bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor stem cell vaccine for NSCLC and GBM-assessment of feasibility, adverse events and efficacy
Authors: Moviglia G. A. , Varela G. , Gaetta C. A. , Guerra M. , Carrizo A. , Costanzo H. , Farina P. , Bastos F. , Moviglia-Brandolino M. T. , Paes de Lima A. , Merino S. 
Published: March 2020

2556 Background: Only a small part of the total cell population of a malignancy has the potential to grow and regenerate the total tumor mass. The rest are only differentiated forms of those stem cells. This biologic characteristic seems to be responsible for the failure to achieve long term remission for several peptide based vaccines. Method: To overcome this obstacle, we have established a technique that uses tumor stem cells (TSC) to develop a TSC-B cell vaccine. To test efficacy and best administration form of this vaccine, we have proceeded as follow: First: Pieces from total or partial resections of GBM or NSCLC were mechanically dissociated to a single cell suspension. Cells were cultured in an appropriate tissue culture medium and allowed to grow for two weeks or until they reach a semi confluent stage. Then, cells were harvested and re-seeded. This procedure was repeated 6 to 24 weeks according to vitality and growth characteristics of cells. Finally, Tumor cells were fused with autologous B cells. The hybrid was kept in culture and used for an intra lymph node immunization every 3 weeks. To potentiate its action, 3 days prior to its administration we co-incubated the hybrid with either autologous dendritic cells or autologous mononuclear cells. Adverse events were evaluated by the “Common terminology criteria for Adverse Events (AE), 2004” developed by NIH. Definitions are available on the web at http://ctep.cancer.gov/reporting/ctc.html . Clinical efficacy of this procedure was evaluated according RESIST criteria for NSCLC and a combination of MRI and spectroscopy for GBM. Results: At present 8 patients with GBM with post surgical second relapse and who had received complete radiotherapy doses were treated. We have also treated 6 patients with NSCLC:4 with minimal residual disease and 2 with measurable residual disease. Patients have presented minor adverse events, mainly referred to inflammation of the injection site. The median survival rates registered to the present are 22 months for GBM patients and 3 years for patients with stage IV NSCLC who had minimal residual disease at the beginning of the treatment. Conclusion: A tumor stem cell vaccine seems to be a feasible and effective therapy with very low toxicity for the treatment of advanced GBM and NSCLC patients. No significant financial relationships to disclose.
Pharmacokinetics (PK) and immunologic responses in a phase I/II study of a sustained release formulation of IL-2 in renal cell carcinoma (RCC) patients
Authors: Oudard S. , Thiounn N. , Fridman H. , Amsellem-Ouazana D. , Colombel M. , Jacqmin D. , Malavaud B. , Kravtzoff R. 
Published: March 2020

2558 Background: The utility of interleukin-2 (IL-2) in treating RCC is limited by its significant toxicity, expense, and limited efficacy. Formulations that reduce post-injection peak concentration (Cmax) and support sustained therapeutic levels may improve efficacy and tolerability of IL-2 therapy. In preclinical studies, IL-2 formulated with Medusa (IL-2XL), a novel sustained drug delivery system, reduces Cmax and supports controlled release of IL-2 for up to 6 days. Methods: The open-label Phase I/II study was designed to accrue 12 patients (pts), with a goal of 10 evaluable pts. Pts aged 18–85 at high risk of recurrence after surgical resection of histologically confirmed RCC, and without CNS metastases, other malignancy, autoimmune disorders were eligible. Pts received one single subcutaneous (SC) injection of 10.6 MIU naked IL-2 (IL-2N) or IL-2XL. At least two weeks later, patients were crossed over to receive a single SC administration of 10.6 MIU of the other agent. Safety, PK, biological activity and immunological responses were assessed. Results: 8 patients have accrued and results from 6 pts evaluable to date show a 4-fold reduction in Cmax following IL-2XL injection compared with IL-2N. IL-2 was detectable in serum 7 days after IL-2XL treatment, compared with 2 days for IL-2N. Relative bioavailability of IL-2XL was approximately 150% of IL-2N, and Tmax was appoximately 48 hrs compared with 2–4 hrs. T50 also was higher following IL-2XL administration compared with IL-2N (48 vs. 8 hrs). Soluble CD25 and neopterine, markers of IL-2 activity, had much higher Cmax (159 vs. 63 pg/ml and 14 vs. 6 pM for sCD25 and neopterin) and AUC (14,749 vs. 7,701 pg/ml/hrs and 1,569 vs. 665 pM/hrs for sCD25 and neopterin) following IL-2XL treatment compared with IL-2N. Compared to IL-2N immunoflowcytometry showed an increase in percentage and activation of lymphocytes (CD3+/CD45+; CD8+/CD25+ and CD4+/CD25+). Conclusions: Weekly dosing of IL-2XL reduces Cmax, increases induction of IL-2 biomarkers and improves immunologic responses compared with IL-2N. Data support the development of IL-2-XL used on a weekly schedule for treating cancer and viral disease such as HIV. No significant financial relationships to disclose.
