bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dendritic cell therapy in glioblastoma multiforme
Authors: Nesselhut J. , Nesselhut T. , Chang R. , Marx D. , Brockmann W. , Wilke I. , Matthes C. , Lorenzen D. , Stücker W. , Peters H. , Lüke W. 
Published: March 2020

3065 Background: Malignant brain tumors belong to the tumors with unfavorable prognosis. The most aggressive form, glioblastoma multiforme (GBM WHO grade IV glioma), is categorized as incurable with median survivals less than 12–18 months and 90–95% of patients surviving less than 2 years. Here we show that immunotherapy with monocyte-derived dendritic cells (MoDC) can induce a clinical response in advanced GMB, especially when combined with the non human pathogenic oncolytic virus NDV (New Castle Disease Virus). Methods: After isolating monocytes from peripheral blood of n=21 patients dendritic cells were generated ex vivo in the presence of recombinant cytokines (IL-4, GM-CSF) and 2,5% autologous serum. If tumor tissue was available the MoDC were primed on day 5 with tumor- lysate and co-cultured with poly:IC and IFN-alpha. The MoDC were harvested on day 7 of culture and administered to the patients, intradermally. In 5 patients NDV was added to the MoDC for one hour prior to administration. These patients received an infusion with NDV one day before vaccination. Results: We were able to induce a clinical response in 33% (n=7) of the treated patients. The median survival after onset of DC-therapy was 10 months. With respect to primary diagnosis the median survival was 19 months with 1- and 2-years survival rates of 81% and 14%, respectively. Improvement of the clinical response can be observed by combination of NDV. None of the 5 patients treated with this combination therapy died of the disease (9–19 months after primary diagnosis). Three of them (60%) show a response with 2 clear partial remissions (40%). Conclusions: Taken together, a dendritic-cell based therapy can be successful in the treatment of GBM. Enhancement of the therapeutically outcome can be induced by a combination therapy with New Castle Disease Virus leading to the suggestion that there may be an interaction between the dendritic cells and the NDV. No significant financial relationships to disclose.
Phase II clinical trial of mutant Ras peptide vaccine in combination with GM-CSF and IL-2 in advanced cancer patients
Authors: Achtar M. S. , Toubaji A. , Herrin V. , Gause B. , Hamilton M. , Berhens R. , Grollman F. , Bernstein S. , Khleif S. 
Published: March 2020

3067 Background: Mutant ras oncogenes produce novel proteins that are processed and displayed through HLA molecules on tumor cells. Therefore, mutant ras is an attractive target for vaccine therapy. We have shown in a previous phase I trial that vaccination with mutant ras peptides produced specific immune responses (IR). Here we tested in a phase II trial the use of specific mutant ras peptides in combination with GM-CSF and IL-2 in advanced cancer patients carrying the ras mutation in their tumors. Methods: We treated 17 patients with advanced cancers (14 CRC, 1 NSCLC and 2 pancreatic) with 5000μg of the corresponding mutant ras peptide given SQ along with GM-CSF and IL-2. GM-CSF was given SQ on days -1,0,1,2 followed by ten days of low dose SQ IL-2. Vaccines were repeated every 5 weeks for a maximum of 15 cycles or until disease progression. Results: 11 patients who received 3 or more vaccinations were tested for immune response by measuring IFN-γ mRNA copies in PBMCs pre and post vaccination. 6/11 patients generated specific IR to the corresponding mutant ras vaccine. The median overall survival and the median progression-free survival for all patients were 25.8 and 13.1 months respectively. However, in the 6 patients with positive IR, it was 39.9 and 17.9 months compared to 18.5 and 15.6 months in the 5 patients who showed no IR. No grade IV toxicity occurred. Most adverse events were Grade I-II toxicities and resolved spontaneously. Grade III toxicities led to IL-2 dose reduction in 3/17 patients (18%). Conclusions: The study showed that vaccination of advanced cancer patients with mutant ras peptides in combination with GM-CSF and IL-2 is safe and can induce specific immune responses. Furthermore, those patients who generated IR showed better clinical outcome, as reflected by PFS and OS. So we believe that this vaccine may form a potentially promising approach in combination with other therapeutic modalities in advanced solid tumors. No significant financial relationships to disclose.
Donor lymphocyte infusions from Ad-sig-TAA/ecdCD40L vector prime-TAA/ecdCD40L protein boost (VPP) vaccinated allodonors decrease tumor cell growth post allograft
Authors: Deisseroth A. B. , Tang Y. , Akbulut H. , Maynard J. , Petersen L. 
Published: March 2020

