bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adoptive immunotherapy plus cryotherapy in murine model of metastatic colon cancer
Authors: Levy M. Y. , Symons H. , Chowdhury W. , Rodriguez R. , Fuchs E. 
Published: March 2020

2520 Background: Cryotherapy provides a known local treatment effect for cancer. Additionally, many reports suggest that preservation of tumor antigens in the cryoablation (cryo) treatment site may lead to a systemic immune response that may treat remote tumor. However, the capacity of cryo to induce a regression of metastatic lesions may be limited by tumor-induced alterations of the immune system, including tumor-specific T cell tolerance and suppression. One method of awakening dormant anti-tumor immunity is by treating cancer-bearing animals with cyclophosphamide (Cy), to eliminate suppressor T cells, and allogeneic donor lymphocyte infusion (DLI), to provide an exogenous source of CD4+ T cell help for endogenous, tumor-specific CD8+ T cells. We therefore asked whether Cy ± DLI could augment the anti-tumor effect of cryo in a mouse metastatic colon cancer model. Methods: BALB-C mice were inoculated on d0 with the 106 syngeneic CT-26 SQ to generate local tumor and 105 IV via tail vein injection to generate lung metastases. The SQ tumor was then treated on d14 with either surgical excision or cryo, and mice were treated further with nothing, Cy alone (200 mg/kg IP on d13), or Cy plus CD8+ T cell-depleted DLI from allogeneic donors. At d102, surviving animals were re-challenged with 105 CT-26 cells IV. 5 previously untreated BALB-C controls were injected at the same time with 105 CT-26 IV. Results: Our data demonstrates a survival advantage of mice treated with Cy plus cryo (med. survival 100.5 days) compared to animals treated with Cy + surgery (med. survival 33d; p = .002). Furthermore, a significant (p = .0006) effect of the adoptive immunotherapy was seen with a comparison between the surgery +Cy group (med. survival 33d), and the surgery +Cy/DLI group (med. survival 60d). There are currently 6/18 mice alive at d143 that received cryo + Cy±DLI. In the re-challenge experiment, all control animals died of tumor by d19 with a med. survival of d18. 6/7 re-treated animals remain alive and free of tumor 41d after tumor re-challenge (p = .0041). Conclusions: These results suggest a systemic immune effect on distant metastases may occur after local cryo when cryo is coupled with Cy alone and Cy+DLI. The results from this experiment warrant further characterization of the mechanisms for the anti-tumor effects observed. No significant financial relationships to disclose.
Radioimmunotherapy (RIT) of refractory or relapsed Hodgkin’s lymphoma with 90Yttrium-labeled antiferritin antibody
Authors: Decaudin D. , Kadouche J. , Levy R. , Belhamiche M. , Arnaud P. , Alberini J. L. , Lokiec F. M. , Pecking A. P. 
Published: March 2020

2534 Background: The aims of this study were to evaluate (1) the tumor targeting of 111Indium-labeled rabbit polyclonal antiferritin antibody (Ab) and (2) the therapeutic efficacy of 90Yttrium-labeled antiferritin Ab in relapsed or refractory Hodgkin’s lymphoma (HL) patients (pts). Methods: After obtention of the patients’ consent, the protocol included a first intravenous injection of 2 mg of antiferritin Ab labeled to 111 MBq (3 mCi) of 111Indium followed by immunoscintigraphy at time 24 and 48 hours and, in case of tumor targeting, one or more intravenous injections of 90Yttrium-labeled antiferritin Ab at various activities. Results: Ten patients were included in the study: median age 32 years (range: 18–43 years); sex ratio M/F 9; stages III and IV at the time of RIT 1 and 9 pts, respectively; median number of chemotherapy regimens 3 (range: 2–4); number of autografted pts 8; number of previously irradiated pts 9; response to last chemotherapy: 6 PR and 4 progressions. All immunoscintigraphies showed a tumor targeting by 111Indium-labeled antiferritin Ab. Nine patients were treated, one case died of HL evolution. Five pts received one 90Yttrium-labeled antiferritin Ab injection, three pts 2 injections (0.5, 5 et 14 months after the first one), and one pt 4 injections (3, 9 et 16 months after the first one). Median injected activity was 13 MBq/kg (0.35 mCi/kg)(range: 7–15 MBq). Among the 9 treated pts, 1 CR, 6 PR, 1 stable disease, and 1 tumor progression were observed (ORR 78%). The median duration of responses were 8 months (range: 7–12 months). Toxicity was mainly hematological, with neutropenia and anemia of grades 1 or 2, and thrombopenia of grades 2 and 3; one pt presented a generalized convulsive crisis 24 hours after the therapeutic injection, without etiologic evidence. Conclusion: These results confirmed those that have been reported by Vriesendorp and Quadri and showed that rabbit polyclonal antiferritin Ab targeted HL tumor sites and had an important therapeutic potential in this discrepancy situation. They warranted therefore further multicentric prospective trials. [Table: see text]
High affinity promotes more effective ADCC by anti-HER2/neu monoclonal antibodies
Authors: Tang Y. , Alpaugh K. , Lou J. , Litwin S. , Shaller C. , Adams G. , Marks J. , Weiner L. 
