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Regulation of Lymphocyte Anti-tumor Response in Metastatic Patients Treated With the mTOR Inhibitor Everolimus

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02441543
Recruitment Status : Unknown
Verified February 2017 by Istituto Clinico Humanitas.
Recruitment status was:  Recruiting
First Posted : May 12, 2015
Last Update Posted : February 10, 2017
Information provided by (Responsible Party):
Istituto Clinico Humanitas

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.

Condition or disease

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.

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Study Type : Observational
Estimated Enrollment : 45 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Regulation of Lymphocyte Anti-tumor Response in Metastatic Patients Treated With the mTOR Inhibitor Everolimus
Study Start Date : April 2015
Estimated Primary Completion Date : April 2018
Estimated Study Completion Date : May 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Everolimus

Primary Outcome Measures :
  1. Sensitivity of mTORC1 and mTORC2 [ Time Frame: 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 :
  1. Determine the phenotype of T cells. [ Time Frame: 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.

  2. Evaluate the ability of T-cells [ Time Frame: 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

Biospecimen Retention:   Samples Without DNA

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Metastatic tumor patients treated with Everolimus

Inclusion Criteria:

  • Metastatic tumor cancer
  • Treated with Everolimus

Exclusion Criteria:

  • Non metastatic tumor
  • Non previously treated with Everolimus

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02441543

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Contact: Enrico Lugli 02 8224 ext 5143
Contact: Matteo Simonelli 02 8224 ext 4559

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Istituto Clinico Humanitas Recruiting
Rozzano, MI, Italy, 20089
Contact: Enrico Lugli    02 8224 ext 5143   
Contact: Matteo Simonelli    02 8224 ext 4559   
Principal Investigator: Lugli Enrico         
Sub-Investigator: Simonelli Matteo         
Sponsors and Collaborators
Istituto Clinico Humanitas
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Principal Investigator: Enrico Lugli Istituto Clinico Humanitas


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Responsible Party: Istituto Clinico Humanitas Identifier: NCT02441543     History of Changes
Other Study ID Numbers: ONC/OSS-01/2015
First Posted: May 12, 2015    Key Record Dates
Last Update Posted: February 10, 2017
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
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Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents