bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decrease of VEGF within malignant ascites during catumaxomab treatment: Results from a pivotal phase II/III study
Authors: Jäger M. , Schoberth A. , Theissen B. , Hess J. , Friccius-Quecke H. , Lindhofer H. 
Published: August 2020

3029 Background: Treatment with the trifunctional anti-EpCAM x anti-CD3 antibody catumaxomab efficiently eliminates tumor cells from the peritoneal cavity (Jäger et al., ASCO 2007) and led to clinically relevant prolongation of puncture-free survival (PuFS) in patients with malignant ascites (MA) in a pivotal phase II/III trial (Parsons et al., ASCO 2008). As vascular endothelial growth factor (VEGF) levels are markedly elevated in MA in comparison to cirrhotic ascites the question was addressed whether catumaxomab treatment impacts the expression or accumulation of VEGF within MA. Here we report that in addition to tumor cell depletion, VEGF protein levels in MA significantly decreased upon catumaxomab therapy. We propose that the strongly correlated tumor cell elimination and reduced VEGF protein levels are causative for the prolonged PuFS of patients suffering from MA. Methods: VEGF and total protein levels were measured by ELISA and BCA from MA supernatants before catumaxomab therapy, after the 1st infusion (10μg; day 3) and after the 4th infusion (150μg; day 11). Data were statistically analysed for the ratio of the VEGF protein concentration versus the total protein concentration for the MA treatment groups with ovarian (OC) or nonovarian cancer (NC) as underlying disease and the corresponding control groups that received paracentesis only. Results: One day after the last catumaxomab infusion 46 or 47 patients analysed in the OC or NC treatment group showed a statistically significant decrease in VEGF to total protein ratio when compared to the measurement before catumaxomab therapy (ANOVA p=0.034 for OC and p<0.001 for NC). These results are consistent with the tumor cell elimination previously assessed in these patients. In contrast, the OC control group showed a statistically significant increase of VEGF to total protein ratio (p=0.009), which is accompanied by an increase in tumor cell numbers. In the NC control group VEGF to total protein ratio remained unaffected (p=0.096). Conclusions: Catumaxomab therapy significantly reduced VEGF protein levels correlating with tumor cell elimination in MA, which in turn led to the prevention of fluid accumulation in the peritoneal cavity and finally to prolonged PuFS of patients suffering from MA. [Table: see text]
Increased humoral and cellular immunity in patients (pts) with advanced melanoma treated with ipilimumab
Authors: Parker S. , Berman D. , Bennett K. L. , Alaparthy S. , Tsuchihashi Z. , Chasalow S. D. , Zhan P. 
Published: August 2020

3031 Background: Ipilimumab is an anti-CTLA-4 monoclonal antibody (Ab) that overcomes T-cell suppression. In this phase II study (CA184004), humoral and cellular responses were assessed in ipilimumab-treated pts with unresectable stage III/IV melanoma. Methods: Ipilimumab 3 or 10 mg/kg was given every 3 weeks x 4. Tetanus boosters were given ≤10 days pre-treatment. Influenza and pneumococcal vaccines were given 5 days after first ipilimumab dose. Tetanus, anti-influenza, and anti-pneumococcal Ab levels were assessed at pre-dose and Wk 7. Humoral response to 5 tumor antigens (Ag) and a control Ag (DHFR) were examined at baseline (BL) and at Wks 4, 8–9, and 12. DTH skin tests were given at pre-dose and Wk 4, with responses recorded 15 minutes (min) and 24–72 hours (hrs) post-test. Peripheral T-cell populations were evaluated through flow cytometry at BL, Wk 