tested for BRCA1/2 status. VG showed no added overall toxicity compared to CG and no grade 4/5 toxicities were observed. Grade 2/3 toxic events were observed in 18% of CG patients (most common bone pain, fatigue) compared to 8% of VG patients (most common nausea, musculoskeletal pain). From time of randomization median RFS for all 91 patients was favorable in the VG (HR 0.69, one-sided p 0.088).Stratified by BRCA status, an advantage in RFS was seen in the BRCA1/2-wt patients in VG (19.4 mo) compared to CG (8 mo) (HR 0.51, 90% CI 0.26 – 1.01, one-sided p 0.050) from time of randomization and HR of 0.49 (90% CI 0.25 – 0.97, one-sided p 0.038) from time of surgery. Median time from surgery to randomization was 208.5 days (6.9 mo) in VG vs. 200 days (6.6 mo) in CG. 37.5% BRCA1/2-wt Vigil treated patients relapsed compared to 71% of placebo at time of data snap for analysis (HR 0.51, one-sided p 0.05), (median follow-up of 34.3 mo for all n=91 subjects). Germline and somatic BRCA1/2 molecular testing via central third party is underway on all 91 patients under continued blinded conditions to validate activity in BRCA1/2-wt. Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed RFS clinical benefit, particularly in BRCA1/2-wt disease. Clinical trial information: NCT02346747. [Table: see text]

TPS5604 Background: Vigil is an immuno-stimulatory autologous cellular therapy, which uses patient tumor cells transfected with a plasmid encoding genes for GM-CSF and furin (to down regulate TGFβ 1&2). In Phase I, systemic immune activation was demonstrated in the majority of patients using an IFNƔ ELISPOT assay. A randomized Phase 2 assessment of Vigil maintenance therapy vs. observation in ovarian cancer demonstrated prolonged relapse free survival (RFS) (Oh J, Barve M, et al. Gynecologic Oncology, 2016; 143: 504–510.). Based on these observations, a Phase 3 study of maintenance Vigil therapy in patients with advanced ovarian cancer was initiated (NCT02346747). Methods: This is a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study of maintenance Vigil in women with Stage IIIb,c or IV high-grade papillary serous/clear cell/ endometrioid ovarian, fallopian tube or primary peritoneal cancer. Patients will have a minimum of 4 and a maximum of 12 Vigil doses manufactured from tumor obtained at primary debulking surgery. Patients must achieve a complete clinical remission following primary surgery and chemotherapy before being randomized 1:1 to receive either monthly intradermal Vigil or placebo. Randomization is stratified by extent of surgical cytoreduction (complete/microscopic vs. macroscopic residual disease) and neoadjuvant vs. adjuvant chemotherapy. The primary objective is to compare RFS of subjects randomized to Vigil vs. placebo, and the key secondary objective is overall survival (OS). The sample size calculation of 222 patients assumes 24 months for accrual and 36 months of follow-up with a median RFS of 19 months from randomization, in the control group. This provides 90% power to detect a hazard ratio (HR) of 0.6 favoring Vigil at the 0.05 level of significance. To date, 61 patients have been randomized and an additional 55 patients are receiving chemotherapy in anticipation of randomization. Tumor tissue is being obtained from approximately 20 patients per month at multiple sites across the U.S. At their last meeting in January, 2017 the independent DSMB recommended that the study continue without change. Clinical trial information: NCT02346747.

