bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular immunotherapy redirected by bispecific antibodies in primary ovarian cancer cells: A preclinical study
Authors: Chan J. K. , Hamilton C. A. , Cheung M. K. , Schulz S. , Thorne S. H. , Anderson E. M. , Baker J. , Husain A. , Teng N. N. , Contag C. H. , Negrin R. S. 
Published: March 2020

2518 Background: Cytokine induced killer cells (CIKs) are ex-vivo activated and expanded CD8+ natural killer T cells that have been shown to have cytotoxic activity against cancers in randomized clinical trials. This preclinical study demonstrates the enhanced effect of CIK killing in primary ovarian carcinoma using bispecific antibodies (BSAbs) and the potential of translating our findings to a clinical trial. Methods: Primary ovarian cancer cells and autologous CIKs were collected and cultured under IRB approval. Cytotoxicity enhancing BSAbs against CA125 (BSAbxCA125) and Her2/neu (BSAbxHer2) were designed using chemical conjugation methods. Tumor cell lysis of ovarian primary ovarian cancer cells was quantified using 51Cr release assays. Anti-NKG2D monoclonal antibodies were used in antibody blocking assays. Using a SCID mouse model of minimal residual disease, tumor progression was monitored using the bioluminescence imaging (BLI) system. Three-color immunofluorescence analysis was performed on pathologic specimens to localize CIK migration to tumor cells. Results: The mean percent lysis with an Effector:Target (E:T) ratio at 100:1 was 22.2% (±2.0) in primary cells in 4-hour killing assays. Redirection with BSAbxCA125 significantly enhanced cytolysis to 65.7% (±0.6). Adding BSAbxHer2 significantly enhanced cytolysis of cell lines to 89.4% (±1.3). Anti-NKG2D antibodies significantly attenuated the CIK activity by 54%. In vivo BLI studies in SCID mice showed that CIK treatment at a 10:1 E:T ratio was well-tolerated and effective in reducing tumor burden by 80% after 21 days post-treatment compared to untreated mice (p<0.0001). Immunofluorescence staining clearly depicted the in vivo infiltration of CIK (CD8+NKG2D+) cells into Her2-expressing tumor targets. Conclusions: Bispecific antibodies effectively enhanced the cytotoxicity of autologous CIK cells against fresh ovarian tumors. Our in vivo studies suggest that CIK cells may ultimately prove to be efficacious immunotheraputic modality in the treatment of resistant ovarian cancer. No significant financial relationships to disclose.
A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of MDX-214, a novel immune-mediated mechanism agent targeting the epithelial growth factor receptor (EGFR), in patients with advanced solid tumors
Authors: Mita C. A. , Papadopoulos K. , Mita M. M. , Ricart A. , Sarantopoulos J. , Berg K. , Uritz B. , Levy E. , Lowy I. , Tolcher A. W. 
Published: March 2020

2523 Background: MDX-214 is a recombinant fusion protein between human EGF and the Fab′ fragment of a fully human anti-CD89 (IgA FcR) MAb. MDX-214 is designed to block EGFR and activate neutrophils via CD89 stimulation, and promotes EGFR+ cell killing in vitro by both mechanisms. Methods: The objectives of this study were to evaluate the safety and tolerability, to determine the maximum tolerated dose (MTD), to characterize the PK, to assess PD markers and to explore the antitumor activity of MDX-214 administered intravenously weekly for 4 weeksin EGFR+ malignancies. PD studies included monitoring immune cell trafficking to tumors by paired In111 WBC scans at the final dose level, MDX-214 saturation of CD89+ neutrophils in blood, as well as EGFR signaling in skin. Pts were permitted only 1 course of therapy. Results: To date, 18 pts (median age 61, range 48–83, 10 M/8 F) have been treated over 4 dose levels at 0.4, 1, 4 and 10 mg/m2, respectively. Tumor types included renal (4), colorectal (2), pancreatic (2), head/neck (2), tracheal, parotid, esophageal, breast, anal, thyroid, hepatocellular, and skin carcinomas. DLT was encountered at 10 mg/m2 with one grade 3 reversible infusion reaction of rigors, erythema and transient hypoxemia. In the 6 pts treated at this dose level, 2 additional pts experienced grade 2 infusion reactions despite premedication, and one grade 2 hypotension. The MTD was therefore 4 mg/m2. Other grade 1–2 toxicities included nausea/vomiting (9), diarrhea (2), fatigue (4), headache (4). There were 7 pts with stable disease at 6 weeks. The serum half-life was < 30 min but neutrophil-bound MDX-214 was detectable for 24 h. In111 WBC scans are under analysis. Conclusion: Weekly administration of MDX-214, a novel immune mediated therapeutic strategy targeting EGFR is feasible with an MTD of 4 mg/m2. This dose results in neutrophil labeling with MDX-214 for over 24 hours, and may permit activated neutrophil localization at tumor sites. Accrual at the MTD is ongoing. [Table: see text]
Open label phase II studies of modified vaccinia ankara expressing the tumor antigen 5T4 given in conjunction with IFL and FOLFOX chemotherapy regimens: Final analysis of safety and immunogenicity of MVA 5T4 given before, during and after chemotherapy
Authors: Harrop R. , Hawkins R. , Anthoney A. , Steven N. , Habib N. , Griffiths R. , Melcher A. , Wassan H. , Naylor S. 
Published: March 2020