Published: March 2020

2538 Background: Although monoclonal antibodies have emerged as useful cancer therapeutics, the antibody structural features and biologic properties that maximize therapeutic benefit are not fully understood. Antibody-dependent cellular cytotoxicity (ADCC) is believed to be a major mechanism of some anti-cancer antibodies. Herein, we describe the relationship between antibody affinity and the biologic properties of ADCC. Methods: A series of human IgG1 antibodies was created from the anti-HER2/neu C6.5 scFv and its affinity mutants (affinity ranging from 10−7 to 10−11 M). The IgGs were tested for their ability to elicit ADCC using a standard 51Cr-release assay. The ability of these IgGs to inhibit tumor cell proliferation and to induce apoptosis was evaluated using a colorimetric cell proliferation assay and homogeneous caspase assay/Annexin-V-FLUOS assay, respectively. Three tumor cell lines with differing levels of HER2/neu expression were used as target cells, and unactivated human PBMC from healthy donors were the effector cells. Results: There was a clear influence of both intrinsic and functional affinity on ADCC, with higher levels of peak cytotoxicity as apparent affinity approached 10−11 M. Among the antibodies with apparent affinity of 10−11 M, antibodies with higher intrinsic affinities elicited more ADCC. There also was an affinity-dependent increase in cytotoxicity at lower antibody concentrations and lower effector: target ratios. These antibodies elicited more cytotoxicity against tumor cells expressing high levels of HER2/neu than against cells expressing lower amounts of HER2/neu. None of these IgGs inhibited tumor cell proliferation, or induced apoptosis. Conclusions: Additional studies are needed to determine why, at the same functional avidity, ADCC is improved in antibodies with higher intrinsic affinities. These findings justify the examination of high affinity antibodies for ADCC promotion, although the impaired tumor targeting associated with high affinity may be an important confounding factor in the design of unconjugated anti-tumor antibodies. A careful examination of antibody structure: function relationships is required to develop optimized therapeutic unconjugated antibodies. No significant financial relationships to disclose.
Treatment of malignant pleural effusion with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3): Results of a phase I/II study
Authors: Sebastian M. , Schuette W. , Schneller F. , Nilius G. , Lodziewski S. , Passlick B. , Hoffken G. , Friccius-Quecke H. , Jaeger M. , Schmittel A. 