Previously we demonstrated not only safety but also provided evidence of clinical benefit to Vigil® vaccine (1 x 107cells/injection 1x/month for 1-8 injections). In addition, we identified a relationship between survival and Vigil® induced circulating activated T-cells against autologous, preprocessed tumor cells (γIFN-ELISPOT) [1,2]. Here we review 15 patients with advanced, heavily pretreated progressive metastatic disease who underwent autologous tumor harvest and subsequent Vigil® construction but in whom manufacturing was only able to construct low-dose Vigil® (1 x 106 – 8.3 x 106 cells/injection 1x/month for 1-8 injections). Of the 12 patients for whom sequential γIFNELISPOT assessment was available, all were γIFN-ELISPOT response negative (<10 spots) at baseline and subsequently developed a positive response. Specifically, 11 converted after 1 cycle of Vigil® immunotherapy and one after 2 cycles. The median (range) γIFN-ELISPOT response was 143.5 (6-474) spots post Vigil® compared to 1 (0-2) pre Vigil®. Median overall survival for these 12 patients was 28.7 months. The three patients without γIFN-ELISPOT assessment had a median survival of 25.3 months. No ≥ grade 1 Vigil® related toxicity was observed. These data which suggest comparable immunological and clinical effectiveness of low-dose Vigil® imply that a smaller harvest tumor volume may be adequate for Vigil® construction, possibly allowing for an image guided core needle biopsy procedure rather than excisional resection for tumor acquisition. Luisa Manning1, Minal Barve2,3,4, Gladice Wallraven1, Padmasini Kumar1, Nicolas Taquet1, Ernest Bognar1, Eric Mendeloff4, Jonathan Oh3, Donald D. Rao5, Beena O. Pappen1, Neil Senzer1,2,5, John Nemunaitis1,2,3,4,5* 1Gradalis, Inc., Dallas, TX, USA 2Mary Crowley Cancer Research Centers, Dallas, TX, USA 3Texas Oncology, P.A., Dallas, TX, USA 4Medical City Dallas Hospital, Dallas, TX, USA 5Strike Bio, Dallas, TX, USA John Nemunaitis, et al., Clinics in Oncology Surgical Oncology Remedy Publications LLC., | http://clinicsinoncology.com/ 2017 | Volume 2 | Article 1254 2 We now report on 15 patients with less than optimal accessible disease volume for harvest or without sufficient tumor harvest for higher dose, in whom only lower dose Vigil® was able to be constructed and administered under protocol. Methods Study design These lower dose patients were participants in an expanded cohort of an ongoing open-label, non-randomized, single-arm Phase 1 study [1,2]. It was established in order to assess lower dose Vigil® above 1 x 106 cells/injection x 4 injections. The standard dose for other Vigil® dosing has been ≥ 1 x 107 cells/injection x 4 injections. Patients with solid tumors following prior standard of care cancer treatment were grouped into 1 of 3 lower dose (1 x 106, 4 x 106, 8 x 106 cells/intradermal injection) cohorts of plasmid transfected autologous tumor cells once a month for up to 12 doses as long as sufficient material was available (minimum of 4 injections). Selection of patients for each dose cohort was dependent on the amount of tumor cell yield following harvest and processing of patients entered into the Phase 1 study. Patients were followed for safety, sequential γIFN-ELISPOT response assessment and survival. Written documentation of full IRB approval of the protocol and consent document was required before a patient could be registered at the site. All patients were treated at a single site, The Mary Crowley Cancer Research Center (Dallas, TX). Inclusion criteria Histologically confirmed advanced or metastatic deemed noncurable with standard of care therapy (if limited to a single lesion may not be a candidate for curative surgery or radiation therapy) was required. Successful vaccine manufacture from one or more tissue sites or fluid obtained from the following major organ systems: digestive, endocrine, reproductive, respiratory and urinary was allowed. Clinically indicated surgical procedure to collect viable tumor for Vigil® EATC manufacturing was required for enrollment. All patients were required to have signed IRB approved informed consent. Vigil® manufacture The construction and GMP manufacturing of Vigil® immunotherapy have previously been described [1,2]. Vigil® cellular immunotherapy was constructed for every patient after surgical collection of autologous tumor tissue, dissociation into single-cell suspension, plasmid transfection, incubation and irradiation. γIFN-ELISPOT assay The γIFN-ELISPOT (enzyme-linked immunospot) assay as previously described [4] was performed using the enzyme-linked immunospot assay for IFN-γ, (BD Biosciences, San Jose, CA, USA). Target (Tumor) cells and Effector (mononuclear) cells were applied in a 3:1 ratio (7.5 x 103 : 2.5 x 103) on an antibody coated microplate reacting with IFN-γ. Quantitative results in form of reactive spots to IFN-γ, secreted by cytotoxic CD8+ T-cells, were measured and used for immune response function analysis. The reading of the γIFN-ELISPOT plates was performed independently by ZellNet Consulting, Inc. (Fort Lee, NJ, USA). A value of ≥ 10 spots and 2x baseline was considered as positive γIFN-ELISPOT response status. Serial γIFN-ELISPOT analyses were performed at baseline, month 2, month 4 and subsequent time points. Vigil® induced γIFN-ELISPOT conversion was defined as ≥ 10 spots and 2x baseline. All patients were γIFN-ELISPOT negative at baseline. Statistical evaluation Survival was analyzed from time of surgical procurement. Patients were censored for survival on the last known date alive. Analyses of time-to-event variables were performed with the use of log-rank statistics and Kaplan–Meier survival curves. Results Patient population Fifteen patients with advanced solid tumors received at least 1 dose of Vigil® (1.0 – 8.3 x 106 cells via ID injection). Demographics are shown in Table 1. All patients underwent tumor procurement as part of the standard medical management for palliative control of disease and qualified for Vigil® immunotherapy. Time of Vigil® treatment was a median of 166 days (range 45-369 days) after tissue procurement. Safety A total of 71 Vigil® autologous tumor cell administrations were given to the 15 patients. All treatment-related AE’s were limited to Vigil® (n=15)