4, and Wk 12. Results: Pts received ipilimumab 3 (n = 40) or 10 mg/kg (n = 42). Increases from BL in humoral responses to pneumococcal (40–50/78 pts, depending on Ab) and tetanus (58/78 pts) vaccines were noted, even in pts who did not receive on-study pneumococcal (4–9 pts) or tetanus (7 pts) vaccines. Increased humoral response to influenza only occurred in pts receiving the influenza vaccine. Maximum increase from BL of ≥ 5-fold titer (clinically meaningful threshold) in humoral response to tumor Ag MELANA (23.2% of pts), SSX2 (20.3%), NYES01 (18.8%), MAGEA4 (10.1%), and P53 (4.3%) (DHFR, 4.3%) was noted without tumor vaccines. Tumor Ag response was not associated with clinical activity (complete or partial response, or stable disease ≥ 24 wks). Increased DTH reactions were noted for tetanus, 24–72 hrs (3 mg/kg: 5/7 pts; 10 mg/kg: 3/6 pts); tuberculin, 15 min (3 mg/kg: 7/15 pts; 10 mg/kg: 4/15 pts); Candida, 15 min (3 mg/kg: 4/6 pts; 10 mg/kg: 2/7 pts); and Trichophyton, 15 min (3 mg/kg: 3/4 pts; 10 mg/kg: 2/5 pts). Significant increases from BL in percents of HLA-DR+ CD4+ (p = 9.3x10-7), HLA-DR+ CD8+ (p = 0.018), and ICOS+ CD4+ (p = 0.0027) effector T cells were noted. Conclusions: Humoral immunity in ipilimumab-treated pts increased (± vaccination) in an Ag-dependent manner and cellular immunity was enhanced. Change in tumor Ag response was not associated with clinical activity. [Table: see text]
Phase I clinical experience of a targeted TCR-IL2 fusion protein in patients with metastatic malignancies
Authors: Pennock G. , Fishman M. , Gonzalez R. , Thompson J. , Huang B. , Tang S. , Rhode P. , Wong H. 
Published: August 2020

3040 Background: ALT-801 is recombinant human interleukin-2 (IL-2) genetically fused to a single-chain T-cell receptor specific to a peptide antigen of human p53 presented in the context of HLA-A2 positivity. In tumor xenografts in animal models, this fusion protein demonstrated potent and targeted antitumor activity. Methods: A phase I/IIa multicenter clinical study was initiated to assess safety and clinical response of ALT-801 in patients with various metastatic malignancies. Patients screened positively for HLA-A2 and tumors expressed p53 peptide/HLA-A2 complex. In this dose escalation trial, patients received ALT-801 as a daily intravenous infusion for 4 days followed by a 10-day rest period and 4 additional daily doses. Results: Data from three dosing cohorts (0.015, 0.04, and 0.08 mg/kg/dose) indicate that ALT-801 is well-tolerated up to 0.04 mg/kg/dose. The half-life of ALT-801 is 2.5–4 hours per pharmacokinetic analysis, depending on the dose. Even at the 0.015 mg/kg level, there were sufficient concentrations of ALT-801 in the patients’ serum to fully activate cell lytic activity in vitro. Treatment with ALT-801 also led to immune activation in patients as demonstrated by elevated serum IFN-γ levels as well as an increase in IFN-γ-producing immune cells in patients’ blood. Interestingly, serum TNF-α, a major inducer of hypotension in patients receiving high-dose IL-2 treatment, was not induced in patients receiving ALT-801. Evidence of antitumor activity (i.e., stable disease, tumor shrinkage) was observed in some patients after one or two courses of ALT-801. Conclusions: At a dose of 0.04 mg/kg, ALT-801 is a well-tolerated agent that generated a vigorous immune response and demonstrated clinical efficacy in a group of patients with various metastatic malignancies. An expansion cohort of patients is in progress at 0.04 mg/kg. [Table: see text]
Mediator release during combined radio chemotherapy in rectal carcinoma
Authors: Matuschek C. , Bölke E. , Gripp S. , Budach W. , Hermsen D. , Peiper M. 
