bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics (PK) of split-dose flavopiridol (F) administered with CPT-11 (CPT) and cisplatin (Cis)
Authors: Carvajal R. D. , Tse A. , Wu N. , Gonen M. , Lefkowitz R. , Dials H. , Barbi A. , Mui J. , Schwartz G. K. , Shah M. 
Published: March 2020

2578 Background: F, a cyclin-dependent kinase inhibitor, induces tumor lysis in CLL when administered as a 30 mg/m2 loading dose over 0.5h followed by a 30 mg/m2 maintenance dose over 4h (hybrid F; Byrd et al, Blood 2006). F given as a 1h bolus (bolus F) demonstrates promising clinical activity when combined with CPT in solid tumors (Shah et al, CCR 2005). Data suggest that F concentrations of 2–3 μM are required to enhance the effects of CPT in solid tumors (Motwani et al, CCR 2001), but controversy exists over the optimal F schedule for chemotherapy potentiation. Methods: We are conducting a phase I trial of CPT/Cis→F, with F administered on both a bolus F and hybrid F schedule. After identifying the maximum tolerated dose (MTD) of bolus F (CPT/Cis→F 50mg/m2), the hybrid F schedule was examined. The F loading dose was escalated from 20→30mg/m2 and the F maintenance dose escalated from 20→50mg/m2. Plasma samples were obtained from patients (pts) treated with bolus F at the MTD and with hybrid F at all dose levels. To better assess F PK interaction with CPT/Cis, F was given before CPT/Cis on cycle 2 only. Results: Complete PK data are available from 6 pts treated at the bolus F MTD (50 mg/m2) and on 20 pts treated with hybrid F (20→20 mg/m2, 25→25 mg/m2 and 30→30 mg/m2) for cycles 1 and 2. Both bolus F and hybrid F PK are consistent with data previously reported. Although cycle 1 AUCs are similar for bolus F 50 mg/m2 and hybrid F 30→30 mg/m2 (10.47±4.97 vs 10.75±15.14 μM/h, p=NS), the Cmax achieved with bolus F 50 mg/m2 is significantly greater than that achieved with hybrid F 30→30 mg/m2 (2.31±0.65 vs 1.21±0.35 μM, p<0.02). No significant PK differences occurred between cycles 1 and 2. Toxicity was not associated with F Cmax. With CPT/Cis→bolus F, the PR rate was 10/29 (35%) vs 3/33 (9%) with CPT/Cis→hybrid F. Conclusions: The Cmax achieved with bolus F is greater than that achieved with hybrid F, with no increase in toxicity. Additionally, the Cmax achieved with hybrid F does not exceed the 2 μM plasma concentration required for potentiation of chemotherapy-induced apoptosis. The greater number of responses achieved with bolus F suggests that bolus F may be more efficacious than hybrid F when used in combination with CPT for the treatment of solid tumors. (Supported by R01-CA67819) No significant financial relationships to disclose.
Comparing immunogenicities of tumor-specific antigens administered as therapeutic vaccines in metastatic melanoma patients
Authors: Baurain J. , Stas M. , Neyns B. , Schuler G. , Velu T. , Thielemans K. , Van Baren N. , Dorval T. , Marchand M. , Coulie P. 