A novel non-HLA-restricted cellular immune assay for monitoring patient (pt) response to targeted immunotherapeutics
Authors: Manson K. , Dolan K. E. , Marshall J. , Kaufman H. , Mazzara G. P. , Schuetz T. J. 
Published: March 2020

2567 Background: Many therapeutic cancer vaccines are designed to elicit T-cell immunity. In vitro monitoring of pt response is limited by the HLA-restriction of ELISPOT assays. We report a novel, non-restricted assay for measuring immune responses generated by PANVAC-VF, which comprises 2 recombinant viral vectors in a heterologous prime-boost immunization regimen. Each vector contains genes encoding the tumor antigens CEA and MUC-1, and 3 immunologic costimulatory molecules B7.1, LFA-3, and ICAM-1. The safety of PANVAC-VF was tested in a Phase 1 study of 10 pts with advanced pancreatic cancer (ASCO 2005 abstr 2576). Methods: Peripheral blood mononuclear cells (PBMCs) were drawn at baseline and each subsequent timepoint (∼2 wks after each injection) to measure cellular immune responses. PBMCs were separated from whole blood over a Ficoll gradient; isolated PBMCs were frozen in liquid nitrogen until analysis. A monkey breast cancer cell line (CMMT 110/C1) was infected with PANVAC-F or control fowlpox recombinant. On Day 2, PBMCs were incubated 10:1 with infected CMMT 110/C1 cells, and the mixtures co-cultivated for 72 h. Supernatants were assayed for interferon γ production. Results: Of 8 pts with PBMCs sufficient for testing, 5 developed an antigen-specific immune response to CEA and/or MUC-1. In general, interferon γ production steadily increased with repeat boosting immunizations. Cellular depletion experiments suggest that the result is dependent on CD4+ cells, allowing analysis of samples from all pts, unlike the ELISPOT, which is restricted to HLA-A2 peptide presentation. Preliminary analysis suggests a positive correlation of immune response with overall survival. Conclusions: We developed a novel, non-restricted cellular assay to assess immune response to a targeted immunotherapeutic, PANVAC-VF. Five of 8 assayed pts developed an antigen-specific cellular immune response. Pt numbers are small, but there appears to be a correlation between immune response and overall survival. This assay will be used for samples from a randomized Phase 3 study in pancreatic cancer and a randomized Phase 2 study in prostate cancer, generating a large data set of immune responses from all pts. [Table: see text]
Antitumor activity of a synthetic agonist of TLR9 in preclinical lung cancer models
Authors: Wang D. , Yu D. , Kandimalla E. R. , Agrawal S. 