3071 Background: Individuals of advanced chronological age exhibit an impaired immune response to vaccines. This may be due to a reduction in the ratio of antigen naïve/memory CD4 and CD8 T cells and acquisition of functional defects in activated “helper” CD4 T cells (eg diminished CD40 ligand (CD40L) expression) during the aging process. Methods: In order to circumvent this defective response to vaccines in individuals in the fifth and sixth decades of life, our laboratory has developed an adenoviral vector (Ad-sig- TAA/ecdCD40L) vaccine which is designed for the in vivo target associated antigen (TAA) loading and activation of dendritic cells (DCs), and to overcome the absence of CD40L expression in activated CD4 helper T cells in older individuals. Results: The subcutaneous (sc) injection of this vector leads to the release of a fusion protein composed of a TAA linked to the extracellular domain (ecd) of the CD40 ligand (CD40L), which binds to the CD40 receptor on DCs, activates the DCs, and leads to the presentation of TAA fragments on Class I MHC. Two sc injections of the TAA/ecdCD40L protein as a booster following the sc administration of the Ad-sig-TAA/ecdCD40L vector (VPP) expands the magnitude of the cellular and humoral immune response induced by the vector in 18 month old aged mice as well as in younger mice. This vaccine decreased levels of negative regulatory CD4 FOXP3 T cells in tumor nodules. We administered TBI and an allogeneic stem cell transplant 7 days post sc injection of the E7 positive TC-1 cells. DLI from an Ad-sig-E7/ecdCD40L vector prime-E7/ecdCD40L protein boost vaccinated donor were injected iv 3 days post transplant, and a single E7/ecdCD40L protein boost sc vaccination one week thereafter. We found that the growth rate of the E7 positive TC-1 tumor cells post allograft was less in the vaccinated than in the control (injection of tumor cells followed in 7 days by TBI), or the animals in which the allograft recipient was vaccinated without DLI. Conclusions: Thus, the use of DLI from VPP vaccinated allodonors decreased tumor cell growth post allograft. No significant financial relationships to disclose.
Xenograft-like destruction of tumors and their conversion into vaccines by intratumoral injection of α-gal glycolipids
Authors: Galili U. , Wigglesworth K. , Abdel-Motal U. 
Published: March 2020

3074 Background: We describe a novel immunotherapy exploiting the natural anti-Gal antibody to destroy tumors and convert them into endogenous vaccines. Anti-Gal constitutes 1% of immunoglobulins in humans and interacts specifically with a-gal epitopes (Gala1- 3Galβ1–4GlcNAc-R) on glycolipids and glycoproteins. a-Gal epitopes are abundant in nonprimate mammals. Binding of anti-Gal to a-gal epitopes on pig cells mediates xenograft rejection. We inject glycolipids carrying a-gal epitopes (a-gal glycolipids) into solid tumors. Methods: a-Gal glycolipids extracted from rabbit RBC have carbohydrate chains capped with a-gal epitopes. Efficacy of treatment was studied in a1,3galactosyltransferase knockout mice bearing B16 melanoma. These mice are unique since they lack a-gal epitopes and can produce anti- Gal, like humans. Also B16 cells lack a-gal epitopes. B16 lesions (∼5 mm) were injected with 1mg a-gal glycolipids. Results: Intratumoral injection of a-gal glycolipids results in local inflammation mediated by anti-Gal binding to the ∼2x1016 a-gal epitopes on these glycolipids, activation of complement and generation of chemotactic factors. a-Gal glycolipids insert spontaneously into tumor cell membranes. Binding of anti-Gal to a-gal epitopes on such tumor cells induces lesion destruction, similar to xenograft rejection. Anti-Gal further opsonizes tumor cells for effective uptake by inflammation recruited dendritic cells (DC), via Fcγ receptors of these APC. The DC transport internalized tumor Ags to draining lymph nodes and present tumor Ag peptides, thus activating tumor specific T cells and eliciting an immune response against micrometastases. Conclusions: Injected a-gal glycolipids effectively destroy lesions and convert them into vaccines. This treatment may be even more effective in humans, since complement activity is much higher than in mice. This treatment may also be considered as neo-adjuvant immunotherapy for converting primary tumor into autologous tumor vaccine that elicits a protective immune response against micrometastases, during the period preceding resection of the tumor. No significant financial relationships to disclose.
Sorafenib but not sunitinib affects the induction of immune responses
Authors: Hipp M. M. , Hilf N. , Walter S. , Werth D. , Kanz L. , Weinschenk T. , Singh H. , Brossart P. 
Published: March 2020