Published: March 2020

3003 Background: Therapeutic vaccination of metastatic melanoma patients with detectable disease is followed by some tumor regression in only about 10% of the patients, with no clear difference observed between studies carried out with various tumor-specific antigens and vaccination modalities. For antigenic peptide MAGE-A3168–176, presented by HLA-A1 molecules and administered as peptide alone or recombinant ALVAC poxvirus, anti-vaccine T lymphocyte (CTL) responses have been observed in no progressor patient and in only half of the regressors, suggesting a poor immunogenicity of these vaccines. Methods and Results: We compiled anti-vaccine CTL responses measured in the blood of 202 metastatic melanoma patients vaccinated with various associations of 10 different tumor antigens administered as peptides, alone or with adjuvant, recombinant ALVAC poxvirus, or peptide-pulsed dendritic cells. Blood lymphocytes collected before and after vaccination were all analyzed with the same method involving in vitro restimulation in limiting dilution condition followed by labeling with tetramers for each antigen. A CTL response was deemed to have occurred if the CTL frequency increased by at least 10 times, and if the pre-vaccination frequency was lower than 2 x 10-6 of the CD8 cells. No responses were detected against peptides MAGE- A4230–239 (0/26) and MAGE-C2336–344 (0/22). Some were observed against MAGE-A3168–176 (11/81), MAGE-A1278–286 (2/22), MAGE-A3112–120 (2/55), and MAGE-A10254–262 (2/35). Responses were frequently found against NY-ESO-1157–165 (10/19), GnTVVLPDVFIRC (18/73), gp100209–217 (21/33), or Tyrosinase369–377 (11/59). For the latter four antigens, there was no correlation between the occurrence of CTL responses and that of tumor regressions. Neither did we find a correlation between the CTL responses and the expression of the antigen-encoding genes in pre- vaccination tumor samples. Conclusions: These results suggest that some of the antigenic peptides that are commonly used in melanoma vaccines are more immunogenic than others but do not induce more tumor regressions. Therefore, inducing strong CTL responses against these immunogenic peptides is probably not the most appropriate endpoint of future vaccine trials. No significant financial relationships to disclose.
Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma
Authors: Wolchok J. D. , Gallardo H. , Perales M. , Rasalan T. , Wang J. , Chapman P. B. , Krown S. E. , Livingston P. O. , Heywood M. , Yuan J. 
Published: March 2020

3005 Background: T-cell and antibody responses to self antigens on cancer are usually constrained by immunologic tolerance and ignorance. We found that DNA vaccines encoding xenogeneic differentiation antigens, such as tyrosinase (TYR), can mediate tumor protection and regression in implantable mouse models and dogs with spontaneously arising melanoma. Based on this, we conducted a trial of DNA vaccines encoding mouse and human TYR in patients with AJCC stage III/IV melanoma. Methods: HLA-A*0201+ melanoma patients were randomized to 2 different schedules: one group received 3 injections of mouse TYR DNA followed by 3 injections of human TYR DNA while the other group received 3 injections of human TYR DNA followed by 3 injections with the mouse gene. The study was conducted a three different dose levels: 100, 500 and 1,500 mcg DNA/injection, administered IM every 3 weeks. A total of 18 patients were treated, 6 at each dose level being randomized to one of the two schedules. Anti-TYR antibodies and CD8+ T cells recognizing the native human tyrosinase369-377 (YMDGTMSQV) peptide were measured at fixed time points. T-cell responses were monitored with MHC tetramer and intracytoplasmic IFN-γ staining assays using 10-day in vitro stimulation. Multiparametric flow cytometry was performed to further define the phenotype of responding cells. Results: Most toxicities were transient grade I injection site reactions. Seven patients had CD8+ T cell responses, defined as a >3 standard deviation increase in baseline reactivity to the TYR peptide in either the tetramer or intracellular IFN-γ assay. There was no relationship between dose level or assigned schedule and occurrence of T-cell response. Phenotypic characterization of responding T cells showed that most were consistent with an effector memory phenotype including the expression of granzyme B and surface expression of CD107a. No antibody responses were observed. At a median of 42 months of follow-up, median survival has not been reached and 6/18 patients have died from melanoma (1 in the group of patients who had a T cell response and 5 in the non-responders). Conclusions: Mouse and human TYR DNA vaccines were safe and induced CD8+ T cell responses in 7/18 patients. T cells recognizing a native TYR peptide had a phenotype consistent with that of effector memory cells. No significant financial relationships to disclose.
