bluuebunny/crossref_metadata_2025_split huggingface dataset:
Presence of survivin-specific cytotoxic T-lymphocytes (CTLs) in pancreatic cancer patients, and specific killing of human pancreatic carcinoma cells in vitro by survivin-specific CTLs
Authors: Chang D. Z. , Zhu K. , Kopetz S. , Voo K. , Li Y. , Hwu P. , Radvanyi L. , Abbruzzese J. L. 
Published: March 2020

3070 Background: The apoptosis inhibitor protein Survivin is an attractive target for a cancer vaccine because of its differential overexpression by most human tumors, its importance for tumor survival, and its demonstrated immunogenicity. To examine Survivin’s potential as a vaccine target for pancreatic cancer (PC), we evaluated the presence of Survivin-specific cytotoxic T-lymphocytes (CTLs) in PC patients and assessed the specific killing of HLA-A*0201+ human pancreatic carcinoma cell lines in vitro by Survivin-specific CTL. Methods: Mononuclear cells from the peripheral blood (PBMC) of PC patients and normal donors and Survivin peptides were used to generate Survivin-specific CTLs in vitro. The presence of Survivin-specific CTLs was evaluated by IFN-γ ELISPOT analysis. Recognition of human PC cell lines (e.g., Panc-1 and CF-Pac-1) was analyzed by 51Cr release assays. Results: Multiple CTL lines were generated from different donors against a number of Survivin 9-mer and 10-mer peptides, including Sur5–14, Sur95–104, and Sur96–104 and altered forms of these peptides with enhanced HLA-A*0201 binding. Sur5–14 (TLPPAWQPFL) and new modified mSur95–104 (ELMLGEFLKL) peptides could generate specific CTL from the PBMC of most donors, and the resulting CTL showed cytotoxicity against Survivin peptide-pulsed Panc-1 and CF-Pac-1 in an HLA-A2-dependent manner. We found for the first time that mSur95–104 could elicit CTL activity that cross-reacted with wild-type peptide and 9-mer Sur96–104 in IFN-γ ELISPOT assays. In our preliminary analysis, we detected Survivin peptide-specific CTLs in four of five PC patients for Sur5–14 and three of five for mSur95–104. All five PC patients had a positive response to a pool of A2 peptides as positive controls, indicating their immune competence. Conclusions: CTLs specific for human Survivin peptide Sur5–14 and the modified peptides mSur95–104 were detected in majority of the PC patients tested. Further, Survivin-specific CTLs killed pancreatic carcinoma cell lines in vitro. Our results suggest that these two peptides are potential vaccines for the treatment of PC. No significant financial relationships to disclose.
Discovery of TH-302: An achiral hypoxia-activated cytotoxic prodrug
Authors: Hart C. P. , Ammons S. , Duan J. X. , Jung D. , Wang J. , Jiao H. , Meng F. , Lan L. , Evans J. W. , Matteucci M. 
Published: March 2020

3515 Background: Selective targeting of the hypoxic compartment of the tumor microenvironment is both a challenge and an opportunity for discovering and developing new cancer therapeutics. Chronic and transient hypoxia underlie resistance to chemotherapeutics and radiation. We have taken a modular design approach to synthesize hypoxia-activated prodrugs. Different nitro-containing heterocyclic triggers were linked to bis alkylating phosphorous mustard toxins and profiled in in vitro and in vivo assays predictive of compound efficacy and pharmacokinetics (PK). Methods: Drug candidates were synthesized and characterized using standard synthetic methods. In vitro efficacy was assessed with cancer cell line cytotoxicity and clonogenic assays. In vivo efficacy was assessed with xenograft models in monotherapy and combination therapy modes. Results: Screening trigger-toxin combinations in H460 lung cancer cell proliferation assays under anoxic, hypoxic, and aerobic conditions yielded structure-activity relationships (SAR) and identified TH- 302, a 2-nitroimidazole triggered bromo analog of ifosfamide, as a potent and selective molecule. TH-302 exhibits in vitro proliferation IC50 values of 0.2, 5, and 90μM and clonogenic IC90 values of 0.1, 5, and 30μM under conditions of 0%, 0.6%, and 21% O2, respectively. In vitro profiling showed sufficient solubility, plasma and microsomal stability, resistance to drug efflux mechanisms, and PK. In vivo efficacy was assessed with the H460 ectopic xenograft model. TH-302 administered alone (100mpk, ip, Q3Dx5) or in combination with cisplatin (6mpk, iv, Q7Dx2) showed mean tumor volume growth delays to 500mm3 (TGD500) of 10 days for TH-302 alone, 4 days for cisplatin alone, and 20 days for the combination. These results have been confirmed and extended using different tumor models, dosing regimens, and combinations which included Taxol and 5-FU. TH-302 demonstrates dose-proportional PK in multiple species. Conclusions: TH-302, a novel hypoxia-activated cytotoxic prodrug, has promising preclinical in vitro and in vivo efficacy and selectivity and has entered IND-enabling studies. Acute and subchronic toxicology is underway in rats and dogs. We expect to file an IND for clinical studies of TH-302 this year. No significant financial relationships to disclose.
Prediction of response to temozolomide (TMZ)-based therapy by loss of MGMT expression in patients with advanced neuroendocrine tumors (NET)
Authors: Kulke M. H. , Frauenhoffer C. S. , Hooshmand S. M. , Ryan D. P. , Enzinger P. C. , Meyerhardt J. A. , Clark J. W. , Hornick J. , Fuchs C. S. , Redston M. S. 
Published: March 2020