Published: August 2020

3043 Background: Bacterial translocation is a well-documented phenomenon after polytrauma and major abdominal surgery. Today neoadjuvant chemoradiotherapy is the gold standard for uT3, N+ rectal cancer. The aim of this study was to evaluate if a gut barrier dysfunction occurred during radiotherapy and elective rectal surgery. Methods: We investigated in 45 patients (25 male, 20 female) with uT3N+ rectal carcinoma and neoadjuvante long-term radio chemotherapy with 5-FU and pelvis irridation up to 50.4 Gy on admission and weekly during radiotherapy and after surgery IL-6, LPS-binding protein, IL-8, TNF-α and procalcitonin. Results: There were no clinical complications in all patients. During radiochemotherapy we could not detect a significant increase of the acute phase response. IL-6 plasma levels showed maximal values 6 h after surgery (270 pg/ml) und CRP had its maximal values 48 h (185 mg/l). IL-8, TNF-α, LPS-BP, and procalcitonin were not elevated during an uncomplicated postoperative course. Conclusions: During an uncomplicated course of radio chemotherapy we could not detect elevated mediator releases. During surgery we could find a significant mediator liberation, which correlated with the amount of the operative trauma. No significant financial relationships to disclose.
Phase I dose escalation trial of tremelimumab (CP-675,206) administered in combination with PF-3512676 in patients with melanoma or other advanced cancers
Authors: Underhill C. , Millward M. , Lobb S. , McBurnie J. , Meech S. , Gomez-Navarro J. , Readett D. , Bulanhagui C. A. 
Published: August 2020

3046 Background: Tremelimumab, a fully human monoclonal antibody specific for cytotoxic T-lymphocyte antigen 4 (CTLA4), and PF-3512676, an oligodeoxynucleotide toll-like receptor 9 agonist, are both novel, targeted immune modulators that can elicit durable antitumor responses in patients with advanced cancer. The tolerability of the combination of these two agents was investigated. Methods: Eligibility criteria included advanced melanoma or other advanced cancer, ECOG performance status of 0 or 1, and no history of autoimmune disease. Patients received intravenous tremelimumab (6.0, 10.0, or 15.0 mg/kg) every 12 weeks plus 0.05 mg/kg subcutaneous PF-3512676 weekly. Further escalation of PF-3512676 (to 0.1 mg/kg and 0.2 mg/kg) was planned once the MTD of tremelimumab had been determined. Primary endpoint was safety of the treatment combination; secondary endpoints included clinical activity, pharmacokinetics (PK), and immunologic measurements. Results: To date, 15 patients (melanoma, n = 12; mesothelioma, n = 2; prostate, n = 1) have been treated in this study: 3 at dose level 1 (6 mg/kg tremelimumab + 0.05 mg/kg PF-3512676); 6 at dose level 2 (10 mg/kg tremelimumab + 0.05 mg/kg PF-351276); and 6 at dose level 3 (15 mg/kg tremelimumab + 0.05 mg/kg PF-3512676). There were two DLTs at dose level 3: G3 diarrhea (n=1) and G3 nausea and vomiting associated with biopsy-proven duodenitis (n=1). One DLT, G3 hypophysitis, occurred at dose level 2. Patients with DLTs responded to corticosteroid therapy. Common adverse events included mild to moderate PF-3512676 injection site reactions (n=14), mild to moderate flu-like symptoms (n=9), G1/2 diarrhea (n=9), and G1/2 nausea (n=8). Presently, there are 2 PRs (13%) and 5 SDs among the 15 patients. Updated safety, efficacy, and PK data will be reported. Conclusions: At dose levels tested to date, the combination of tremelimumab and PF-3512676 has been tolerable and showed evidence of antitumor activity in patients with advanced melanoma. The MTD for this combination has yet to be determined, and a fourth intermediate dose level (10 mg/kg tremelimumab + 0.1 mg/kg PF-3512676) is currently being explored. [Table: see text]
Characterization of an antitumor immune response after light-activated drug therapy using talaporfin sodium in a spontaneously metastasizing mammary tumor model
Authors: Bromley E. , Owczarczak B. , Keltner L. , Wang S. , Gollnick S. O. 