Human papillomavirus (HPV) 16/18 l1 AS04 virus-like particle (VLP) cervical cancer vaccine is immunogenic and well-tolerated 18 months after vaccination in women up to age 55 years
Authors: Schwarz T. F. , Dubin G. 
Published: March 2020

3007 Background: Although prevalence of oncogenic HPV infection is highest in women younger than 25, incident infection is estimated to occur in 5% - 10% of women aged 25–55. New infections decrease with age, but the proportion that persists is higher. Therefore, women over 25 also may benefit from HPV vaccination. In a primary Phase III study (GSK 105879/014), an HPV-16/18 AS04 cervical cancer vaccine candidate was highly immunogenic and well tolerated in women up to age 55. This extension study evaluates the persistence of immune response and safety through 18 months after the first vaccine dose. Methods: Healthy women aged 15–55 years in Germany and Poland who had received 3 doses of HPV-16/18 L1 AS04 VLP vaccine at months 0, 1, and 6 in the primary study were invited to participate in a follow-up extension (15–25 years [n=169], 26–35 years [n=83], 36–45 years [n=89], and 46–55 years [n=176]). Immunogenicity and safety were assessed up to 18 months after vaccination. Results: At 18 months, 100% of subjects remained seropositive for both antigens in all age groups. For HPV-16, GMCs were 2,220.1 in women 15–25, 1,276.9 in women 26–35, 905.6 in women 36–45, and 809.0 in women 46–55. For HPV-18, GMCs were 828.2 in women 15–25, 441.8 in women 26–35, 289.7 in women 36–45, and 275.5 in women 46–55. In women over 25, GMCs tended to be higher in those initially seropositive. In the oldest age group, HPV-16 and HPV-18 GMCs remained at least 10-fold higher than natural infection levels reported in another study.The HPV-16/18 AS04 vaccine was well tolerated among all age groups. Conclusions: The HPV-16/18 AS04 vaccine candidate was highly immunogenic and well-tolerated. As with other vaccines, an age- dependent decrease in GMCs was observed, but GMCs remained substantially higher than natural infection levels previously reported in women 15–25. More importantly, GMCs at month 18 for women over 25 remained in the same range as GMCs observed in another study in women 15- 25 that were associated with sustained efficacy up to 4.5 years. Thus, in women up to age 55, an HPV-16/18 AS04 vaccine may protect against new infections with oncogenic HPV types that can cause cervical cancer. [Table: see text]
Phase II trial of patients (pts) with extensive stage small cell lung cancer (ES-SCLC) immunized with p53-transduced dendritic cells (p53-DC): Immune sensitization to chemotherapy (CT)
Authors: Chiappori A. , Sereno M. , Gabrilovich D. , Mirza N. , Dunn M. , Janssen W. , Smilee R. , Menander K. , Chada S. , Antonia S. 