2527 Background: 5T4 is a tumour associated antigen that is widely expressed on the surface of most human adenocarcinomas, including colorectal, but rarely in normal cells. Modified Vaccinia Ankara (MVA) has been employed as a vaccine vector to deliver 5T4. Previously, MVA-5T4 has been evaluated in a phase I/II clinical trial in stage IV colorectal cancer patients. MVA-5T4 was shown to be safe and well tolerated and induced 5T4 specific immune responses in most patients. Furthermore, 5T4 specific antibody titres correlated with clinical benefit. Methods: Two open label phase II clinical trials were initiated in which patients with advanced colorectal cancer received MVA-5T4 in conjunction with either 5-FU/leukovorin and irinotecan (TV2-IFL; n=19 patients) or 5-FU/leukovorin and oxaliplatin (TV2-FOLFOX; n=17 patients). MVA-5T4 was administered up to 6 times, 2 prior to, 2 during and 2 post-chemotherapy. The primary objectives were to assess the safety and immunogenicity of MVA-5T4 given in combination with chemotherapy. Results: Recruitment to both trials is complete and MVA-5T4 was well tolerated in all ITT patients, with no serious adverse events being associated with MVA-5T4. 5T4-specific cellular and humoral immune responses were monitored before, during and after chemotherapy in all 23 per protocol patients (n=12 for TV2-IFL and n=11 for TV2-FOLFOX). Following vaccination, all 23 patients mounted 5T4 cellular and/or humoral responses. Immune responses were detectable during chemotherapy in the majority of patients. IFNγ ELISPOT responses to 5T4 peptides revealed precursor frequencies as high as 1 in 1000 PBMCs. Assessment of clinical responses in all PP patients demonstrated an overall response rate of 65% across both trials. Conclusions: MVA-5T4 is safe and well tolerated when administered in conjunction with IFL and FOLFOX chemotherapy regimens. Furthermore, 5T4 specific immune responses are induced in all per protocol patients and can be boosted or maintained during chemotherapy. Encouraging clinical responses have been observed and 5T4 immune responses shown to correlate with clinical benefit. [Table: see text]
Phase I pharmacokinetics (PK) of humanized anti-MUC-1 antibody R1550
Authors: Pegram M. D. , Borges V. , Fuloria J. , Ibrahim N. , Shapiro C. L. , Perez E. S. , Wang K. , Schaedeli Stark F. , Yeon C. , Courtenay-Luck N. 
Published: March 2020

2533 Background: MUC-1 glycoprotein establishes a molecular barrier at the epithelial surface, and engages in morphogenetic signal transduction. A 20 amino acid MUC-1 core tandem repeat is aberrantly glycosylated in >90% of epithelial tumors, exposing peptide sequence PDTRP. Humanized IgG1 κ monoclonal antibody R1550 binds PDTRP (Kd∼1nM) and induces potent antibody-dependent cellular cytotoxicity. Methods: R1550 clinical tolerability and PK was determined in advanced, PDTRP-expressing (by IHC), breast cancer patients progressing after anthracyclines and taxanes. Key eligibility: informed consent, WHO PS 0–1, life expectancy >4 mos, non-inflammatory histology, and no CNS metastasis. R1550 was infused IV over 1–3 hrs: cohort 1 (N = 3) 1 mg/kg; cohort 2 (N = 9) 3 mg/kg; cohort 3 (N = 6) 9 mg/kg; cohort 4 (N=3) 16 mg/kg, with repeat dosing every 1–2 weeks (patient-individualized PK assessment) until disease progression. Plasma [R1550] was measured by quantitative ELISA. PK parameters were analyzed by a non-compartmental model, and a 2-compartment population PK model. Results: 21 patients (mean age 54, median # of prior chemotherapy agents = 4) have been dosed. Safety data (n=18): R1550 is generally well tolerated with fatigue (28%), gastrointestinal symptoms (22%), skin rash (17%), pyrexia (11%), and elevated liver function tests (11%) as the most frequently reported adverse events (AEs). Two grade 4 AEs were reported: elevated AST, and hyperglycemia, both in cohort 2. Neither have been observed in expanded or subsequent cohorts. Median number of doses received per patient = 3 (range, 3–4), 4 (1–13) and 6 (4–21), in cohorts 1, 2, and 3, respectively. No anti-humanized antibodies were detected. PK parameters of cohorts 1–3 are shown below. Conclusions: R1550 is well tolerated, with MTD exceeding 9 mg/kg. PK parameters using non-compartmental, and 2-compartment population PK models are in agreement. R1550 half-life suggests weekly dosing. Plasma exposure and dose relationships are linear within 1–9 mg/kg dose range. Accrual to cohort 4 is ongoing. [Table: see text] [Table: see text]
Treatment of non-small cell lung cancer (NSCLC) patients with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3): Results of a phase I/II study
Authors: Passlick B. , Schmittel A. , Friccius-Quecke H. , Kanniess F. , Wiewrodt R. , Lindhofer H. , Jaeger M. , Sebastian M. 
Published: March 2020