OBJECTIVES:The majority of women with Stage III/IV ovarian cancer who achieve clinical complete response with frontline standard of care will relapse within 2years. Vigil immunotherapy, a GMCSF/bi-shRNA furin DNA engineered autologous tumor cell (EATC) product, demonstrated safety and induction of circulating activated T-cells against autologous tumor in Phase I trial Senzer et al. (2012, 2013) . Our objectives for this study include evaluation of safety, immune response and recurrence free survival (RFS).METHODS:This is a Phase II crossover trial of Vigil (1.0×107 cells/intradermal injection/month for 4 to 12 doses) in Stage III/IV ovarian cancer patients achieving cCR (normal imaging, CA-125≤35units/ml, physical exam, and no symptoms suggestive of the presence of active disease) following primary surgical debulking and carboplatin/paclitaxel adjuvant or neoadjuvant chemotherapy. Patients received Vigil or standard of care during the maintenance period.RESULTS:Forty-two patients were entered into trial, 31 received Vigil and 11 received standard of care. No≥Grade 3 toxicity related to product was observed. A marked induction of circulating activated T-cell population was observed against individual, pre-processed autologous tumor in the Vigil arm as compared to pre-Vigil baseline using IFNγ ELISPOT response (30/31 negative ELISPOT pre Vigil to 31/31 positive ELISPOT post Vigil, median 134 spots). Moreover, in correlation with ELISPOT response, RFS from time of procurement was improved (mean 826days/median 604days in the Vigil arm from mean 481days/median 377days in the control arm, p=0.033).CONCLUSION:In conjunction with the demonstrated safety, the high rate of induction of T-cell activation and correlation with improvement in RFS justify further Phase II/III assessment of Vigil.

3077 Background: Over the last 3 years, follow up in a series of Phase I (study # CL-PTL-101) and phase II studies (study # CL-PTL-105, -107, -114, -110, -112) involving FANG (BB-IND 14205) have been performed involving 123 advanced cancer patients, most of whom previously failed prior systemic therapy. ELISPOT assay which quantitatively measures responding mononuclear cell γIFN release to patient personal tumor was utilized to track immunotherapy activity. Methods: Sequential ELISPOT assessment utilizing patient blood mononuclear cells and autologous tumor tissue as antigen source (harvested prior to immune therapy) were measured at baseline and sequentially afterward. Results: Sixty-four advanced cancer patients received monthly intradermal injections of FANG and 53 had FANG constructed but elected other therapy (No FANG group). Median survival of FANG treated patients was 729 days vs. No FANG patients 260 days, p=0.001. Patients (4%) who were ELISPOT positive at baseline or before receiving FANG or who crossed over (1%) from No FANG to FANG as part of Phase II trial were excluded. Forty-seven patients received FANG and had sequential ELISPOT analysis. Thirty-five were ELISPOT positive, and 12 were ELISPOT negative. Median survival of the FANG ELISPOT positive patients was 995 days vs. 554 days of the ELISPOT negative patients (p=0.011). No significant toxic effect was demonstrated to FANG over the three year follow up period. Seventy-one percent of the ELISPOT positive FANG treated patients were alive at 2 years and 44% were alive at 3 years. By comparison, only 25% of the FANG treated patients who were ELISPOT negative were alive at 2 years and none have reached 3 year survival. Conclusions: Treatment with FANG demonstrates safety and suggests survival benefit in coordination with γ-interferon ELISPOT assessment. Randomized phase II assessment is ongoing. Updated results will be presented. Clinical trial information: NCT01061840, NCT01309230, NCT01505166, NCT01453361, NCT01867086, NCT01551745.