Published: March 2020

2568 Background: Synthetic agonists of TLR9 induce potent Th1-type innate and adaptive immune responses. In the present study, we have studied antitumor activity of a synthetic agonist of TLR9 referred to as immune modulatory oligonucleotide (IMO) in lung cancer models either alone or in combination with chemotherapeutic agents. Methods: Two different models are evaluated. In one model, mice implanted peritoneally with 3LL-C75 lung carcinoma cells were administered with IMO or PBS once in every two days for six times for evaluating antitumor activity of IMO alone. In a second model, to evaluate combination treatment of IMO with Gemcitabine or cyclophosphamide, mice bearing subcutaneously implanted 3LL tumor were administered with peritumoral injections of IMO and i.p. injections of Gemcitabine or cyclophosphamide. Results and Conclusions: Administration of IMO to mice bearing 3LL-C75 lung carcinoma inhibited tumor growth. Tumor free mice from this study failed to grow tumor when rechallenged with 3LL-C75 lung carcinoma cells, suggesting tumor bearing mice administered with IMO developed memory responses for the same tumor. Further more, naïve mice adoptively transferred with splenocytes obtained from mice that remained tumor free from the above treatment group failed to grow tumor to a rechallenge with 3LL-C75 tumor cells. The co-administration of IMO with chemotherapeutic agents, Gemcitabine and cyclophosphamide resulted in enhanced antitumor effects in 3LL lung cancer model. The present studies show potent antitumor activity of IMO when administered alone and in combination with Gemcitabine and cyclophosphamide in preclinical lung cancer models. [Table: see text]
Phase II trial of vaccination with full length NY-ESO-1/IMX in patients with advanced malignant melanoma
Authors: Nicholaou T. , Davis I. D. , Marakovsky E. , Miloradovic L. , Hopkins W. , Chen W. , McArthur G. , Pan L. , Hoffman E. W. , Old L. J. , Cebon J. 
Published: March 2020

2571 Background: NY-ESO-1 is an immunogenic “cancer-testis” (CT) antigen, expressed in many cancers including melanoma. Iscomatrix adjuvant (IMX), a saponin-based adjuvant, was formulated with NY-ESO-1 (ESO) protein (ESO/IMX). ESO/IMX was highly immunogenic as defined by ESO specific antibody (Ab), delayed type hypersensitivity (DTH) & T-cell responses in patients (pts) with resected ESO+ve cancer. Disease free survival in vaccine recipients with resected melanoma appeared longer than in controls. A prospective evaluation was subsequently undertaken to determine whether ESO/IMX could mediate antitumor responses in pts with advanced NY ESO-1+ve melanoma. Methods: 27 pts were vaccinated in a trial designed to assess objective clinical responses, safety, & immunogenicity. Vaccination consisted of 100 μg ESO/IMX administered q 4 wk × 3; this cycle was repeated in pts without symptomatic progression unless they required other treatment. Pts were then eligible to continue vaccination q12 weeks so long as they were responding or stable. Results: ESO/IMX was well tolerated. 13 pts progressed when evaluated after the first cycle at week 11. No objective clinical responses were seen. Vaccine-induced antibody titers to NY-ESO-1 were comparable to those seen in the earlier minimal residual disease trial (ranging to > 1: 390,000). DTH & T-cell responses were less marked. This occurred despite many pts with advanced measurable disease having pre-existing spontaneous ESO immunity ( Table ). DTH responses were seen in 11 pts; 5 had pre-existing responses (2 were boosted) and 6 were induced. The DTH responses were lost by week 33. Conclusion: No objective responses were seen. Vaccine-induced immunity appeared to be attenuated in the presence of advanced metastatic disease. Ongoing laboratory studies are investigating the role of regulatory T cells in the suppression of ESO-specific immunity in these pts with a view to adopting strategies to counter regulatory responses e.g. low-dose cyclophosphamide prior to vaccination. [Table: see text] [Table: see text]
Dendritic cell based vaccination in combination with IL-2 as a treatment for advanced renal cell carcinoma patients: Results from a phase I/II trial
Authors: Berntsen A. , Geertsen P. , Trepiakas R. , Wenandy L. , Andersen M. H. , Straten P. T. , Lorentzen T. , Johansen J. S. , Johnsen H. E. , Svane I. M. 