2540 Background: Catumaxomab is a trifunctional monoclonal antibody with binding specificities to human EpCAM, human CD3 and Fc gamma receptor I/III-positive accessory cells leading to induction of cell mediated, tumor specific cytotoxicity. As EpCAM is overexpressed in NSCLC patients (pts.) the present study was conducted in order to evaluate safety and tolerability of intravenous (i.v.) treatment with catumaxomab. Methods: Patients with NSCLC (UICC stage IB - IV) with at least one prior therapy were included into this trial. Escalating doses of 2–7,5 μg catumaxomab were given as a single i.v. infusion. Various doses of dexamethasone premedication (10 and 40 mg) were investigated at five different dose levels (level: catumaxomab (μg)/dexamethasone (mg)/number of pts. treated: I: 2/40/3, II: 2/0/1, III: 5/40/4, IV: 5/10/5, V: 7,5/40/2, respectively). Primary objectives were toxicity and definition of the maximum tolerated dose (MTD). In addition, time to progression (TTP) and survival were evaluated. Results: 24 pts. were included into this trial; 15 pts. were evaluable for safety analysis, 13 pts. for follow up. 13/15 pts. experienced a total of 68 AEs, of which 55 were reported as drug related and 9 defined as critical AEs. The majority (77%) of AEs were mild (CTC grade 1 and 2), 19% were grade 3 and 4% grade 4. 73% of the AEs were elevation of liver enzymes (gamma-GT, AST and ALT). Other toxicities were increase of blood ALP, dizziness, lymphopenia and pyrexia. Dose limiting toxicity (DLT) was a transient grade 3 and 4 elevation of ALT, AST and gamma-GT, observed at dose levels IV and V. Maximum tolerated dose (MTD) was defined at dose level III. Remarkably, follow up data showed 4/4 pts. stage IIIB and 1/4 pts. stage IV still alive at 26–28 months after catumaxomab treatment. Conclusion: 5 μg of catumaxomab can safely be administered intravenously with 40 mg dexamethasone as premedication. Based on the current results we recommend this regimen as first dose in a future study consisting of multiple catumaxomab infusions in pts. with locally advanced NSCLC. [Table: see text]
Ex vivo blood stimulation assay as a translational research tool in the development of the ticilimumab (CP-675,206)
Authors: Millham R. , Pavlov D. , Canniff P. , Guyot D. , Hanson D. , Ribas A. , Camacho L. H. , Gomez-Navarro J. 
Published: March 2020