Published: March 2020

2548 Background: The trifunctional antibody catumaxomab specifically binds EpCAM+ tumor cells, CD3+ T lymphocytes and accessory cells via the Fcγ RI/III. Thus the antibody induces tumor specific cell mediated cytotoxicity in vitro and in vivo. Its intraperitoneal administration has demonstrated safety and led to efficient tumor cell killing and reduction of malignant ascites in ovarian cancer patients (pts.). The present study was conducted to evaluate safety, tolerability and preliminary efficacy of catumaxomab administered intrapleurally (i.pl.) into pts. with EpCAM+ malignant pleural effusion. Methods: This phase I/II trial was a multi-center uncontrolled, dose-escalating study. Pts. (ECOG ≤3) with recurrent malignant pleural effusion containing EpCAM+ tumor cells were included. Three escalating doses from 5–200 μg catumaxomab were administered i.pl. Primary objectives were toxicity and definition of the maximum tolerated dose (MTD). In addition, preliminary data on efficacy (reduction of pleural fluid and tumor cell killing) were generated. Results: 13/24 pts. received 3 infusions as planned. Reasons for early termination of infusions were 3 deteriorations of performance status, 2 exanthemas, 2 dyspnoea, 2 others. The dose regimen of 20–50–100 μg catumaxomab was defined as MTD. Most frequent drug related AEs were symptoms of cytokine release syndrome. 32 SAEs were reported in 18 pts., 4 SAEs were possibly drug related (1 death due to pleural empyema, 1 pneumonia, 1 erythema, 1 increase of liver enzymes). 8/9 deaths were not drug related but due to underlying disease. Induction of human-anti-mouse (HAMA) or human-anti-rat (HARA) antibodies after treatment was found in 8/11 pts. 8/13 fully treated pts. were defined as responders (1 complete, 4 partial, 3 NA) showing reduction of effusion and of drainage necessity. 5/13 were non-responders. A reduction of tumor cells up to log 5 was seen in 10/13 pts. Conclusions: 20–50–100 μg of catumaxomab can safely be administered i. pl. This regimen will further be investigated in a randomized phase II trial comparing catumaxomab to talcum-based pleurodesis. [Table: see text]
A phase I vaccine trial of a HER-2/neu peptide incorporated into PLG microspheres in patients with advanced stage HER2-expressing cancers
Authors: Salazar L. G. , Murray J. L. , Disis M. L. , Cheever M. 
Published: March 2020

2572 Background: Standard methods for immunization with peptides to elicit cytotoxic T lymphocytes (CTL) have not been well defined. Injection of soluble antigens in most standard vaccine formulations induce helper T cell and antibody responses, but generally fail to elicit CTL. Preclinical studies have shown that peptides incorporated into Poly-lactide-co-glycolide (PLG) microspheres are more effective in eliciting CTL than soluble peptides. Additionally, studies in HLA-A2 transgenic mice have shown GM-CSF and monophosphoryl lipid A (MPL-AF) to be effective adjuvants for induction of CTL with PLG peptide. A Phase I vaccine study was conducted to evaluate the safety and immunogenicity of HER2 peptide p369–377 incorporated in PLG microspheres in combination with GM-CSF or MPL-AF as adjuvant in patients with advanced stage HER2 overexpressing cancers. Methods: Twenty-four HLA-A2+ patients with stage III/IV breast, ovarian, or non-small cell lung cancer were enrolled sequentially into 4 treatment arms (6 patients/arm) and received escalating doses of the vaccine (Arms 1 and 2 received 0.5 mg of HER2 peptide; Arms 3 and 4 received 1.5 mg HER2 peptide) with different adjuvants (Arms 1, 2 and 3 received GM-CSF; Arm 4 received MPL-AF) and by different administration routes (Arm 1 received intradermal injection; Arms 2, 3, and 4 received subcutaneous injection). Vaccines were administered every 28 days for a total of 6 immunizations. Toxicity assessments were conducted at baseline, prior to each vaccine and at follow-up. Immunologic responses were evaluated with IFN-γ ELIspot assay. Results: Fourteen subjects completed all 6 vaccinations. 7 patients withdrew from study because of disease progression. No serious or grade 4 toxicity related to vaccine occurred. Eighteen of 24 subjects were evaluable for immunologic responses. 11/18 subjects (61%) developed a p369–377-specific CTL response. Immune responses did not appear to be related to treatment arm. Conclusions: The HER2 p369–377/PLG vaccine plus adjuvant is safe and elicits HER2-specific T cells in patients with HER2 positive cancers. No significant financial relationships to disclose.
Increased efficacy and toxicity with combination anti-VEGF therapy using sorafenib and bevacizumab
Authors: Azad N. S. , Posadas E. M. , Kwitkowski V. E. , Annunziata C. M. , Barrett T. , Premkumar A. , Kotz H. L. , Sarosy G. A. , Minasian L. M. , Kohn E. C. 
Published: March 2020

3004 Background: The multikinase inhibitor, sorafenib (sor), targets raf-kinase and vascular endothelial growth factor receptor 2 (VEGFR2). Bevacizumab (bev) is a monoclonal antibody against VEGF. We theorized that combining the two agents would have synergistic therapeutic effects. Methods: Eligible pts had advanced solid tumors, good end organ function, and PS ≤ 1. A phase I dose-escalation study (cohort 1) used sor 200 mg po BID, and bev 5 mg/kg q2 wks IV (dose level, DL1) or 10 mg/kg (DL2). After DLT was reached, DL4 was added to cohort 1 which tested sor 200 mg po BID on days 1–5 q wk with bev IV 5 mg/kg q 2 wks in an attempt to minimize toxicity. Cohort 2 is an expansion phase at MTD (DL1: sor 200 mg po BID daily with bev IV 5 mg/kg), randomized to start with single drug for 4 wks. Cohort 2 has extensive translational endpoints, including imaging. Results: 34 pts have enrolled, 16 in cohort 1 and 18 in cohort 2. Tumor types include ovarian cancer (13), melanoma (4), and renal cell carcinoma (3). The median age was 58 yrs (30–76); pts received a median of 6.5 (1–15) prior regimens. In cohort 1, 3/16 pts had PR (19%; duration 4, 5+, 12+ mos), all with ovarian cancer, and 11/16 had stable disease (SD; 69%; 3+ - 13+ mos). 10/13 assessable cohort 2 pts had SD (77%; 3+ - 6.5+ mos). The most common DL1 AEs Gr ≥ 2 were hypertension (HTN; 6/6) and hand-foot syndrome (4/6). Other Gr 3 AEs in DL1 were leukopenia and infection (2; 2). DLT was reached at DL2 when 2/6 patients developed Gr 3 proteinuria (4, 5 gm/24 hr) and 3/6 developed uncontrolled Gr 3 HTN. Dose reduction on daily sor (DL1 and DL2) occurred for 11/12 pts at a median of 2 cycles, but is delayed on the intermittent schedule (DL4). In all pts, common Gr 1–2 AEs were elevated AST/ALT (18), rhinorrhea (12), fatigue (10), and anorexia (4). 4 pts developed Gr 2–3 diarrhea and 4 Gr 2–3 nausea/vomiting. Gastrointestinal fistulae occurred in two pts with PR, occurring within 4 wk of initiation of therapy, both in areas of tumor regression. Serial PET and DCE-MRI results and proteomic signal pathway analysis will be reported. Conclusions: The combination of sorafenib and bevacizumab appeared to increase both clinical effect and toxicity at below recognized single agent doses. Sor 200 mg po BID d1–5 qwk and bev of 5 mg/kg q2 wks is suggested for further study, pending further dose escalation. No significant financial relationships to disclose.
A phase I pharmacokinetic (PK) and molecular pharmacodynamic (PD) study of the combination of two anti-EGFR therapies, the monoclonal antibody (MAb) cetuximab (C) and the tyrosine kinase inhibitor (TKI) gefitinib (G), in patients (pts) with advanced colorectal (CRC), head and neck (HNC) and non-small cell lung cancer (NSCLC)
Authors: Baselga J. , Schöffski P. , Rojo F. , Dumez H. , Ramos F. J. , Macarulla T. , Cajal R. , Kisker O. , Van Oosterom A. , Tabernero J. 