3504 Background: The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are approved for the treatment of patients with metastatic renal cell cancer. To analyze the possible use of these compounds in combination with immunotherapeutic approaches we investigated the effects of both TKIs on function of human dendritic cells (DCs) and induction of primary immune responses in vitro and in vivo. Methods: Human monocytes-derived DCs were treated with DMSO, sorafenib or sunitinib. Functional and phenotypic analyses as well as the possible impact on signal transduction pathways were performed. Furthermore, induction of immune responses in vivo was analyzed in animals treated with both compounds. Results: Sorafenib but not sunitinib inhibits function of DCs. Exposure of DCs to sorafenib reduces expression of CD1a, MHC and costimulatory molecules in response to stimuli via TLR ligands. Sorafenib reduces cytokine production by DCs as well as their ability to migrate and stimulate T cell (TC) responses. We found that these inhibitory effects of sorafenib are mediated via inhibition of PI3K, MAP kinases and NFκB signaling. The TKIs have no influence on phenotype and proliferation of TCs. To analyze the effects of TKIs on the generation of immune responses in vivo, induction of TC responses was assessed by peptide vaccination with the model antigen OVA-001 in C57BL/6 mice. When mice were pretreated with both TKIs which were also given during vaccination, it was observed that sorafenib, but not sunitinib significantly reduces the generation of vaccine-specific CD8+ TCs. Numbers of CD4+ CD25+ regulatory TCs are reduced in sunitinib-treated mice, but not in sorafenib-treated animals. All effects of the TKIs are reversible, and the immune responses go back to normal levels if mice are immunized after discontinuation of treatment. Conclusions: In summary, sunitinib represents an interesting compound to be used in combination with immunotherapeutic approaches to treat cancer patients. No significant financial relationships to disclose.
Phase 1 study of ARQ 197, a selective inhibitor of the c-Met RTK in patients with metastatic solid tumors reaches recommended phase 2 dose
Authors: Garcia A. , Rosen L. , Cunningham C. C. , Nemunaitis J. , Li C. , Rulewski N. , Dovholuk A. , Savage R. , Chan T. , Bukowksi R. , Mekhail T. 
Published: March 2020