Published: March 2020

2575 Background: Autologous dendritic cells (DC) pulsed with tumor-associated antigens as peptides or tumor lysate derived proteins can induce generation of cytotoxic T-cells in cancer patients. Survivin and telomerase are tumor-associated antigens overexpressed in renal cell carcinoma, and telomerase and survivin derived HLA-A2 binding peptides are able to induce effector T-cells cytotoxic to tumor cells. Tumor lysate can be generated from allogeneic renal carcinoma cell lines and has a natural high amount of antigens potentially enabling the induction of a polyclonal immune response against multiple targets on tumor cells. Methods: Twenty-two patients with progressive metastatic renal cell carcinoma were included and toxicity and efficacy of DC-based immunotherapy were evaluated. HLA-A2 positive patients were treated with mature autologous DCs pulsed with a broad panel of HLA binding telomerase and survivin peptides and PADRE; HLA-A2 negative patients received DCs pulsed with allogeneic tumor lysate and KLH. The vaccines were administered intradermally or intranodally weekly/biweekly ten times and repeated monthly until tumor progression. Patients received low dose IL-2 as an adjuvant. Immune response was monitored using ELISPOT assay. IL-6 and the biomarker YKL-40 were measured in serum using ELISA assay. Results: Vaccinations were well tolerated. 17/22 patients were evaluable and 10 patients had stable disease (SD) for up to 11+ months (range 2–11+ months). Interestingly, serum IL-6 increased in patients with progressive disease compared with a decrease in patients with SD. After vaccination mean values of YKL-40 were 91ng/ml in patients with SD and 208ng/ml in patients with PD. Immune monitoring is ongoing and preliminary data demonstrate that peptide specific CTLs are induced by the treatment. Conclusions: This pilot study demonstrates, that vaccination with autologous DCs pulsed with tumour antigens is safe and without severe toxicity. Disease stabilization was observed in half of the treated patients. Serum IL-6 and YKL-40 values might be useful parameters to predict clinical response during vaccination therapy. No significant financial relationships to disclose.
Dendritic cells loaded with wild-type p53 peptides induce T cell immunity and disease stabilization in patients with advanced breast cancer
Authors: Svane I. M. , Pedersen A. E. , Johnsen H. E. , Nielsen D. , Kamby C. , Nikolajsen K. , Ottesen S. , Zocca M. , Johansen J. S. , Claesson M. H. 
Published: March 2020

2577 Background: p53 mutations and over-expression are found in up to 30% of breast cancers and are associated with poor prognosis following conventional therapy. Peptides derived from over-expressed p53 protein are presented by class I MHC molecules and may act as tumor-associated epitopes and thereby as target for vaccination. Due to the diversity of p53 mutations, immunogenic peptides representing wild-type sequences are preferable as basis for a broad-spectrum p53-targeting cancer vaccine. Furthermore, single amino acid modified p53 peptides can increase HLA-A2 binding capacity and induction of p53-specific cytotoxic T cells. Methods: In a phase I-II trial a total of 32 HLA-A2+ patients with progressive advanced breast cancer were treated with autologous dendritic cells (DC) loaded with six HLA-A2 binding peptides: 3 wild-type [p5365–73 RMPEAAPPV, p53264–272 LLGRNSFEV, p53187–197 GLAPPQHLIRV], 3 modified [p53149–157 SLPPPGTRV, p53139–147 KLCPVQLWV, p53103–111 YLGSYGFRL]. Each patient received up to 10 sc vaccinations with 5x106 p53-peptide loaded DC with 1–2 weeks interval. Concomitantly, 6 MIU/m2 IL-2 was administered s.c. Results: Clinical benefit, mainly as SD or minor regression was obtained in 12 out of 32 patients. Using ELISPOT assay vaccine induced p53 peptide specific T cells were demonstrated in 7/11 of the analyzed response patients but only in 4/14 patients with continued progression, in contrast, 2 patients in this group had reduction of pre-existing reactivity. In most cases T cells specific for several of the six p53 peptides were found and no single p53-epitope was predominant. SD was associated with cessation of serum LDH rise and reduction in serum IL-6 level. In addition more response patients had significant p53 tumor expression. T cell immunity was further explored by dextramer technology and CD107 cytotoxicity assay, and serum YKL-40 was measured and compared to clinical response. Conclusions: A significant fraction of breast cancer patients with progressive disease obtained disease stabilization during treatment with p53-peptide loaded DCs. Induction of p53 specific immunity and changes in disease markers support the clinical results. No significant financial relationships to disclose.