4505 Background: TMZ, an oral alkylating agent, has recently been shown to be active in a subset of patients with NETs. In other tumor types, methyl-guanine methyl transferase (MGMT) expression is associated with TMZ resistance through its ability to remove methyl/alkyl groups from the O6 -position of guanine, thereby preventing TMZ-induced DNA damage. Methods: To better define NET pts who benefit from TMZ, we performed a retrospective analysis of 76 NET pts treated with TMZ-based regimens at 3 institutions, identified using IRB-approved observational and clinical trial databases. Immunohistochemical MGMT expression was measured in a subset of pts with available paraffin-embedded archival tissue specimens in a blinded fashion, utilizing mouse monoclonal antibodies to MGMT. Nuclear MGMT expression was scored as either present or absent in tumor cells and correlated with tumor type and treatment outcome. Results: Of 76 pts, 30 received TMZ/thalidomide and 46 received TMZ/bevacizumab. Both regimens incorporate oral TMZ, administered at a dose of 150 mg/m2 qd for 7d, every other week. 63 pts were enrolled on phase II studies, and 13 pts were treated outside a formal study protocol. Pt characteristics were: M:F=42:34; median age 57.5 (20–75); tumor type carcinoid (38), pancreatic NET (35), paraganglioma/pheochromocytoma (3). PR or CR (as measured by RECIST) was observed in 11/35 (31%) pancreatic NETs and 0/38 carcinoid pts (P<0.001), as well as 1/3 pts with paraganglioma/pheo. In 21 pts with available specimens, complete absence of MGMT expression was observed in 5/8 pancreatic NET and 0/13 carcinoid tumors (P<0.01). In this pt subset, absence of MGMT expression was associated with response to TMZ ( Table 1 ). Conclusions: Treatment with TMZ is associated with radiologic response in approximately one third of pts with pancreatic NET, but not in pts with carcinoid tumors. Absence of MGMT expression appears to define pts with pancreatic NET who achieve significant benefit from TMZ. [Table: see text] No significant financial relationships to disclose.
Management of clinical stage (CS) I and II patients with non-seminomatous germ cell tumors of the testis (NSGCTT) avoiding upfront retroperitoneal lymph node dissection (RPLND)
Authors: Flechon A. , El Karak F. , Salas C. , Rivoire M. , Droz J. 
Published: March 2020