3525 Background: ARQ 197 is a selective inhibitor of the c-Met receptor tyrosine kinase, an oncogene implicated in tumor invasiveness, metastasis, cancer cell proliferation, resistance to apoptosis, chemoresistance and angiogenesis. The c-Met RTK is a high-affinity receptor for hepatocyte growth factor (HGF). c-Met and HGF are dysregulated in a broad spectrum of cancers, thus inhibitors of c-Met could be promising targeted agents deserving clinical investigation. Methods: A phase 1 dose escalation study in metastatic pts who failed standard therapy was initiated to determine safety, tolerability, RP2D, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of ARQ 197. Cycles consisted of twice-daily oral dosing of ARQ197 for two out of 3 weeks. Results: Thirty-eight pts were enrolled with data available for 36 pts (21M/15F; median age 61). Ten cohorts were assessed ranging from 10 to 360 mg/day. ARQ 197 was well tolerated and no DLT was observed. All treated pts achieved plasma drug concentrations significantly above the in vitro IC50. Doses through 70 mg b.i.d. revealed Cmax and AUC(0–12hr) increased linearly. There was no further increase in systemic exposure in pts treated with 90 through 180 mg b.i.d. There was notable inter-patient variability in Cmax and AUC(0–12hr), typical of oral dosing. The effects of cytochrome P450 polymorphism will be discussed. Adverse events (N=29) were generally mild with the most common being: fatigue (24 %), diarrhea (21%), and constipation (21%). Grade 3 or greater events possibly or probably related to ARQ 197 include: elevated ALP (3%), ALT (3%) and AST (3%). Of the 38 pts enrolled, 36 received at least one complete cycle of ARQ 197 with 33 evaluable for efficacy. Two pts achieved a PR (1 confirmed) and 19 had stable disease (SD) 21 10+ to 34+ weeks. Conclusions: Based on pharmacokinetic data, a RP2D for ARQ 197 was determined to be 120 mg b.i.d. Higher oral doses did not result in increased systemic systemic exposure to the drug. Eleven pts remain on study and continue to receive ARQ 197 treatment. A favorable adverse event profile and encouraging signs of anti-tumor activity was observed and continuous daily dosing of ARQ 197 is now being explored to better define clinical toxicity and efficacy. [Table: see text]
First in human phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of KU-0059436 (Ku), a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in cancer patients (p), including BRCA1/2 mutation carriers
Authors: Yap T. A. , Boss D. S. , Fong P. C. , Roelvink M. , Tutt A. , Carmichael J. , O’Connor M. J. , Kaye S. B. , Schellens J. H. , de Bono J. S. 
Published: March 2020

3529 Background: Ku is a novel, potent, orally active PARP-1 and 2 inhibitor. It induces selective cytotoxicity in cells with defective homologous recombination repair such as BRCA1/2 deficient tumor cells. Methods: Starting at 10 mg daily (qd) for 2 out of 3 weeks (w), Ku dose escalation was guided by toxicity and PK data. Cohorts of 3–6 p with advanced solid tumors were treated, with provisions for enrichment with BRCA1/2 mutation carriers. PD studies evaluated PARP functional activity in surrogate tissue, including peripheral blood mononuclear cells (PBMC), and tumor tissue when available. Results: 44 p were treated; 17 M/ 27 F; mean age 56 (range 19–82). ECOG PS =2. 11 p had BRCA1/2 mutations and 2 p had strong family histories suggesting BRCA1/2 mutations. Dose levels tested were 10, 20, 40 and 80 mg qd, then 60 and 100 mg twice daily (bid) - all for 2 out of 3 w; followed by 100, 200, 400 and 600 mg bid continuously. Dose limiting toxicity was seen in 1 of 6 p at 400 mg bid. This p had grade (G) 3 neurocognitive toxicity, nausea and vomiting, all of which resolved within 24 hours of drug discontinuation. Other Ku toxicities included G1–2 fatigue, anorexia, constipation and diarrhea. PK data supports dose proportionality up to 200mg bid; mean elimination half-life was 6 hours (range 4.6–7), mean clearance/bioavailability (F) was 4.55 L/h (range 1.8–9.1), and mean volume of distribution/F was 39.9L (range 17–92.1). PD studies indicate a significant (>50%) inhibition of PARP functional activity in PBMC and tumor at doses >40 mg qd. Encouraging anti-tumor activity was seen. 4 p had significant tumor marker declines, 3 of whom also had radiological evidence of response (including 1 partial response by RECIST criteria for 6 months). 7 other p had stable disease for 3 to 6 months. Several of these p had BRCA1/2 mutations and were chemotherapy resistant. Conclusions: Ku leads to significant PARP inhibition with minimal toxicity. The final dose level (600 mg bid continuously) is being tested to maximize tumor PARP inhibition. Both radiological and biochemical evidence of antitumor activity have been seen in BRCA1/2 cancer p. Exploration of Ku in phase II and combination studies is warranted. [Table: see text]
Inhibition and flare patterns of metabolic response to the heat shock protein 90 (Hsp90) inhibitor IPI-504 visualized by FDG-PET in patients (pts) with advanced gastrointestinal stromal tumors (GIST) resistant to tyrosine kinase inhibitor (TKI) therapy
Authors: Van den Abbeele A. D. , Yap J. T. , Grayzel D. S. , Walker J. , Demetri G. D. 
Published: March 2020

