scholarly journals The IL-4 and IL-13 pseudomonas exotoxins: new hope for brain tumor therapy

2006 ◽  
Vol 20 (4) ◽  
pp. E11 ◽  
Author(s):  
Takeshi Shimamura ◽  
Syed R. Husain ◽  
Raj K. Puri
Keyword(s):  
Clinical Trials ◽  
Brain Tumor ◽  
Phase I ◽  
Tumor Cells ◽  
Cell Lines ◽  
Solid Tumor ◽  
Tumor Therapy ◽  
Glioma Cells ◽  
Human Tumors ◽  
Brain Tumor Therapy

✓ Targeting cell surface receptors with cytotoxins or immunotoxins provides a unique opportunity for brain tumor therapy. The authors have discovered that receptors for two cytokines, interleukin (IL)-4 and IL-13, are overexpressed on tumor biopsy samples and on cell lines derived from a variety of human tumors, including brain tumors. These investigators have demonstrated that the structure of these cytokine receptors on tumor cells is different from that found on normal immune cells. In human solid tumor cells, IL-4 binds to two chains (IL-4Rα and IL-13Rα1), whereas IL-13 binds to three chains in many solid tumor cells, including glioma cells (to IL-4Rα, IL-13Rα1, and IL-13Rα2). To target IL-4Rs and IL-13Rs, the authors generated two recombinant fusion cytotoxins composed of IL-4 or IL-13 and a mutated form of pseudomonas exotoxin (PE), which for simplicity are called IL4-PE and IL13-PE in this paper. These chimeric cytotoxins are highly toxic in vitro to human tumor cell lines and primary cell cultures, including glioma cells, and in vivo to animal models of human tumors, including gliomas. In contrast, normal cells, including immune, endothelial, and brain cells, are spared from their cytotoxic effects. Based on numerous preclinical studies, IL13-PE (also known as IL13-PE38QQR or cintredekin besudotox) has been tested in four Phase I/II clinical trials. The agent IL13-PE was administered intracranially by using convection-enhanced delivery (CED). The drug was delivered through catheters placed either directly into the tumor bed or in the peritumoral region after resection of the lesion. The CED of IL13-PE was fairly well tolerated, with a reasonable benefit/risk profile for treatment of patients with glioma. Based on Phase I/II clinical trials, the Phase III Randomized Evaluation of CED of IL13-PE Compared to Gliadel Wafer with Survival Endpoint Trial (also known as the PRECISE Trial) in patients with initial recurrence of glioblastoma multiforme has recently been completed. Patients are being monitored for safety of the agents, duration of overall survival, and quality of life.

scholarly journals Prognostic Factors for Survival in Adult Patients With Recurrent Glioma Enrolled Onto the New Approaches to Brain Tumor Therapy CNS Consortium Phase I and II Clinical Trials

2007 ◽  
Vol 25 (18) ◽  
pp. 2601-2606 ◽  
Author(s):  
Kathryn A. Carson ◽  
Stuart A. Grossman ◽  
Joy D. Fisher ◽  
Edward G. Shaw
Keyword(s):  
Clinical Trials ◽  
Brain Tumor ◽  
Prognostic Factors ◽  
Phase I ◽  
Frontal Lobe ◽  
Median Survival ◽  
Tumor Therapy ◽  
Recurrent Glioma ◽  
New Approaches ◽  
Brain Tumor Therapy

Purpose Prognostic factor analyses have proven useful in predicting outcome in patients with newly diagnosed malignant glioma. Similar analyses in patients with recurrent glioma could affect the design and conduct of clinical trials substantially. Patients and Methods Between 1995 and 2002, 333 adults with recurrent gliomas were enrolled onto 10 phase I or II trials of systemic or local therapy. The studies had similar inclusion criteria and were conducted within the New Approaches to Brain Tumor Therapy CNS Consortium. Ninety-three percent of the patients have died. Cox proportional hazards (PH) regression and recursive partitioning analysis (RPA) were performed to identify prognostic factors. Results Factors associated with an increased risk of death were increased age, lower Karnofsky performance score (KPS), initial and on-study histologies of glioblastoma multiforme (GBM), corticosteroid use, shorter time from original diagnosis to recurrence, and tumor outside frontal lobe. The final PH model included initial histology of GBM (relative risk [RR] = 2.01), 10-year increase in age (RR = 1.23), KPS less than 80 (RR = 1.54), and corticosteroid use (RR = 1.49). RPA resulted in seven classes. Median survival time was poorest in non-GBM patients with KPS less than 80 or GBM patients, age ≥ 50 years, corticosteroid use (4.4 months; 95% CI, 3.6 to 5.4 months); median survival was best in patients with initial histology other than GBM with KPS ≥ 80 and tumor confined to the frontal lobe (25.7 months; 95% CI, 18.7 to 52.5), and was 7.0 months (95% CI, 6.2 to 8.0 months) for all patients. Conclusion Initial histology, age, KPS, and corticosteroid use are prognostic for survival in recurrent glioma patients. To allow comparisons across phase II trials, enrollment criteria may need to be restricted.