2542 Background: Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA4) is an activation-induced T lymphocyte negative costimulatory receptor which down-regulates cellular immune responses. CTLA4 blockade may break peripheral immunological tolerance, leading to an effective immune response to cancer. Tools for assessing the effects of such a blockade are limited, as CTLA4 is not constitutively expressed on circulating T cells, and because activated lymphocytes are difficult to access in vivo. Therefore, we have employed ex vivo blood stimulation assays to define pharmacodynamic properties of the anti-CTLA4 antibody, ticilimumab. Methods: Ex vivo blood stimulation assays employed staphylococcal enterotoxin A (SEA) to stimulate isolated peripheral blood mononuclear cells (PBMC) or whole blood. Stimulation was monitored by production of interleukin 2 (IL-2). This assay was used preclinically to predict in vivo responses in animal models and in samples from cancer patients, as a batch release assay for production runs of ticilimumab, and clinically as a pharmacodynamic measurement in clinical trials of ticilimumab. Results: Screening experiments using the SEA assay allowed us to identify the lead candidate mAb with optimal CTLA4 blockade activity, ticilimumab. Dose-dependent increases in IL-2 production were observed in PBMC and whole blood samples up to an in vitro concentration of 100 ug/mL of ticilimumab, with 10 ug/mL identified as the minimum predicted efficacious concentration (Ceff). This functional potency assay was adapted for qualification of production lots of ticilimumab. Whole blood taken from cynomolgus monkeys dosed with ticilimumab demonstrated significant enhancement of IL-2 production at the same magnitude observed in in vitro experiments. Additionally, longitudinal samples taken from healthy volunteers and cancer patients suggested that an enhancement of 2.8 fold would be indicative of a pharmacodynamic effect of ticilimumab. Conclusions: The SEA assay provides a functional assessment of ticilimumab activity and can be used to guide the clinical development of this agent. Our data suggest that T cell reactivity is enhanced in the presence of ticilimumab in vitro, in primate models and in humans. [Table: see text]
SOX2 antibody responses in patients with various tumor types and SCLC with and without paraneoplastic neurologic syndromes
Authors: Chen L. , Narayanan S. , Posner J. , Ozbek U. , Ritter E. , Gnjatic S. , Chen Y. , Old L. , Gure A. 
Published: March 2020

2562 Background: SOX2, a member of the SOX Group B family of transcription factors, is expressed in normal adult brain, testis and prostate as well as in many SCLC cell lines. Spontaneous antibody responses to SOX2 have previously been shown to be detectable in SCLC patients. We undertook a retrospective study to determine whether antibody responses were detectable in patients with other malignancies and in patients with paraneoplastic neurologic syndromes (PND/PNS). Methods: Previously obtained serum samples from patients with no known disease (n = 84), breast and ovarian cancer (n = 35 each), melanoma (n = 42), NSCLC (n = 150), and SCLC patients, 90 from Turkey and 68 patients studied for PND, were tested by ELISA using serial 4-fold dilutions for anti-SOX2 and anti-HuD antibody. Results: Preliminary data shows SOX2 reactivity in 5/84 (6%) normal volunteer sera, 8/35 (23%) in both breast and ovarian cancer patients, 4/42 (9%) melanoma patients, 20/150 (13.3%) NSCLC patients, and 56/158 (35.4%) SCLC patients. Compared to controls, there was a statistically significant difference in SOX2 immunoreactivity in breast, ovarian (p = 0.007 for both) and SCLC patients (p < 0.001), and a trend was noted in NSCLC patients (p = 0.080). No breast, ovarian, melanoma or normal patient had SOX2 antibody titers ≥1:6400, compared with 32/56 (57.1%) of SCLC (p < 0.01) and 6/20 (30%) NSCLC patients (p < 0.16). Nine SCLC patients had neurologic symptoms and were previously found to have anti-HuD antibodies, associated with a diagnosis of PND. This was confirmed in 8/9 patients in our assay. However, none of the nine patients displayed anti-SOX2 reactivity. Eleven additional SCLC patients were found to be HuD positive by our ELISA. Conclusions: Anti-SOX2 responses are found in a significant proportion of patients with SCLC, breast and ovarian cancer, but not in melanoma patients compared to normal controls. Patients with SCLC have higher titer antibodies when compared with the other groups, and anti-SOX2 antibodies do not appear to associate with anti-HuD responses, supporting the hypothesis that SOX2 immune responses are not associated with PND and may be useful as a vaccine target. Supported by the Cancer and Leukemia Group B/Aventis Oncology Award and the Steps for Breath Foundation. No significant financial relationships to disclose.
A multicenter phase I study of adenoviral p53 in Japanese patients with advanced non-small cell lung cancer
Authors: Kagawa S. , Fujiwara T. , Saijo Y. , Nukiwa T. , Yoshimura K. , Nakamura H. , Kato H. , Chada S. , Tanaka N. 
Published: March 2020