A phase I study of BIBF 1120, an orally active triple angiokinase inhibitor (VEGFR, PDGFR, FGFR) given continuously to patients with advanced solid tumours, incorporating dynamic contrast enhanced magnetic resonance imaging (DCE-MRI)
Authors: Lee C. P. , Taylor N. J. , Attard G. , Nathan P. D. , De Bono J. S. , Temple G. , Tang A. , Padhani A. R. , Judson I. R. , Rustin G. J. 
Published: March 2020

3015 Background: BIBF 1120 is a potent inhibitor of VEGFR, PDGFR, FGFR kinases, and of members of the Src family of tyrosine kinases (Src, Lck, Lyn). Methods: Patients (Pts) with advanced solid tumours were enrolled. BIBF 1120 was administered orally once daily (q.d.) continuously, starting at 100 mg/day. Dosing was later amended to twice daily (b.i.d.) in view of transaminitis seen with q.d. dosing. DCE-MRI studies were performed at baseline, days 2 and 28. All pts underwent pharmacokinetic (PK) sampling. Results: 51 pts (26M/25F; median age 57 y, range 22–78 y; ECOG PS 0/1 = 22/27) were treated at: 100 mg q.d. (n = 6), 200 mg q.d. (n = 6), 300 mg q.d. (n = 7), 400 mg q.d. (n = 16), 450 mg q.d. (n = 5); 250 mg b.i.d. (n = 11). Median treatment duration was 57 days (range: 1 day– 22 m). The most common toxicities were nausea, vomiting, diarrhoea, abdominal pain and fatigue, all ≤ grade (G)2. Asymptomatic, reversible elevation of liver enzymes which was dose limiting in 2/5 pts at 450 mg q.d. defined the MTD at 400 mg q.d. At 250 mg b.i.d., 2/11 pts had DLT (G3 elevation in liver enzymes: n = 1; G3 abdominal pain: n = 1). 44 pts treated for ≥2 m were assessable for response: 13 pts had SD for ≥3 m (median 7m, range 3–22 m; renal, prostate, colorectal, chondrosarcoma, leiomyomatosis, fibromatosis). 3 pts with renal cancer had SD for 8, 14+ and 22 m respectively. PK evaluations generally showed increasing gMean Cmax and AUC values with increasing doses, with high inter-patient variability. Tmax was ∼2h post-dosing. gMean t1/2 values ranged from 6.8–26.4h. DCE-MRI of target lesions in 35 pts showed significant antivascular/antiangiogenic effects in some patients and dose cohorts, particularly at 200 mg q.d. and ≥400 mg q.d. DCE-MRI effects were most pronounced at 28 days, especially in metastatic liver lesions. Conclusions: BIBF 1120 is well-tolerated in patients with advanced solid malignancies and induces in vivo antiangiogenic effects detectable by DCE-MRI. Some patients experienced clinically meaningful disease stabilisation. The recommended dose for future Phase II studies was determined to be 250 mg b.i.d. [Table: see text]
Final clinical and pharmacokinetic (PK) results from a phase 1 study of the novel N-cadherin (N-cad) antagonist, Exherin (ADH-1), in patients with refractory solid tumors stratified according to N-cad expression
Authors: Stewart D. J. , Jonker D. J. , Goel R. , Goss G. , Maroun J. A. , Cripps C. M. , Wells J. , Wargin W. , Malik R. K. , Peters W. P. 