Published: August 2020

3052 Background: An innovative light-activated drug therapy (Litx) is a cytoreductive treatment that uses light-emitting diodes to activate talaporfin sodium (LS11), a water-soluble drug, resulting in the production of singlet oxygen. Tumor destruction involves direct and indirect tumor kill through apoptosis, vascular occlusion, and potentially antitumor immunologic effects. To provide evidence for the potential antitumor immunologic effects, we have used the therapy to treat primary tumors and examine prevention of metastases in the 4T1 tumor model, an aggressive, spontaneously metastasizing murine mammary tumor model that mirrors human breast cancer. When grown in the mammary fat pad of BALB/c mice, untreated 4T1 tumors rapidly metastasize to lung, liver, lymph nodes, and brain. Methods: To confirm tumor kill by this therapy, the primary 4T1 tumors grown in mice were treated and animal survival was followed. To determine whether the therapy could enhance antitumor immunity and reduce metastases, the lymph node (LN) cells from treated and control mice were transferred to naïve recipient mice. Recipients were challenged with a tumorigenic dose of 4T1 cells 3 days after adoptive transfer and primary and secondary tumor growth in the recipients was examined. Results: Treatment of primary tumors significantly increased survival (p≤0.01) when compared to animals treated with either light or drug alone. LN cells isolated from treated mice, but not control mice, significantly inhibited primary tumor growth in recipients (p≤0.0001) and dramatically reduced the number of lung metastases present 40d after tumor challenge (p≤0.02). The ability to inhibit primary and secondary tumor growth in recipients depended on the presence of CD8+ T cells; depletion of CD8+ T cells from the LN abolished the effect. Preliminary evidence for such effect on untreated tumors has been observed in human trials of this therapy. Conclusions: These results indicated that this light-activated drug therapy not only destroyed the treated tumors directly but also controlled growth of untreated tumors through induction of a specific host antitumor immune response mediated by CD8+ T cells. [Table: see text]
A phase I study of a DNA plasmid based vaccine encoding the HER2/neu (HER2) intracellular domain (ICD) in subjects with HER2+ breast cancer
Authors: Salazar L. G. , Slota M. , Wallace D. , Higgins D. , Coveler A. L. , Dang Y. , Childs J. , Bates N. , Waisman J. , Disis M. L. 
Published: August 2020

3054 Background: HER2 is overexpressed in 25% of breast cancers and plays a role in the malignant transformation of cells. Vaccine-induced immunity against the HER2 ICD correlates with antitumor responses in animal models. DNA-based vaccines offer a strategy to immunize against multiple tumor antigens and are able to elicit both CTL and T helper immune responses. Plasmid DNA can also remain at the vaccine site, providing a constant source of antigen. However, DNA vaccines have been poorly immunogenic due in part to inefficient APC transfection. Intradermal (i.d.) delivery of DNA vaccines with GM-CSF as adjuvant may enhance immunogenicity due to local influx of dermal Langerhans cells. A phase I study was conducted to evaluate the safety and immunogenicity of a DNA-based vaccine encoding the HER2 ICD. Methods: 44 subjects with stage III and IV HER2+ breast cancer in complete remission were enrolled sequentially into 2 vaccine arms (22 subjects/arm) and received 10μg pNGVL3-hICD (Arm 1) or 100μg pNGVL3-hICD (Arm 2). All vaccines were admixed with 100μg GM-CSF and given i.d. monthly for a total of 3 vaccines. Toxicity was assessed at baseline, during vaccination, and at follow-up. Immune responses were assessed with IFN-γ ELISPOT at baseline and post-vaccination. Vaccine site biopsies were analyzed for plasmid persistence via RT-PCR, 1 and 6 months after vaccination. Results: 43 subjects (21 in Arm 1; 22 in Arm 2) completed 3 vaccines. Vaccine-related toxicity in both arms was primarily grade I/II; no cardiac or grade IV toxicity was observed. 13/21 (62%) subjects in Arm 1 developed T-cell immunity, defined as HER2-specific T cell precursors:PBMC, to the HER2 protein (median 1:5,972, range 1:717–1:3,000,000) and to p776, a HER2 pan DR binding epitope (median 1:3,150, range 1:543–1:108,696). 13/19 (68%) subjects in Arm 1 had persistent plasmid DNA at the vaccine site. ELISPOT and RT-PCR analysis for Arm 2 are on-going. Conclusions: Immunization with a DNA plasmid-based HER2 vaccine is safe and immunogenic. Moreover, plasmid DNA persists at the vaccine site post-immunization and HER2+ cancer patients are able to develop immunity to the HER2 ICD. No significant financial relationships to disclose.