5090 Background: CS I, Is, IIa and IIb may be treated by either upfront RPLND or upfront medical management followed by RPLND in selected cases. We retrospectively analyzed the later approach. Methods: From 1993 to 2003, 225 NSGCTT patients CS I and Is, IIa, IIb were treated at our center. In total, 148 patients with CS I were managed by surveillance followed by CT and surgical exeresis of residual disease in case of relapse and 77 with CS Is, IIa and IIb underwent upfront chemotherapy and RPLND in case of residual masses. Median follow-up was 52 months for all patients (0.16–165 months). Results: In CS I: 47/148 (32%) patients relapsed: 22/42 (52%) patients with microvascular involvement versus 25/106 without (24%). The median time to relapse was 5 months (0.16–79 months). All relapsing patients received CT except one for whom we have no information. Twenty-two patients (46%) had RPLND. Two patients died, one probably of haemorrhage one month after RPLND and one in a car accident. In CS II: 4 (5%) patients had CS Is, 40 (52%) CS IIa and 33 (43%) CS IIb. Respectively 71 (92%), 5 (6.5%) and 1 (1,5%) patients had good, intermediate or poor prognosis according to the IGCCCG. All patients received cisplatin-based chemotherapy. Forty-one (53%) patients had RPLND after CT and one refused surgery for residual disease. Histological review showed a teratoma in 22 cases (54%), necrosis in 16 (39%) and residual active disease in 3 (7%). Six patients (8%) relapsed: 1 of them had a growing teratoma. One patient died of disease and all others are alive with no evidence of disease. In total, after medical management of CS I and II, avoiding primary RPLND, only 124 (55%) and 63 (28%) patients had eventually CT and RPLND respectively. Ninety-nine percent patients were cured. Conclusions: Upfront medical treatment of CS I and CS II NSGCTT is a good option which allows to avoid unnecessary CT and RPLND indications. [Table: see text] No significant financial relationships to disclose.
Sequential therapy with carboplatin (C) followed by paclitaxel (P) as first-line chemotherapy in 105 patients with advanced ovarian cancer (AOC): Results of a multicenter phase II study of the Northeastern German Society of Gynecological Oncology
Authors: Oskay-Oezcelik G. , Mustea A. , Sommer H. , Keil E. , Höckel M. , Pfisterer J. , Camara O. , Hindenburg H. J. , Lichetenegger W. , Sehouli J. 
Published: March 2020

5533 Background: For the adjuvant setting of AOC after primary radical surgery the combination of paclitaxel and platinum in a three weeks schedule has emerged as the current standard. Exposition duration of the drug is important for cell death. In animal model additional anti-angionetic effects of low dose paclitaxel infusion was observed. A sequential schedule of these agents can potentially yield in an improved therapeutic index. Methods: In this multicenter-phase II trial after primary radical surgery 4 cycles of Carboplatin at a dose of AUC 5 (d1/q21d) followed by 12 cycles weekly paclitaxel at a dose of 80mg/m2 (d1/q7d) was applied. All patients with haemoglobin levels < 12mg/dl get primary erythropoietin. No primary use of other growth factors were allowed. Eligibility criteria were: AOC (FIGO IIb-IV), ECOG performance status 0–2, normal organ functions. Results: Between 07/2003 and 05/2005, 105 patients from 27 institutions were enrolled. The median age was 60 years (23–80). FIGO-stages were: II: 11.4%, III: 67.6%, IV: 14.2%. 1,441 cycles were analyzed and in median 16 courses were applied (range 0–16). The incidence of non-hematological toxicities was very low. 25 % of all patients experienced alopecia (grade 1–2). Neurotoxicity and nausea/vomiting (grade III-IV) occurred in no patients. Grade 3–4 hematological toxicity (% of all pts) included: thrombocytopenia (16 %), anemia (3%), leucopenia (22%), neutropenic fever (0%). 96% received erythropoietin. Thromboembolic events (5%) were not increased in patients who received erythropoietin. After a median follow-up interval of 10 months (range: 1–27 months) 20 patients died, the median overall survival is already not reached. The progression free survival is 19 months (range:10–23 months). Conclusions: These results suggest that this sequential regimen using weekly paclitaxel represents an efficacious and well-tolerated regimen. A randomized study comparing this new schedule with the conventional 3-week protocol is warranted. (Supported by Bristol Myers Squibb Germany and Ortho Biotech Germany) No significant financial relationships to disclose.
Molecular targeting in acute myeloid leukemia (AML) therapy: APcK110 is a new inhibitor of c-Kit activity in AML blasts
Authors: Faderl S. , Bornmann W. , Maxwell D. , Peng Z. , Van Q. , Liu Z. , Verstovsek S. , Ferrajoli A. , Kantarjian H. M. , Estrov Z. 
Published: March 2020