3530 Background: We have previously demonstrated the inhibition and rebound of GIST glycolytic metabolism with FDG-PET while pts were on or off TKI in prior trials of imatinib and sunitinib. We tested the same principle in a phase I trial of IPI-504, a novel potent inhibitor of Hsp90 (a chaperone for protein homeostasis) that results in selective destruction of the mutated KIT kinase in human GIST cell lines regardless of TKI-resistance mutations. Methods: Twenty-one patients with metatastic and/or unresectable GIST following failure of prior therapy with TKI were treated with IPI-504. Serial FDG-PET imaging was performed at baseline, during the 1st cycle after at least 2 doses (C1, days 4–11, “ON”, n = 18), and at the end of the 10-day off-treatment period prior to the start of the 2nd cycle (C1, “OFF”, n = 20). A subset of 5 pts also had FDG-PET at the end of the 3rd cycle (C3, day 11, “ON”). Maximum standardized uptake values (SUVmax) were measured in up to 3 lesions/pt with the greatest FDG uptake, and the SUVmax of all lesions was summed at each time point. Percent change in the summed mean SUVmax was calculated at each time point relative to the previous scan. Temporal changes were evaluated in those pts showing more than a 10% decrease in SUVmax during C1 “ON” compared to baseline. Results: We observed a >10% reduction in SUVmax (mean = - 28%) during the 1st cycle (C1, “ON”) in 8/18 pts. All these pts showed an increase in SUVmax (mean = +29%) when off therapy (C1, “OFF”). Three of these 8 pts had a scan during cycle 3. All demonstrated a decrease in SUVmax (mean = -30%) while on the drug (C3, “ON”). Conclusion: These preliminary findings suggest that: (1) tumor metabolic response as measured with FDG-PET parallels the intermittent pattern of IPI-504 administration in this study as early as after the 2nd dose administration; and, (2) IPI-504 has a rapid downstream effect on glucose metabolism similar to that observed with TKIs despite the very different mechanism of action of IPI-504. The pattern of response to Hsp90 inhibition seen in this heavily pretreated population strongly supports further clinical investigation. No significant financial relationships to disclose.
First in-human phase 1 trial of a novel amino-peptidase inhibitor, CHR-2797
Authors: Protheroe A. , Reid A. , Attard G. , Davies A. , Spicer J. , Vidal L. , Bone E. , Hooftman L. , Harris A. , De-Bono J. 
Published: March 2020

3537 Background: CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, Noxa. CHR-79888 is an active metabolite of CHR-2797. Patients and Methods: This study was conducted according to an accelerated titration design to define the MTD, DLT, toxicity profile and PK of CHR-2797 when administered orally for 28 days or longer. Patients (ECOG PS = 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. Results: 37 pts (median age 61.5 years [range 22.4–80.1]; 30M/7F; median ECOG PS 1; median prior regimens 2, range 0–6) enrolled in 12 cohorts (doses between 10 and 320mg). The first four patients received a 10 mg dose for 7, 14, 21 or 28 days respectively. Subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity = Grade 2. Thereafter the study followed a 3+3 design with = 40% dose increments. Common (gr 1–2) toxicity included fatigue (47%), diarrhea (47%), dizziness (24%), constipation, vomiting, abdominal pain (all 21%), and thrombocytopenia (18%). Toxicities show dose dependency for thrombocytopenia and fatigue. MTD was declared at 320 mg after 2 DLT’s were reported: 2 patients were unable to complete 28 days of daily dosing due to syncope/anemia, and dizziness/visual disturbances/thrombocytopenia, respectively. Patients recovered fully after cessation of the drug. The dose level below (240 mg) was expanded to 13 patients. Plasma PK was determined for both CHR-2797 and -79888, on days 1 and 28, which showed dose proportional increases in AUC and Cmax. Intracellular and intratumoral levels of both the parent and metabolite were also measured. So far 4 patients continued therapy for 7–9 months: one patient (RCC [130 mg]) achieved a PR, and 3 patients (ovarian ca [40 mg], NSCLC [130 mg], and breast ca [180 mg] had confirmed SD (> 3 months). Conclusion: Once daily oral CHR-2797 can be administered safely for 28 days in doses up to 240 mg and exhibits favorable PK. No significant financial relationships to disclose.