Published: March 2020

3016 Background: Malignant transformation and invasiveness correlate with upregulation of N-cad, a cell adhesion molecule expressed on tumor cells and vascular endothelium. N-cad antagonism by ADH-1, a cyclic pentapeptide (CHAVC), causes rapid tumor vascular disruption and apoptosis in preclinical models. We report the final clinical and PK results from the first human study (AHX-01–001). Methods: 46 subjects with incurable solid tumors stratified according to tumor N-cad expression were enrolled. 99 doses of ADH-1 were given by IV bolus or short infusion (31 in a Special Access Program). Doses ranged from 50–1000 mg/m2, with 3–6 subjects/cohort. Blood and urine were collected for PK on Day 1, assayed by LC/MS/MS, and a 2 compartment analysis was performed. Results: ADH-1 was generally well tolerated and the maximum tolerated dose was not defined. The most commonly reported adverse events were grade 1–2 fatigue (59%), nausea (32%), dysgeusia (25%), and flushing (20%). 4 subjects in the N-cad positive group (n=28, including 3 N-cad unknown) demonstrated anti-tumor activity; a PR of 6 month duration in refractory esophageal carcinoma; a minor response in lung metastases from an unknown primary following a single dose; and >7 months SD in refractory adrenocortical and colorectal carcinoma. No anti-tumor activity was noted in the N-cad negative group (n=18). The mean initial ADH-1 half-life (t½) was 20 min and the mean terminal phase t½ was 2.2 hr. Mean systemic clearance (CL) was 6.5 L/hr/m2. Both t½ and CL were independent of dose. Cmax increased dose proportionally, ranging from 7 to148 μg/mL, and AUC0-∞ tended to increase dose proportionally. The volume of distribution at steady-state (Vss) averaged 14.3 L/m2, indicating modest tissue distribution. Approximately 30% of the dose was excreted unchanged in the urine. Conclusions: ADH-1 was generally well tolerated and demonstrated evidence of anti-tumor activity in subjects with N-cad positive tumors. The PK profile was biphasic and the t½ averaged 2.2 hr. Cmax and AUC0-∞ increased dose proportionally, and CL was independent of dose. No significant financial relationships to disclose.
Phase I trial involving the pharmacodynamic (PD) study of circulating tumour cells, of CP-751,871 (C), a monoclonal antibody against the insulin-like growth factor 1 receptor (IGF-1R), with docetaxel (D) in patients (p) with advanced cancer
Authors: Attard G. , Fong P. C. , Molife R. , Reade S. , Shaw H. , Reid A. , Spicer J. , Hamlin J. , Gualberto A. , De Bono J. S. 
Published: March 2020

3023 Background: C is the first specific, fully human, monoclonal antibody to target IGF-1R in clinical trials. It potently inhibits IGF-1R signaling, enhancing D antitumour activity. This trial investigated the safety, feasibility, dose limiting toxicity (DLT), PK and antitumor activity of D administered with C every 3 weeks. PD studies evaluated circulating tumor cell (CTC) IGF-1R expression and CTC counts pre- and post-treatment. Methods: The C doses tested were 0.1, 0.4, 0.8, 1.5, 3.0, 6.0 and 10 mg/kg in sequential cohorts of 3–6 p. D was fixed at 75mg/m2. P achieving disease control continued on C alone if experiencing D toxicity. Results: 21 p (20 male) have received 100 courses of C with D. 7 p received 8 or more courses of the combination. A further 21 courses of C alone have been administered. No toxicity has been attributed to C to date with the observed toxicities being attributable to D. Grade 3/4 toxicities were neutropenia (16/21 p) and neutropenic fever in 2/21 p. Grade 3 diarrhea was reported in 3 p, but this was easily controlled with antidiarrheals. Transient grade 1 hyperglycaemia was noted largely on day 1, following steroid premedication (14 p), but no significant C related hyperglycemia has been observed. An MTD has not been reached. Serial echocardiograms demonstrated no cardiac toxicity. Of 18 castration resistant prostate cancer (CRPC) p treated, 4 have had a confirmed PR, with 2 unconfirmed PR and 2 having disease stabilization for > 6 months (median number of courses: 10; range: 3–12). 5 p have maintained SD with C alone for 2–7 courses. CTC were detected in 16 of 18 p (CTC numbers ranged from 1 to 202 in 7.5ml of blood). IGF-1R expression was detected in 12 p. CTC IGF-1R was undetectable following treatment with C at doses above 3 mg/kg. Conclusions: This combination is safe and feasible with no toxicity attributed to C and encouraging antitumor activity in CRPC. [Table: see text]