Brain-tumor therapy

1977 ◽  
Vol 46 (2) ◽  
pp. 145-154 ◽  
Author(s):  
Mark L. Rosenblum ◽  
Kathy D. Knebel ◽  
Dolores A. Vasquez ◽  
Charles B. Wilson
Keyword(s):  
Brain Tumor ◽  
Tumor Cells ◽  
Dose Response ◽  
Response Curve ◽  
Tumor Therapy ◽  
Latency Period ◽  
Dose Response Curve ◽  
Clonogenic Tumor Cells ◽  
Brain Tumor Therapy

✓ A recently developed colony-formation assay has been used to evaluate in vivo 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) therapy of a transplantable rat brain-tumor model. A comparison of the in vitro colony-forming capacity of treated and untreated tumor cells permits calculation of the fraction of clonogenic tumor cells surviving in vivo therapy. The plateau that we previously observed on the BCNU dose-response curve is not the result of repair of potentially lethal damage, since no change in the 0.1% of surviving clonogenic tumor cells occurs during the first 2 to 4 days after treatment. Although reanalysis of the dose-response curve indicates that sublethal damage exists, its repair is probably minimal. The most likely explanation for the observed limitation of the BCNU effect is the drug's failure to reach all clonogenic cells. A dose of BCNU that kills more than 99.9% of clonogenic tumor cells within 30 minutes of treatment results in only a 60% decrease in tumor weight by Day 14. This disparity is explained by retarded removal of dead cells, and, along with a previously determined 90% cell-kill threshold necessary to appreciate increased animal survival, demonstrates the inherent limitations of measurements of tumor size (including brain scans and clinical patient evaluations) in evaluating the efficacy of brain-tumor therapy. Following an LD10 dose of BCNU the surviving clonogenic tumor cells increase in number after a latency period of 2 to 4 days; during regrowth the cell doubling time is 40 hours. Marked variability in tumor response and regrowth was noted. The determination of information regarding disturbed tumor cell kinetics and tumor heterogeneity is essential for the proper planning of combination chemotherapy and multimodality regimens.

New Delivery Systems for Brain Tumor Therapy

1995 ◽  
Vol 13 (4) ◽  
pp. 813-825 ◽  
Author(s):  
Eric P. Sipos ◽  
Henry Brem
Keyword(s):  
Brain Tumor ◽  
Tumor Therapy ◽  
Delivery Systems ◽  
Brain Tumor Therapy

Recent Advances in Brain Tumor Therapy: Local Intracerebral Drug Delivery by Polymers

2004 ◽  
Vol 22 (1) ◽  
pp. 27-37 ◽  
Author(s):  
Christopher Guerin ◽  
Alessandro Olivi ◽  
Jon D. Weingart ◽  
H. Christopher Lawson ◽  
Henry Brem
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Tumor Therapy ◽  
Recent Advances ◽  
Brain Tumor Therapy

scholarly journals Self-Replicating RNA Viruses for RNA Therapeutics

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3310 ◽  
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Tumor Cells ◽  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Vaccine Development ◽  
Rna Viruses ◽  
Antibody Responses ◽  
Phase Iii ◽  
Phase I Clinical Trials

Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans.

Mouse models for brain tumor therapy

Brain Tumors ◽  
2012 ◽  
pp. 316-328
Author(s):  
Nikki Charles ◽  
Andrew B. Lassman ◽  
Eric C. Holland
Keyword(s):  
Brain Tumor ◽  
Mouse Models ◽  
Tumor Therapy ◽  
Brain Tumor Therapy
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