Published: March 2020

3006 Background: C and G are two anti-EGFR agents with different mechanisms of action. We had previously shown a synergistic effect combining the two agents in preclinical models (Matar et al, Clin Cancer Res 2004). This study aims to explore safety, PK and PD changes in tumor and skin at different doses of C/G to define the recommended dose (RD) for further development. Methods: pts were treated at the RD of weekly iv C (400 mg/m2 initial dose, 250 mg/m2 weekly) and oral daily G (250 mg/d) as single agents (5 pts each) and in successive cohorts of combined C/G (3–6 pts each): C (320/200) / G (100), C (400/250) / G (100), C (400/250) / G (250), C (320/200) / G (500) & C (400/250) / G (500) (ongoing). Dose escalation depended on dose limiting toxicity (DLT) rate during the first 28 d. Pre- & on-treatment steady-state (14 d) tumor & skin biopsies were obtained and have been evaluated by IHC for total (t) and phospho (p)-EGFR, p-MAPK, p-Akt, proliferation (Ki67), p27 expression and apoptosis by TUNEL. Gene profiling analysis is ongoing. Results: 35 pts have been treated so far: 20 CRC, 13 HNC & 2 NSCLC; median KI 90 % (70–100); median age 60 years (38–80); 24 males, 11 females. DLTs occurred in 3 pts: 1 pt with G alone with reversible ILD; 1 pt with G (250) / C (400/250) with reversible deafness & 1 pt with G (500) / C (320/200) with grade 3 anorexia and nausea. There were 1 CR (HNC) and 5 PRs (CRC) in the C/G cohorts, and 1 PR (CRC) in the C cohort. Overall, 5 out of 9 (56%) pts with CRC treated in the C/G cohorts presented a PR. PD studies show superior inhibition of p-EGFR, p-MAPK and p-Akt, reduction of proliferation and increased apoptosis (all p values <0.05) in the tumors of pts treated with C/G compared with the single agent cohorts. PK evaluation shows no PK interactions with the 2 drugs. Conclusions: This combination of an anti-EGFR MAb (C) and a TKI (G) is feasible at the RD of both agents. Our findings show encouraging clinical activity, especially in CRC, and superior PD signaling inhibition with the combination without any significant PK interaction. Combined anti-EGFR therapy deserves further evaluation. [Table: see text]
Phase I study of isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 given as three-times weekly oral dose in patients (pts) with advanced solid tumors
Authors: Carducci M. , Siu L. L. , Sullivan R. , Maclean M. , Kalita A. , Chen E. X. , Pili R. , Martell R. E. , Besterman J. , Reid G. K. 
Published: March 2020

3007 Background: MGCD0103 is a novel isotype-selective inhibitor of human HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumor suppressor genes leading to neoplastic transformation. Inhibition of these enzymes might restore normal growth control. Methods: A phase I trial of MGCD0103, given as a three-times weekly oral dose 2 out of every 3 weeks, has been performed in pts with advanced solid tumors. Main endpoints are safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity and histone acetylation status in buffy coat white cells. Results: Five dose levels have been evaluated (mg/m2): 12.5, 20, 27, 36, and 45. As of January, 2006, 28 pts have been enrolled with the following demographics: M:F = 18:10; median age (range) = 60 (29–75); ECOG 0:1:2 = 9:13:1 (n = 23); primary tumor sites: colorectal (8), renal (5), lung (4), others (11); prior chemotherapy, radiotherapy, immunotherapy were given to 22, 12 and 2 pts, respectively (n=23). A total of 62 cycles have been administered, with median = 2 and range=1–7 cycles. MGCD0103 has been well tolerated; most common AEs (23 pts): grade 1–3 fatigue (91% of pts), grade 1–2 nausea and vomiting (70 and 48%), anorexia (26%), constipation (39%). Disease stabilization > 2 cycles has been observed in 3 renal cell cancer pts (4, 6, and 7 cycles) and 1 colorectal cancer pt (4 cycles). Preliminary PK analyses demonstrated intra-pt PK variability, however co-administration of acidic carbonated beverage (protocol amendment) appears to reduce variability without altering average Cmax or AUC (0–24) comparing Day 1 with Day 14. There was little accumulation or decrease in concentrations with extended dosing, and t1/2 was dose-independent at 7.7–11.3 hr. (±0.6–1.6). PD data reveal dose-dependent maximal inhibition of HDAC activity in patients co-administered an acidic beverage. Conclusions: At doses evaluated MGCD0103 appears tolerated and exhibits favourable PK and PD. [Table: see text]
Role of pharmacogenetic studies in early clinical development: Phase I studies with lapatinib
Authors: Zaks T. Z. , Akkari A. , Briley L. , Mosteler M. , Stead A. G. , Koch K. M. , Sampson C. , Ehm M. , Harris E. , Roses A. 
Published: March 2020

3029 Background: Rash and diarrhea are a class effect of ERBB1 inhibitors. These events are relatively mild with Lapatinib (a dual ERBB1/ERBB2 kinase inhibitor). Finding a genetic basis for patients who may be predisposed to these adverse events, from the outset of clinical development, may improve the understanding of the mechanisms of these side effects and may have implications for use and dosing. Methods: DNA was isolated from peripheral blood of 107 Caucasian subjects from eight monotherapy phase I studies including 73 healthy volunteers and 34 cancer patients, 100 of whom had associated pharmacokinetic data. 284 single nucleotide polymorphisms (SNPs) from five candidate genes of transporters (ABCB1, ABCG2) and enzymes (CYP 3A4 and 3A5, and 2C19) for which lapatinib is a substrate were genotyped and examined for associations with pharmacokinetic variables (dose-normalized AUC, Cmax, and Tmax) as well as rash (15 cases) and diarrhea (18 cases). Results: Skin rash and diarrhea in this phase I cohort were only mild, (i.e. grade I or II). Statistically significant associations were observed between 34 SNPs in CYP2C19, rash (22 SNPs) and diarrhea (6 SNPs), and between 15 SNPs in ABCB1 and Tmax. Notably, 3/3 subjects (2 healthy volunteers, one patient) homozygous for the CYP2C19*2 allele experienced both mild rash and diarrhea. Extensive linkage disequilibrium was observed among these associated SNPs. Conclusions: Our results suggest that it is possible to determine pharmacogenetic associations with side effect phenotypes during the earliest phase of clinical drug development. These results are currently being validated on a larger cohort of patients from phase II lapatinib clinical trials. [Table: see text]
A phase I trial of AEG35156 (XIAP antisense) administered as a continuous intravenous infusion in patients with advanced tumors
Authors: Ranson M. , Dive C. , Ward T. , Cummings J. , Connolly K. , Evans S. , Robson L. , Durkin J. , Jolivet J. , Jodrell D. 
Published: March 2020

3059 Background: The X-linked inhibitor of apoptosis (XIAP) is a potent anti-apoptotic protein. AEG35156 is a synthetic 2nd generation antisense oligonucleotide to human XIAP that enhances cancer cell apoptosis preclinically as a single agent and in combination with chemotherapeutics. Methods: The primary objective was to establish the maximum tolerated dose (MTD) of AEG35156 given as a 7-day continuous infusion every 3 weeks. Other objectives were to determine AEG35156 pharmacokinetics, XIAP inhibition in peripheral blood mononuclear cells and in tumour cells where feasible and document anti-tumour activity. Results: Sixteen adult patients have completed at least one 7-day infusion. Two dose-limiting toxicities (DLT) were observed in five patients treated at 160 mg/m2/day: grade 3 thrombocytopenia for more than 7 days and grade 3 ALT and AST elevation. Seven patients have been treated at 125 mg/m2/day with one DLT of grade 3 transaminase elevation. An approximately 50% decrease in XIAP mRNA was seen in peripheral blood leucocytes three days after the start of infusions at 160mg/m2/day. One patient with small lymphocytic non-Hodgkin’s lymphoma had marked but short lived decreases in peripheral lymphoblasts during AEG35156 administration closely associated with XIAP mRNA knockdown. One patient with breast cancer had an unconfirmed partial response. The trial has now been amended to also determine the MTD of a 3-day continuous infusion every 3 weeks. Three patients have been treated with 3-day infusions at 160mg/m2/day every 3 weeks with no significant toxicities observed and patients are currently being accrued at 213mg/m2/day. Conclusions: AEG35156 can be safely delivered by continuous infusion and preliminary evidence of XIAP mRNA knockdown and antitumour activity has been observed. [Table: see text]