HER2/neu (HER2) specific T-cell immunity in patients with HER2+ inflammatory breast cancer (IBC) and prognosis
Authors: Salazar L. G. , Wallace D. , Mukherjee P. , Higgins D. , Childs J. , Bates N. , Coveler A. L. , Disis M. L. 
Published: August 2020

3057 Background: IBC is rare, highly aggressive, and associated with worse prognosis when compared to non-IBC tumors. Moreover, multimodality treatment has had little impact on overall prognosis. HER2 is overexpressed in about 40% of IBC tumors and is associated with worse overall survival (OS). We have developed vaccines that elicit both HER2-specific CD4+ and CD8+ T-cell immunity in HER2+ cancer patients. Generation of HER2-specific T-cell immunity could (1) target immunogenic and biologically relevant proteins such as HER2 in IBC, (2) result in immunogenic eradication of HER2+ tumor cells, and (3) potentially prevent disease relapse when used in the adjuvant setting after standard therapy. A retrospective analysis of IBC patients immunized with HER2 vaccines was conducted to better understand the development of HER2-specific T-cell immunity and its possible impact on overall prognosis in IBC. Methods: Clinical and immunological data of IBC patients enrolled in University of Washington IRB approved HER2 vaccine trials was collected and reviewed. 27 patients immunized between 1996–2008 were identified; and 24/27 subjects who received vaccines designed to elicit both CD4+/CD8+ immunity were included in immunologic and survival analysis. The 24 subjects received either a HER2 DNA or HER2 peptide-based vaccine that were admixed with GM-CSF and given intradermally monthly for a total of 3 DNA or 6 peptide vaccines. Immune responses were assessed via IFN-γ ELISPOT at baseline and post-vaccination. Results: All 24 subjects had stage III IBC and median age was 48 (range 34–77). 10/24 (42%) patients had ER/PR+ tumors, 9/24 (37%) had received trastuzumab, and 15/24 (62%) had received multimodality treatment (chemotherapy, mastectomy, radiotherapy). 12/18 subjects (66%) evaluable for immunologic response developed HER2-specific T-cell immunity post-vaccination. Median OS for patients (n=6) not generating HER2-specific immunity was 31 months and median OS for the 12 patients who developed HER2-specific immunity has not been reached at median follow-up of 46 months, (p=0.026). Conclusions: Patients with IBC are able to generate HER2-specific T-cell immunity after HER2 vaccination, and development of HER2-specific immunity may impact survival. No significant financial relationships to disclose.
Association of the level of HER2/neu (HER2) gene amplification in breast cancer and the magnitude of antigen specific T-cell immunity achieved after HER2 vaccination
Authors: Wallace D. , Disis M. , Coveler A. , Higgins D. , Childs J. , Bates N. , Salazar L. , Slota M. , Dang Y. , Waisman J. 