Published: March 2020

3012 Background: Although ES-SCLC is initially, very responsive to CT, responses are not durable and relapse is characterized by chemoresistance. High incidence of p53 gene mutations, which prolong the protein’s half life, result in its frequent overexpression and enhanced detection in SCLC cells. This in turn allows for their recognition by p53-specific cytotoxic T cells. Here, we evaluated the clinical and immune response of a vaccine (vac) using p53-DC. Methods: Eligibility: Untreated, ES-SCLC pts. Age = 18 years. Performance status (PS) 0–2. Treated and controlled brain metastases. Adequate renal, hepatic and bone marrow function. Toxicity (T), survival (MST) and clinical and p53- specific immune responses were determined by CTCAE v2.0, Kaplan-Meier, RECIST and ELISPOT and tetramer staining respectively. Pts first received CT to best clinical response. Eight weeks later, those with minor progression (PD) or better, underwent leukapheresis. DC, generated from peripheral blood precursors, were infected with an adenoviral construct containing p53 (Advexin; Ad-p53) to produce the p53-DC vac. Each vaccination consisted of subcutaneous injections in 4 different nodal basins every 2 weeks x3 (2–5×106 p53-DC/dose). Results: Thirty-six pts received at least one vac; median age=58.8, (range=39–79), M/F=13/23, PS 0/1=16/20. All pts were evaluable for T and MST. Total vac=127 (median=3, range=2–6). Overall, vac was well tolerated (no > grade 2 toxicities detected). p53-specific immune response was positive in 11/21 (52.4%) pts; pending in 15 pts. After 3 vac doses, 10 (27.7%) pts. had stable disease (SD) and 26 (72.2%) had PD. Pts with SD were re-vaccinated (x3). Upon PD, all pts were offered further CT. Clinical response to post-vac CT was evaluated in 22 pts. Ten pts (45%) responded to post-vac CT (second line=7, third line=3) and 6 pts had SD. MST=473 days (95% CI: 380,534). Conclusions: ES-SCLC pts were treated safely with p53-DC vaccine and demonstrated significant immune response. The p53-DC vaccine appears to sensitize ES-SCLC to subsequent CT resulting in improved survival. [Table: see text]
Interferon-alpha-2b induced signal transduction and gene regulation in patient immune cells is not enhanced by a dose increase from 5 MU/m2 to 10 MU/m2
Authors: Zimmerer J. M. , Lehman A. , Ruppert A. , Olencki T. , Kendra K. , Walker M. J. , Carson W. E. 
Published: March 2020

3026 Background: High dose interferon-alpha-2b (IFN-a) is employed as an adjuvant in melanoma patients who have had surgery for high-risk lesions. It mediates its anti-tumor effects via activation of the transcription factor STAT1 (signal transducer and activator of transcription) within host immune cells. We hypothesized that intermediate doses of IFN-a would be just as effective as higher doses in stimulating the activation of STAT1 and gene transcription in immune cells. Methods: Samples for analysis were obtained from patients with metastatic melanoma who were enrolled in a clinical trial of bevacizumab in combination with escalating doses of IFN-a (5 MU/m^2 and then 10 MU/m^2). Peripheral blood mononuclear cells (PBMCs) were procured before and 1 hour after the administration of IFN-a and analyzed for the presence of phosphorylated STAT1 (P-STAT1) and P-STAT2 by intracellular flow cytometric analysis and the induction of interferon stimulated gene (ISG) transcripts by Real Time PCR. Results: P-STAT1 in response to 5 MU/m^2 IFN-a was higher than that for the 10 MU/m^2 dose (p = 0.0617). The 5 MU/m^2 dose also led to a greater activation of STAT2 (p = 0.0388). The induction of interferon stimulated genes (ISGs; IFIT1, IFIT2, OAS3) within PBMCs was not enhanced following the increase in IFN-a dose to 10 MU/m^2 at 2 weeks although inhibitors of IFN-a-signaling (SOCS1 and SOCS3) were activated to a greater degree. In addition, microarray analysis was performed on 4 patients and revealed that only one of 36 interferon regulated genes was expressed to a greater extent following treatment with 10 MU/m^2 IFN-a as compared to 5 MU/m^2. Conclusions: These results suggest that 5 MU/m^2 of IFN-a are as effective as higher doses with respect to the induction of STAT signal transduction and ISGs within immune effector cells. No significant financial relationships to disclose.
The response of IFNAR2 to high-dose IFNα2b during a neoadjuvant clinical trial
Authors: Wang W. , Edington H. , Rao U. , Jukic D. , Land S. , Kirkwood J. M. 