Study Background: Previously, we demonstrated safety and correlated induced immune response with survival in a Phase I study of FANG immunotherapy in advanced cancer patients. We now report long term follow-up (FU) of Phase I treated patients including assessment of relationships of dose, γIFN-ELISPOT response, and patient demographics to safety and survival. Methods: Safety, γIFN-ELISPOT response, and survival have been followed through 3+ years in advanced cancer patients who received ≥ 2-12 intradermal monthly injections of 1×107 or 2.5×107 cells/injection. Clinical and serological assessments were performed monthly, radiographic evaluations bimonthly, and γ-IFN-ELISPOT at baseline, and start of Cycle 2, 4, 6, 9, 12 then sequentially at FU. Results: Previously, we reported results on 45 patients with successful FANG construction followed for 1 year (28 treated (designated FANG); 17 not treated based on availability of other alternative treatments or failed manufacturing (designated No FANG)). We now report FU results through year 3 on those patients and an additional 29 patients (7 FANG, 22 No FANG) subsequently entered into Phase I study (total N=35 FANG; total N=39 No FANG). The median survival of the current expanded Phase I trial population is 562 days vs. 122 days (p=0.00001). This is similar to the originally published data from two years earlier. The γ-IFN-ELISPOT reaction was positive in 14 of the current FANG treated patients and negative in 12 FANG treated patients at Month 3 or less post first injection. Survival correlated with γ-IFN-ELISPOT reaction; median 836 days vs. 440 days with positive and negative ELISPOT respectively, (p=0.04). No long term adverse toxicity has been seen and there was no significant correlation of immune response or survival with either dose or demographics. Conclusions: Treatment with FANG vaccine continues to show long term safety and evidence of benefit in patients with many types of advanced cancer thereby justifying further efficacy testing.

We performed a phase I trial of FANG vaccine, an autologous tumor-based product incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a novel bifunctional short hairpin RNAi (bi-shRNAi) targeting furin convertase, thereby downregulating endogenous immunosuppressive transforming growth factors (TGF) β1 and β2. Patients with advanced cancer received up to 12 monthly intradermal injections of FANG vaccine (1 × 10(7) or 2.5 × 10(7) cells/ml injection). GMCSF, TGFβ1, TGFβ2, and furin proteins were quantified by enzyme-linked immunosorbent assay (ELISA). Safety and response were monitored. Vaccine manufacturing was successful in 42 of 46 patients of whom 27 received ≥1 vaccine. There were no treatment-related serious adverse events. Most common grade 1, 2 adverse events included local induration (n = 14) and local erythema (n = 11) at injection site. Post-transfection mean product expression GMCSF increased from 7.3 to 1,108 pg/10(6) cells/ml. Mean TGFβ1 and β2 effective target knockdown was 93.5 and 92.5% from baseline, respectively. Positive enzyme-linked immunospot (ELISPOT) response at month 4 was demonstrated in 9 of 18 patients serially assessed and correlated with survival duration from time of treatment (P = 0.025). Neither dose-adverse event nor dose-response relationship was noted. In conclusion, FANG vaccine was safe and elicited an immune response correlating with prolonged survival. Phase II assessment is justified.