Published: August 2020

3059 Background: Studies have demonstrated that the level of HER2 gene amplification in breast cancer, assessed by fluorescence in situ hybridization (FISH), correlates with favorable clinical response after treatment with trastuzumab. We questioned whether HER2 gene amplification impacted the development of HER2-specific T-cell immunity following immunization with a HER2 vaccine. Methods: Patients with HER2+ stage III or IV breast cancer, treated to complete remission or stable bone only disease, were enrolled in one of two concurrent clinical trials of HER2-specific vaccines. Eligibility criteria between the two studies were similar. Patients received either a plasmid DNA-based vaccine encoding the HER2 intracellular domain or a peptide-based vaccine composed of 3 HER2 class II epitopes. Peripheral blood was assessed for HER2-specific T-cell responses by interferon gamma (IFN-g) ELISPOT prior to, immediately after, and 6 months to 1 year after the end of vaccinations. Both immune response and FISH data were available on 31 patients. Results: Correlation of FISH levels to IFN-g spots/well in evaluable patients revealed the level of HER2 gene amplification was not related to the presence of pre-existent HER2-specific T-cell immunity prior to vaccination (p=0.43), the generation of a HER2-specific immune response after vaccination (p=0.35), or the persistence of the HER2-specific T-cell response (p=0.33). However, the magnitude of the T-cell response achieved was less as HER2 gene amplification increased (p=0.05). Conclusions: The level of HER2 gene amplification in the primary tumor can adversely impact the magnitude of HER2-specific T-cell immunity achieved after vaccination. No significant financial relationships to disclose.
Anticancer effects of polyadenylic-polyuridylic acid (poly[A:U]) and uncoupling of chemokine receptor signaling: Role of CCR5 and CXCR3
Authors: Conforti R. , Ma Y. , Morel Y. , Paturel C. , Terme M. , Viaud S. , Chaput N. , Andre F. , Kroemer G. , Zitvogel L. 
Published: August 2020

3063 Background: Several tumor cells express toll-like receptors (TLRs) which constitute putative therapeutic targets. Methods: To dissect the clinical outcome of the host versus cell autonomous effects of the TLR3 agonist poly(A:U), we took advantage of two murine TLR3 expressing tumor models (melanoma and glioblastoma) that produced large amounts of CCL5 (a CCR5 ligand) and CXCL10 (a CXCR3 ligand) in response to the poly(A:U) and type I IFN in vitro and in vivo. We tested in vivo a triple combination based on vaccine against tumor antigens (V), chemotherapy (C), and TLR3 agonist (poly[A:U]) (T). Results: Single agents (V, C, or T) and combinations of two agents (VC, VT, or CT) failed to improve tumor progression. However, the sequential tritherapy (VCT) significantly retarded tumor growth and prolonged the survival of tumor-bearing C57BL/6 mice. The antitumor effects of VCT (immunochemotherapy) failed to be observed in nu/nu and TRIF-/- mice, indicating the contribution of T cells and TRIF-dependent signals to the therapeutic effect. Knockout of CCR5 improved the efficacy of immunochemotherapy. The VCT combination induced the recruitment of IFNγ+/CD8+/CXCR3+ T lymphocytes supporting the notion that this subset of T cells contributes to the antitumor efficacy of immunochemotherapy. Knockout of the CXCR3 gene annihilated the beneficial effects of VCT. The source of the deleterious CCL5 was the TLR3-activated tumor cells in that stable inhibition of the chemokine production by targeted shRNA CCL5 ameliorated the efficacy of VCT tritherapy. Altogether, 11% of wild-type mice were completely protected from melanoma by VCT sequential regimen. Conclusions: This study supports the notion that poly(A:U) can act on tumor epithelia to promote the release of beneficial CXCL10 for the recruitment of intratumoral CTLs but also the release of deleterious CCL5 acting on host immunosuppressors. Uncoupling chemokine release and/or prior vaccination may enable the CXCR3L-dependent CTL to overrule the CCR5-dependent suppression and may be integrated in future trials using TLR3 agonists. [Table: see text]