Published: March 2020

3027 Background: The appropriate subgroup of melanoma patients to select for high-dose IFNa2b (HDI) adjuvant therapy has been undefined since approval of this modality in 1996. A biomarker appropriate for clinical practice and relevant to the biological effects of this agent would be of great importance. IFNAR2 is required for type I IFN-dependent signaling. Therefore, the response of IFNAR2 during HDI was evaluated during a prospective neoadjuvant clinical trial of HDI. Methods: Following diagnostic biopsy and before definitive surgery, HDI was administered as a neoadjuvant therapy for patients with stage IIIB melanoma, in the context of an IRB-approved protocol UPCI 00- 008, separately reported. Immunohistochemical analysis of IFNAR2 was performed on fixed paired biopsies of 8 patients. Paired-sample permutation tests and two-sample permutation tests were used to evaluate the findings of this study. Mean values of the percentage of IFNAR2 positive cells are presented with standard errors (SE). Results: HDI down-regulates IFNAR2 in both responders and non- responders, from 86.875 ± 5.82 (pre-treatment) to 34.375 ± 9.919 (post-treatment), p = 0.0145. However, the decrease in IFNAR2 differs between responders (25.0 ± 12.583) and non-responders (69.0 ± 3.588), p = 0.021. Conclusions: HDI down-regulates IFNAR2 expression, and may provide a biomarker relevant to HDI benefit, given differences between patients with and without response to neoadjuvant therapy. A larger clinical trial is needed to evaluate these pilot data. No significant financial relationships to disclose.
Humanized anti-CEACAM6 PEGylated scFv: A promising novel therapy for pancreatic cancer
Authors: Mahadevan D. , Garewal H. , Riley C. , Zhu Y. , Engelhardt K. , Cooke L. , Nagle R. , Saldanha J. , Von Hoff D. 
Published: March 2020

3042 Background: Novel Therapies for pancreatic cancer (PC) based on biological insight are urgently needed. CEACAM6, a member of the carcinoembryonic antigen (CEA) family, is a cell surface oncogene on PC cells. It is a glycoprotein composed of 3 Ig-like domains (Mr ∼35.2kD) and is linked to the plasma membrane via a glycophospholipid linked anchor. It is over-expressed on ≥95% PC patients’ found irrespective of stage of disease and represents a target for antibody therapy. Methods: Murine anti-CEACAM6 monoclonal antibody (Mab) 13–1 was humanized by a structure-based approach and single chain variable fragments (scFv) designed consisting of a Gly/Ser-linker which includes a cysteine residue for PEGylation. Murine scFv and 4 humanized scFv fragments (Version.1, 2, 7, 8) were bacterially expressed, purified, PEGylated and evaluated for activity alone or in combination with gemcitabine in human PC cell lines and mouse xenograft tumors. Cell viability, apoptosis and in-cell Westerns were done for efficacy and binding. Mouse xenograft tumors were treated with scFv or PEGylated scFv or combination with gemcitabine. Tumors (treated Vs untreated) were analyzed by immunohistochemistry for Ki-67, CD31, CEACAM6 and Caspase 3 Results: Mab 13–1, murine and 4 humanized scFvs’ were cytotoxic to CEACAM6 expressing PC cells (BxPC-3, HPAF-2) and not to PC cells that lack CEACAM6 (CaPan-2) with increased PARP-cleavage that was dose dependent (IC50=10μg/mL). Western blotting of culture media and serum from xenograft mice showed that CEACAM6 is not shed. In-cell Western confirmed humanized V.7 to be the best binder (KD=1–10μg/mL) confirming protein-protein interaction studies performed in silico with homology models of murine and humanized scFvs’ and CEACAM6. The murine scFv alone or the humanized scFV (V.8) in combination with gemcitabine delayed tumor growth by >50%. This tumor reduction correlated well with the immunohistochemical markers of response. Conclusions: We have demonstrated that CEACAM6 is a clinically relevant target in PC and that a PEGylated humanized scFv is a novel effective therapy alone and/or in combination with gemcitabine. Humanized scFv V.7 is undergoing mouse xenograft evaluation and expect will be the most effective agent to take forward into clinical development. No significant financial relationships to disclose.