A 46-year-old Caucasian woman with mental retardation experienced discomfort and irregular menstrual bleeding, which had been increasing for 2 years. The physician from her group home sent her to a gynecologist, where a mass prolapsing through the cervix was noted on physical examination. Cervical and endometrial biopsies were done. Both showed polypoid fragments of endometrium with complex hyperplasia with cytologic atypia and squamous metaplasia (Figure ​(Figure11). A computed tomography scan showed the mass in the uterine cavity, but everything else appeared normal. She was referred to a gynecologic oncologist. Figure 1 Endometrial curettings. A low-power view demonstrating irregular atypical glands with very little intervening stroma. Squamous differentiation is present (arrow). The patient had three risk factors for endometrial cancer: obesity (she weighed 210 pounds, and her body mass index was 36 kg/m2), nulliparity, and hypertension. Both her hypertension and a seizure disorder were well controlled with medications. It was unclear if Pap smears had been done in the past. The probability of endometrial cancer was discussed with her, and she agreed to surgery. Informed consent was obtained through her brother, her legal guardian who also had medical power of attorney. Procedures included exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oopho-rectomy, and bilateral pelvic lymph node dissection. The findings at surgery were a normal appearing uterus, ovaries, and fallopian tubes, with no evidence of obvious disease. The left external iliac vein lymph node appeared pathologically enlarged to 2 cm. The remainder of the pelvic and paraaortic lymph nodes were of normal size, and no other gross abnormalities were seen in the abdomen or pelvis. Clear surgical margins were obtained. On gross pathological examination, the uterus was 223 g and measured 12.3 ⊠ 7 ⊠ 5.3 cm. A polypoid tumor, 9.5 ⊠ 3.2 ⊠ 3.5 cm, was identified, and gross involvement of the lower uterine segment was noted. The cervix and both ovaries were free of disease, both grossly and microscopically, but a right paratubal cyst and left hydrosalpinx were found. Microscopic examination revealed endometrial adenocarcinoma of the endometrioid type (Figure ​(Figure22). Myometrial invasion of 18/20 mm of myometrial thickness was present, and the lower uterine segment was involved up to the endocervical junction. In addition, multifocal lymphovascular invasion was present (Figure ​(Figure33). Figure 2 (a) Section of endomyometrium of the hysterectomy specimen, consisting predominantly of irregular atypical glands infiltrating the myometrium. Focus of solid tumor is present. (b) A high-power view of endometrial carcinoma, endometrioid type, FIGO grade ... Figure 3 Multifocal lymphovascular invasion present within the myometrium (single arrow). The tumor invades the myometrium (double arrow). A total of 28 lymph nodes were excised from the left pelvic, right pelvic, and paraaortic regions. One lymph node in the left pelvis showed metastatic adenocarcinoma, with the largest focus 1.5 cm (Figure ​(Figure44). Figure 4 Extensive involvement of the left pelvic lymph node by metastatic endometrial adenocarcinoma. Note the thin rim of lymph node tissue at the periphery (arrow). Estrogen receptor staining (2–3+) was present in 70% of tumor nuclei; progesterone receptor (3+), 75%; and MIB1, 20% and focally 40% to 50%.

International Journal of Gynecology & ObstetricsVolume 70, Issue S5 p. E34-E34 Free communication Trophoblastic disease and unusual tumors Hydatidiform mole: 25 years experience at the Parkland memorial hospital (PMH) Jonathan Oh, Jonathan OhSearch for more papers by this authorMinal Barve, Minal BarveSearch for more papers by this authorW. Michael Lin, W. Michael LinSearch for more papers by this authorRobert L. Coleman, Robert L. ColemanSearch for more papers by this authorJoseph T. Santoso, Joseph T. SantosoSearch for more papers by this authorCarolyn Y. Muller, Carolyn Y. MullerSearch for more papers by this authorDiana Ferrar, Diana FerrarSearch for more papers by this authorMelanie King, Melanie KingSearch for more papers by this authorEnoch Lowe, Enoch LoweSearch for more papers by this authorDavid Scott, David ScottSearch for more papers by this author Jonathan Oh, Jonathan OhSearch for more papers by this authorMinal Barve, Minal BarveSearch for more papers by this authorW. Michael Lin, W. Michael LinSearch for more papers by this authorRobert L. Coleman, Robert L. ColemanSearch for more papers by this authorJoseph T. Santoso, Joseph T. SantosoSearch for more papers by this authorCarolyn Y. Muller, Carolyn Y. MullerSearch for more papers by this authorDiana Ferrar, Diana FerrarSearch for more papers by this authorMelanie King, Melanie KingSearch for more papers by this authorEnoch Lowe, Enoch LoweSearch for more papers by this authorDavid Scott, David ScottSearch for more papers by this author First published: 11 December 2003 https://doi.org/10.1016/S0020-7292(00)82453-4AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume70, IssueS52000Pages E34-E34 RelatedInformation

Article Free Access Share on Knowledge acquisition and retrieval based on conceptual graphs Authors: Gi-Chul Yang View Profile , Jonathan Oh View Profile Authors Info & Claims SAC '93: Proceedings of the 1993 ACM/SIGAPP symposium on Applied computing: states of the art and practiceMarch 1993 Pages 476–481https://doi.org/10.1145/162754.165207Published:01 March 1993Publication History 3citation379DownloadsMetricsTotal Citations3Total Downloads379Last 12 Months9Last 6 weeks0 Get Citation AlertsNew Citation Alert added!This alert has been successfully added and will be sent to:You will be notified whenever a record that you have chosen has been cited.To manage your alert preferences, click on the button below.Manage my AlertsNew Citation Alert!Please log in to your account Save to BinderSave to BinderCreate a New BinderNameCancelCreateExport CitationPublisher SiteeReaderPDF