7019 Background: Tyrosine kinases (TK) are important for most cellular functions and require stringent control and regulation. C- Kit, a TK and transmembrane receptor for stem cell factor, plays a crucial role in hematopoiesis. Mutations of c-Kit can contribute to AML pathophysiology and have been associated with shorter survival and higher relapse risk following standard AML therapy. On the other hand, responses have been observed following TK inhibitor therapy such as imatinib. Identification of c-Kit or its pathways in AML leukemogenesis and development of new compounds targeting these mutations may therefore hold promise for therapy. Methods: APcK110 is the result of a structure-based design of c-Kit inhibitors and was derived of a set of compounds with favorable IC50 values in a c-Kit kinase assay. Here we present results of the activity and mechanism of action of APcK110. We used the mastocytosis cell line HMC1.1 carrying an activating c-Kit mutation and two AML lines (OCIM2 and OCI/AML3) as well as primary samples from patients with AML. Results: We demonstrate that: (1) APcK110 inhibits proliferation of all three cell lines in a dose dependent fashion using an MTT assay. Inhibition of proliferation is most significant in the SCF-dependent cell line OCI/AML3; (2) inhibition of OCIM2 cells (SCF-responsive) by APcK110 can be enhanced when adding SCF suggesting recruitment of c-Kit-dependent signaling components and increased activity of the c-Kit inhibitor under these circumstances; (3) APcK110 is a more potent inhibitor of OCI/AML3 proliferation than imatinib and dasatininb; (4) using Western immunoblotting, APcK110 decreases levels of phospho-Akt, phospho-Stat3 and 5 in a time- and dose-dependent fashion demonstrating activity of APcK110 on c-Kit downstream signaling pathways; (5) APcK110 induces apoptosis by cleavage of caspase 3 and PARP; (6) APcK110 inhibits proliferation of primary AML cells in a clonogenic assay, but does not affect proliferation of normal controls. Conclusions: APcK110 is a potent inhibitor of AML cell lines and primary samples from patients with AML. Activation of c-Kit or downstream pathways increases activity of APcK110. APcK110 and similar compounds should be evaluated in clinical trials of patients with AML. No significant financial relationships to disclose.
Incorporating a FLT3 inhibitor into AML therapy
Authors: Levis M. J. , Small D. 
Published: March 2020

7060 Background: Activating mutations of FLT3 occur in 30% of adults with AML and are associated with worse survival. Lestaurtinib (CEP-701), an oral FLT3 kinase inhibitor, has activity as monotherapy in relapsed/refractory AML patients with FLT3 mutations. Using the results of pre-clinical models, a trial was designed in which patients with AML and FLT3 mutations in first relapse were randomized 1:1 to receive chemotherapy alone or chemotherapy followed by treatment with lestaurtinib. The primary endpoint was complete remission (CR), with a target accrual of 220 patients. We present here correlative data from this trial. Methods: Efficacy of FLT3 inhibition was measured using the plasma inhibitory activity (PIA) assay for FLT3. This assay method has been previously published (Blood 108(10):3477–83). Prior to initiation of chemotherapy, leukemia cells of the patients randomized to lestaurtinib were tested for in vitro sensitivity to lestaurtinib using a cytotoxicity assay. Plasma samples were obtained at baseline and at trough time points on Days 15 and 42. PIA assay and in vitro cytotoxicity results were correlated with the clinical results from the first 40 patients enrolled. In addition, plasma levels of lestaurtinib and alpha-1 acid glycoprotein (AAG; the principle plasma binding protein for this drug) were measured. Results: Accrual is ongoing. Twenty-three of 35 patients treated with lestaurtinib achieved a PIA result of 85% or greater (i.e., successful FLT3 inhibition). Of the first 40 patients enrolled, all those who achieved a FLT3 PIA results of 85% or greater and whose pretreatment leukemia cells were sensitive in vitro to lestaurtinib achieved a clinical response. Conversely, patients with insensitive cells or inadequate PIA did not respond. Ten of 17 patients randomized to lestaurtinib showed response (5 CR, 3 CRp, 2 PR). Four of 17 patients randomized to receive chemotherapy alone responded (2 CR, 2 CRp). Conventional pharmacokinetic analysis showed no correlation whatsoever with response, due to the high degree to which lestaurtinib is bound to AAG. Conclusions: These results demonstrate that the PIA assay for FLT3 is able to accurately predict response to lestaurtinib, and provides important evidence that targeting FLT3 remains a valid therapeutic approach for AML with FLT3 activating mutations. No significant financial relationships to disclose.
Erlotinib for first line treatment in unselected patients (p) with advanced or metastatic non-small cell lung carcinoma (NSCLC)
Authors: Jimenez U. , Gurpide A. , Isla D. , Garcia-Campelo R. , Firvida J. , Vinolas N. , Jaen A. , Montalar J. , Regueiro P. , Massuti B. 
Published: March 2020

