Regulation of Lymphocyte Anti-tumor Response in Metastatic Patients Treated With the mTOR Inhibitor Everolimus
Study Details
Study Description
Brief Summary
Preclinical studies and clinical observations have shown the Phosphoinositide 3-kinase (PI3K) /Protein kinase B (AKT) /mammalian (mechanistic) target of Rapamycin (known as the 'mTOR-pathway') signaling to be deregulated in several tumors.
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Detailed Description
Cancer is the second most-common cause of death in industrialized countries. Preclinical studies and clinical observations have shown the PI3K/AKT/mammalian (mechanistic) target of Rapamycin (known as the 'mTOR-pathway') signaling to be deregulated in several tumors.
The mTOR is evolutionary conserved Serine/Threonine protein kinase that senses and integrates signals from different environmental cues. It is a central regulator of cell growth, cell cycle progression, proliferation and metabolism. It has been found to form two distinct, multiprotein complexes based on the binding with different partners. In a complex with Regulatory-Associated Protein of mTOR (Raptor) mTOR forms mTORC1, whereas when bound to Rapamycin-Insensitive Companion of mTOR (Rictor) than the mTOR Complex 2 (mTORC2) is formed. Not only the structure of both mTOR complexes is different, but also they are characterized by distinct biological functions mediated by individual downstream targets. The mTORC1 promotes cap-dependent translation and elongation, increases Messenger RNA (mRNA) biogenesis as well as promotes ribosome biogenesis - via regulation of p70 ribosomal S6 kinase 1 (p70S6K) as well as the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4EBP-1). In addition mTORC1 promotes lipid synthesis via sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor-γ (PPARγ). The role of the mTORC2 is less defined. The best characterized, mTORC2 target is AKT, which regulates cell survival, metabolism and proliferation as well as differentiation in many primary and cancer cell types. Another direct targets of mTORC2 are the serum- and glucocorticoid-regulated kinase (SGK) controls cell survival and anabolism and protein kinase Cα (PKCα) involved in the control of cytoskeletal organization. Thus constitutive, oncogenic activation of mTOR signaling promotes protein and lipid synthesis needed for the increase in cell mass and it enhances surface transporters expression sustaining better uptake of glucose, amino acids and other nutrients sustaining cell growth and proliferation of transformed cells.
Since mTOR signalling pathway is critical for tumorigenesis, its inhibitors have been strongly wanted. As first approved by FDA in clinical setting was Rapamycin for its activity against transplant organ rejection and as a prophylactic agent in Graft-versus-Host disease after allogenic bone marrow transplantation. The immunosuppressive effects of Rapamycin were initially attributed to its ability to block the Interleukin 2 (IL-2) induced proliferation. However, later this was found not to be the case, and rather work through immunomodulation, in part due to the induction and expansion of T cells with regulatory phenotype. Moreover, in T cells mTORC1 modulates T helper cell differentiation towards Th1 and Th17 fate, while mTORC2 controls Th2 development. Also, Rapamycin is involved in immunostimulation of long-lived memory cluster of differentiation 8+ (CD8+) T cells. In addition to the Rapamycin effect on T cells, the drug exerts an inhibitory effect on the proliferation and function of other immune cells such as dendritic cells, B lymphocytes, Natural Killer cells (NK), neutrophiles and mast cells. Lastly, Rapamycin has been tested as a chemotherapy agent against cancer and it was shown to delay the growth and proliferation and to promote apoptosis of many cancer cell lines, and also to possess anti-angiogenic properties. During the past years different rapalogs have been synthesized among which is Everolimus (RAD001, Afinitor®) that is currently tested in clinical trials phase IV in patients with renal cell carcinoma (RCC) or advance large cell lung cancer with neuroendocrine differentiation as well as in the phase III of metastatic breast cancer. In addition, it is already approved in different tumors when the first-line treatment was ineffective. Even Everolimus seems to be very promising neoplastic agent, there is no clinical data about its effect on the immune competence of the patients. And it still remains unknown whether Everolimus exerts similar to Rapamycin effect on the modulation of the immune system when administrated into cancer patients.
Study Design
Outcome Measures
Primary Outcome Measures
- Sensitivity of mTORC1 and mTORC2 [3 years]
Evaluate the sensitivity of mTORC1 and mTORC2 to Everolimus in T and NK cells.Everolimus inhibits kinase activity of mTOR when bound to Raptor (mTORC1). Whether mTORC2 is sensitive to Everolimus will be elucidated.
Secondary Outcome Measures
- Determine the phenotype of T cells. [3 years]
Determine the phenotype of T cells in patients with the use of mass cytometry and polychromatic flow cytometry. Everolimus alters the phenotype and dynamics of circulating T and NK cells.
- Evaluate the ability of T-cells [3 years]
Evaluate the ability of T-cells from patients to differentiate into effector cells (anti-tumor and anti- viral in vitro responses. Everolimus potentiates anti-tumor and anti-viral immune responses and that will affect the differentiation of naive T cell precursors into memory cells
Eligibility Criteria
Criteria
Inclusion Criteria:
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Metastatic tumor cancer
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Treated with Everolimus
Exclusion Criteria:
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Non metastatic tumor
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Non previously treated with Everolimus
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Istituto Clinico Humanitas | Rozzano | MI | Italy | 20089 |
Sponsors and Collaborators
- Istituto Clinico Humanitas
Investigators
- Principal Investigator: Enrico Lugli, Istituto Clinico Humanitas
Study Documents (Full-Text)
None provided.More Information
Publications
- Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012 Aug 1;30(22):2718-24. doi: 10.1200/JCO.2011.39.0708. Epub 2012 May 7.
- Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005 Jun 15;105(12):4743-8. Epub 2005 Mar 3.
- Bendall SC, Simonds EF, Qiu P, Amir el-AD, Krutzik PO, Finck R, Bruggner RV, Melamed R, Trejo A, Ornatsky OI, Balderas RS, Plevritis SK, Sachs K, Pe'er D, Tanner SD, Nolan GP. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science. 2011 May 6;332(6030):687-96. doi: 10.1126/science.1198704.
- Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G, Provasi E, Bondanza A, Bordignon C, Peccatori J, Ciceri F, Lupo-Stanghellini MT, Mavilio F, Mondino A, Bicciato S, Recchia A, Bonini C. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood. 2013 Jan 24;121(4):573-84. doi: 10.1182/blood-2012-05-431718. Epub 2012 Nov 15.
- Hasskarl J. Everolimus. Recent Results Cancer Res. 2014;201:373-92. doi: 10.1007/978-3-642-54490-3_23. Review.
- Lugli E, Gattinoni L, Roberto A, Mavilio D, Price DA, Restifo NP, Roederer M. Identification, isolation and in vitro expansion of human and nonhuman primate T stem cell memory cells. Nat Protoc. 2013 Jan;8(1):33-42. doi: 10.1038/nprot.2012.143. Epub 2012 Dec 6.
- Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. doi: 10.1002/cncr.25219.
- Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39-68. doi: 10.1146/annurev-immunol-020711-075024. Epub 2011 Nov 29. Review.
- Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M, Konopleva M. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood. 2007 Apr 15;109(8):3509-12. Epub 2006 Dec 19.
- Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35. doi: 10.1038/nrm3025. Epub 2010 Dec 15. Review.
- ONC/OSS-01/2015