2564 Adenovirus expressing p53 gene, Advexin (A), has shown antitumor activity in a variety of human cancer in preclinical and clinical studies. The goals of this study were to determine the feasibility, safety, humoral immune response, and biological activity of multiple intratumoral injections of A and to characterize the pharmacokinetics of A in Japanese patients with advanced non-small cell lung cancer (NSCLC). Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled into this phase I trial. Nine patients received escalating dose levels of A (1 × 109 to 1 × 1011 plaque-forming units [PFU]) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with A in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, tumor response, antibody formation, and vector distribution. Fifteen patients received a total of 63 intratumoral injections of A without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting > 9 months, and 2 patients had progressive disease. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Despite of the presence of neutralizing anti-adenovirus antibody, specific p53 transgene expression was detected in biopsied tumor tissues throughout the period of treatment using reverse-transcriptase polymerase chain reaction We conclude that multiple courses of intratumoral A injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit. [Table: see text]
A vaccinia-based vaccine (TroVax) targeting the oncofetal antigen 5T4 administered before and after surgical resection of colorectal cancer liver metastases: Phase II trial
Authors: Dangoor A. , Burt D. , Harrop R. , Drury N. , Hamer C. , Andrews D. , Sherlock D. , Stern P. , Hawkins R. 
Published: March 2020

2574 Background: Oncofetal antigen 5T4 is expressed by most colorectal cancers. Administration of a vaccine combining a Modified Vaccinia Ankara (MVA) vector with 5T4 elicits immune responses in late-stage colorectal cancer patients. This trial seeks to investigate the immunological effects of the vaccine both in peripheral blood and locally in tumour tissue resected during potentially curative surgery for colorectal liver metastases. Some patients may have micrometastatic disease, a potential target for immunotherapy. Methods: Colorectal cancer patients selected for resection of liver metastases were eligible. Recruitment of up to 20 patients was planned. Following screening they received 2 vaccinations prior to, and 2 after, surgery. Primary endpoint was assessment of the immune response at time of surgery. Blood was taken for analysis at screening and 2 weeks after each vaccination. A tumour biopsy was obtained at surgery. T-cell responses were assessed using proliferation and gamma-interferon ELISPOT assays; ELISA used to assess serological response. Immunohistochemical analysis was used to confirm tumour antigen expression and the nature of T-cell infiltration into the liver. If 5T4-specific immune responses were demonstrated patients were offered further vaccinations at 20 and 28 weeks post surgery. Results: Of 20 patients recruited, 16 were eligible for assessment, 4 excluded, 1 due to hepatocellular carcinoma, 3 with inoperable disease. There was no grade III/IV toxicity related to vaccination. Tumour expression of 5T4 was confirmed in all cases, local T-cell infiltration consisted predominantly of CD4 cells. According to proliferation assays, 8 of 16 patients had T-cell responses at time of surgery and 12 of 16 in total to date. 14 patients have developed 5T4-specific antibody responses. At median follow up of 8.4 months 7 of 16 patients have disease recurrence. Conclusions: The MVA-5T4 vaccine (TroVax) was safe and well tolerated in all patients undergoing resection of colorectal liver metastases. 5T4 specific cellular and/or humoral immune responses were induced in the majority of patients following vaccination with TroVax. [Table: see text]
Durable clinical responses in patients with metastatic melanoma vaccinated with dendritic cells loaded with killed allogeneic melanoma cells
Authors: Fay J. W. , Ueno H. , Connolly J. , Banchereau J. , Palucka K. 
Published: March 2020

2576 Background: We demonstrated that DCs loaded with killed allogeneic tumors can cross-prime tumor-specific naïve CD8+T cells in vitro. Clinically this approach would overcome HLA restriction inherent to peptide vaccines and allow diversification of immune responses including priming of many clones of CD8+ and CD4+ T cells. Methods: Twenty (20) patients with metastatic melanoma were vaccinated with autologous monocyte-derived DCs loaded with killed allogeneic Colo829 melanoma cell line. A total of 8 vaccines were administered at monthly intervals. DCs were generated from monocytes by culturing with GM-CSF and IL-4 and activated by additional culture with TNFα and CD40 ligand. KLH was used as a control antigen. The first patient was accrued December, 2002 and the last November, 2003. Results: DC vaccinations induced durable objective clinical responses in two patients who had progressive metastatic disease after previous cytotoxic chemotherapy. One patient experienced a CR and one patient a PR both remissions have lasted ≥ 20 months. Fourteen patients were alive at 12 months and 9 patients are alive at the end of 2005. The estimated median overall survival is 22 months with a range of 2–31 months. DC vaccination led to elicitation of CD8+T cell immunity specific to MART-1 tissue differentiation antigen, suggesting that cross-priming/presentation of melanoma antigens by the DC vaccines had occurred in vivo. Vaccinations were safe and tolerable. There were no significant adverse events. Conclusions: The present results justify the design of larger follow-up studies to assess the immunological and clinical response to DC vaccines in patients with metastatic melanoma and other malignant diseases. No significant financial relationships to disclose.