Combined neoadjuvant weekly paclitaxel and trastuzumab for HER2-overexpressing breast cancer
Authors: Horiguchi J. , Koibuchi Y. , Rokutanda N. , Nagaoka R. , Kikuchi M. , Sato A. , Ishikawa Y. , Odawara H. , Iino Y. , Takeyoshi I. 
Published: March 2020

3045 Background: The purpose of this study is to determine the clinical efficacy of neoadjuvant paclitaxel and trastuzumab in women with advanced breast cancer, with or without metastatic disease. Methods: Patients with HER2-positive breast cancer (clinical stage IIB-IV) were included in this study. The patients received trastuzumab 4mg/kg loading dose intravenously then 2mg/kg weekly and concurrently paclitaxel 80mg/m2 (Day 1, 8, 15) weekly for 4 cycles followed by surgery. Results: Preliminary results from 15 patients are reported. Of these, six patients (40%) had a clinical complete response and nine patients (60%) a clinical partial response. Fourteen of 15 patients received surgery; eight breast-conserving surgery and six modified radical mastectomy. Six patients (43%) had pathological complete response. With a median follow-up of 19 months (range, 5–32 months), these 15 patients are alive. Patients with clinical stage IIB-III breast cancer are alive without any distant metastasis. Conclusion: Combined neoadjuvant weekly paclitaxel and trastuzumab had high clinical and pathological response rates for HER2 overexpressing breast cancer. No significant financial relationships to disclose.
A phase I study of a CanAg-targeted immunoconjugate, huC242-DM4, in patients with Can Ag-expressing solid tumors
Authors: Mita M. M. , Ricart A. D. , Mita A. C. , Patnaik A. , Sarantopoulos J. , Sankhala K. , Fram R. J. , Qin A. , Watermill J. , Tolcher A. W. 
Published: March 2020

3062 Background: HuC242-DM4 is a novel, targeted anti-cancer agent in development for the treatment of CanAg-expressing tumors such as carcinomas of the colon and pancreas. The compound is formed by the conjugation of the potent cytotoxic maytansinoid drug, DM4, to the humanized monoclonal antibody, huC242. This agent was highly active across a broad spectrum of CanAg-expressing human tumor xenograft models. Methods: Patients were enrolled with metastatic or inoperable colorectal, pancreatic, and other CanAg-expressing tumors who have failed standard therapy (about 95% of pts. had received = 4 prior chemotherapy regimens). Results: Thirty patients were treated with huC242-DM4, receiving a single intravenous (IV) infusion once every three weeks. Cohorts of 3 patients initially were enrolled on each dose level. Patients have received huC242-DM4 at 18, 36, 60, 90, 126, 168, 223, and 297 mg/m2. To date, dose limiting toxicity (DLT) was experienced by two of six patients treated at the 223 mg/m2 dose level during their second cycle of treatment. The patients experienced decreased visual acuity, corneal deposits and keratitis. Both patients were subsequently treated with lubricating eye drops. At present, these adverse events have markedly improved in one patient, while the other patient has completely returned to baseline. Of 10 patients treated at the168 mg/m2 dose level (including two patients who were dose reduced to 168 mg/m2), seven patients have received at least two cycles of treatment. One patient had grade 3 diarrhea and dehydration during his second cycle at 168 mg/m2. The latter improved with intravenous fluids. Preliminary pharmacokinetic data reveal a half-life of huC242-DM4 of about 5 days in patients with low plasma CanAg levels. In patients with high plasma CanAg levels (>900 units/mL), clearance of huC242-DM4 is increased. There has been no clinically significant myelosuppression and no formation of antibody to humanized antibody (HAHA) or drug (HADA). One patient had a 36% decline in CEA (not associated with tumor shrinkage). Conclusions: HuC242-DM4 was well tolerated at the 168 mg/m2 dose level. The MTD is not yet defined and approaches to prevent /ameliorate ocular toxicity are planned. No significant financial relationships to disclose.