7639 Background: Erlotinib is an orally available selective EGFR tyrosine-kinase inhibitor. Erlotinib is approved for the treatment of patients (p) with advanced or metastatic NSCL that have progressed at least to one prior chemotherapy regimen. In certain subgroups erlotinib has demonstrated to be active when administered as first line treatment. We retrospectively analysed efficacy and safety of patients treated with erlotinib as first line included in the Target Study. Methods: The TargeT trial is a multicentric, open-label, non-randomized, phase II study carried out in 101 Spanish institutions. Eligibility criteria included chemonaive p with stage IIIB-IV NSCLC. Subjects were treated with 150 mg/day po until disease progression or unacceptable toxicity. Dose reductions were allowed. Primary end-point was survival. Results: By the time of this interim analysis, data from 437 p treated with erlotinib as first line were available. Median age 72 y (range 26–90). Demographics (%): M/F 59/41; PS0/1/2 19/51/30; pathology adeno 53; current or former smoker 63. In the evaluable population for efficacy best response was: 6 CR, 68 PR, 93 SD, 69 PD (RR 31.35%). Time to progression was 6.6 mo (95% CI 4.8–8.6/ OS 7.1). Overall survival was 7.1 mo (95% CI 5.9–9.1). Most common erlotinib-related adverse events were skin rash (61%) and diarrhea (31.2%) with no unexpected toxicities having been observed. Conclusions: Although at this moment clinical trials are ongoing trying to find the best predicitive factor of response, erlotinib first line was active and well tolerated in this analysis in an unselected population. No significant financial relationships to disclose.
Targeted radiopharmaceutical therapy for advanced lung cancer: Phase I trial of rhenium Re188 somatostatin analogue P2045
Authors: Edelman M. J. , Clamon G. , Kahn D. , Magram M. , Line B. R. 
Published: March 2020

7672 Background: Both small cell (SCLC) and non-small cell lung cancer (NSCLC) overexpress somatostatin receptors (SSTR). P2045 peptide is an 11-amino acid somatostatin analogue that binds with high affinity to SSTR. The analogue can be labeled with Tc-99m to gauge receptor prevalence, or with Re-188 for 2.1MeV beta radiotherapy. To evaluate the safety of this approach a phase I dose-escalation study of Re-188 P2045 in SSTR positive lung cancer was performed. Methods: Patients (pts) were required to have progressive advanced lung cancer, PS 0–1, and normal organ function. There were no limitations on the number of prior therapies. Tumor SSTR was detected with Tc-99m P2045. If positive, treatment with escalating doses of Re-188 P2045 was instituted. Three doses were evaluated, 30 mCi/m2, 60 mCi/m2 and 90 mCi/m2. A single dose of Re-188 P2045 was allowed. Dose limiting toxicity was defined as ≥ grade 3 non-hematologic toxicity, grade 4 hematologic toxicity or projected renal radiation dose of >20 Gy. Results: 15 pts entered, 7 M, 8 F, median age 61y, 9-PS0, 6 PS1. 13 NSCLC, 2 SCLC. 14 pts had ≥ 2 prior chemotherapy regimens. 1 pt refused standard therapy. All pts were imaged with Tc-99m P2045, 8 pts received Re-188 P2045. The 7 pts who did not proceed to Re-188 P2045 were due to rapid progression (n=2) non-uptake of Tc 99m P2045 (n=2) or projected renal radiation dose above the 20 Gy limit (n=3). All pts treated with Re-188 P2045 (4 at 30 mCi/m2, 3 at 60 mCi/m2 and 1 at 90 mCi/m2) had NSCLC. The major toxicity was grade 1 or 2 lymphopenia. No dose limiting toxicities were seen. All tumors imaged by Tc-99m had uptake of Re- 188. The trial was halted at the 90 mCi/m2 level when 3 pts had projected renal radiation doses above 20Gy. No responses were seen. 5 of the 8 pts (62.5%, 95% CI: 24%, 91%) had stable disease at 8 weeks, all of whom entered with progressive disease.. Median overall survival was 11.5 mo. Conclusions: 1) Re-188 P2045 was well-tolerated. 2) Tc-99m P2045 imaging allows identification of pts who may benefit from Re-188 P2045. 3) While responses were not seen, survival for these heavily pretreated pts is encouraging. 4) Further exploration of this approach utilizing amino acid infusion to ameliorate potential renal toxicity is warranted. No significant financial relationships to disclose.