Activation of the mammalian target of rapamycin (mTOR) pathway has been demonstrated in sarcoma. Trials using mTOR inhibitor in sarcoma have shown low objective response rates but progression-free survival (PFS) rates suggest cytostatic effects. The combination of sirolimus and cyclophosphamide demonstrated synergistic anti-sarcoma activity in preclinical models; therefore, we conducted a phase II trial of sirolimus and cyclophosphamide in patients with advanced sarcoma.
Patients received 4 mg sirolimus daily and 200mg cyclophosphamide d1-7 and 15-21 every 28 days. The primary objective was to estimate the 24-week PFS rate with a target of ≥ 25%. Patients were followed for World Health Organisation (WHO) criteria tumour response by imaging every 8 weeks. Serum levels of sirolimus, lipids and vascular endothelial growth factor were measured. Tumour tissue was analysed for mTOR, S6 ribosomal protein and cytochrome P450 3A4/5 by quantitative immunofluorescence.
Forty-nine eligible patients were enrolled from September 2008 to December 2009. Patients received a median of four cycles of therapy. Starting doses of drugs were tolerated in 79%. One patient achieved partial tumour response, 10 were progression-free for ≥ 24 weeks and two completed 12 cycles of treatment. Median PFS and overall survival (OS) were 3.4 and 9.9 months, respectively. Serious adverse events attributed to therapy occurred in 11% and included infection, pneumonitis and thrombosis. Hypertriglyceridaemia from treatment and lower tumour phosphorylated-mTOR are associated with longer survival.
Sirolimus and cyclophosphamide were tolerated by the majority of patients. About 20% of patients had stable sarcoma for at least 6 months but objective tumour response was infrequent.
"The therapeutic efficacy of Treg targeted immunotherapies has been demonstrated in numerous preclinical studies in which targeted depletion of Tregs was observed to improve antitumour immunity and shown to prevent tumour development and decreased established tumour progression [55–57]. In the clinic, similar outcomes have been observed, albeit without complete tumour regression, with protocols aiming at reducing Treg using cyclophosphamide alone , or as combination therapies [59, 60]. These studies demonstrate the critical role of Treg in suppressing antitumour immunity and highlight the importance of gaining a complete understanding of their role during tumour development so that more effective immunotherapies can be developed. "
[Show abstract][Hide abstract] ABSTRACT: Most anticancer therapies including immunotherapies are given systemically; yet therapies given directly into tumorsmay be more effective, particularly those that overcomenatural suppressive factors in the tumor microenvironment.The“TrojanHorse” approach of intratumoural delivery aims to promote immune-mediated destruction by inducing microenvironmental changes within the tumour at the same time as avoiding the systemic toxicity that is often associated with more “full frontal” treatments such as transfer of large numbers of laboratory-expanded tumor-specific cytotoxic T lymphocytes or large intravenous doses of cytokine. Numerous studies have demonstrated that intratumoural therapy has the capacity to minimizing local suppression, inducing sufficient “dangerous” tumor cell death to cross-prime strong immune responses, and rending tumor blood vessels amenable to immune cell traffic to induce effector cell changes in secondary lymphoid organs. However, the key to its success is the design of a sound rational approach based on evidence. There is compelling preclinical data for local immunotherapy approaches in tumor
immunology. This review summarises how immune events within a tumour can be modified by local approaches, how this can affect systemic antitumor immunity such that distal sites are attacked, and what approaches have been proven most successful so far in animals and patients.
Research Journal of Immunology 05/2014; 2014. DOI:10.1155/2014/789069
"Subsequently, ridaforolimus showed promising efficacy in various trials enrolling patients with advanced sarcoma [15,35], but as an indication for the maintenance of remission in patients treated for metastatic sarcoma it was not approved because of the failure of the drug to exhibit a meaningful clinical activity . In combination, the mTOR inhibitor, sirolimus, with cyclophosphamide is tolerated by the majority of sarcoma patients with a clinical benefit rate of about 20% . "
[Show abstract][Hide abstract] ABSTRACT: mTOR inhibitors are emerging as important anti-neoplastic agents with a wide range of clinical applications. The topoisomerase I inhibitor irinotecan is a potent DNA damaging drug, with a broad spectrum of anticancer activities. mTOR appears to enhance cancer cell survival following DNA damage, thus the inhibition of mTOR after irinotecan could theoretically show synergistic activities in patients. Both mTOR inhibitors and irinotecan have been used as single agents in soft tissue sarcomas with limited efficacy. We completed a phase I trial of the combination of the mTOR inhibitor, temsirolimus, and irinotecan in patients with advanced soft tissue sarcoma. Seventeen patients were recruited. The Phase II recommended dose is 20 mg of temsirolimus and 80 mg/m2 of irinotecan administered on weekly basis for three out of four weeks. Most frequently encountered toxicities include cytopenias, fatigue, and gastrointestinal toxicities. Two patients (one with leiomyosarcoma and one with high grade undifferentiated sarcoma) had stable disease for more than 12 months.
"Furthermore, the addition of rapamycin to either cyclophosphamide or vincristine resulted in enhanced responses in the OS models (Houghton et al., 2010b). A phase II trial for treatment of advanced sarcoma patients with rapamycin and cyclophosphamide, did not meet the primary endpoint of greater than 25% 6-month PFS rate (Schuetze et al., 2012). Initial reports for everolimus, temsirolimus, and ridaforolimus (Spunt et al., 2011) have provided evidence of favorable anti-tumor activity in patients with a broad range of solid tumors. "
[Show abstract][Hide abstract] ABSTRACT: Osteosarcoma, the most common malignant bone tumor of childhood, is a high-grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical endpoints for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early-phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP) has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease.
Frontiers in Oncology 05/2013; 3:132. DOI:10.3389/fonc.2013.00132
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