Rapamycin

Srivastava, Rupesh K.; Utley, Adam; Shrikant, Protul

doi:10.4161/onci.20663

Cited by 12 publications

(10 citation statements)

References 10 publications

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“…Mouse models for the study of the effect of rapamycin on breast cancer [ 69 ] and melanoma [ 70 ] have been described and have proved useful for determining biomarkers. Establishing the optimal dose of rapamycin will be critical to its efficacy as its beneficial effects must be balanced against its immunosuppressive properties, and achieving the optimal dose has been likened to adjusting a rheostat [ 71 ].…”

Section: Reviewmentioning

confidence: 99%

The Concept of Hormesis in Cancer Therapy – Is Less More?

Gaya

Akle

Mudan

et al. 2015

Cureus

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There has, in recent years, been a paradigm shift in our understanding of the role of the immune system in the development of cancers. Immune dysregulation, manifesting as chronic inflammation, not only facilitates the growth and spread of tumors but prevents the host from mounting effective immune defenses against it. Many attempts are being made to develop novel immunotherapeutic strategies, but there is growing evidence that a radical reevaluation of the mode of action of chemotherapeutic agents and ionizing radiation is required in the light of advances in immunology.Based on the concept of hormesis – defined as the presence of different modes of action of therapeutic modalities at different doses – a ‘repositioning’ of chemotherapy and radiotherapy may be required in all aspects of cancer management. In the case of chemotherapy, this may involve a change from the maximum tolerated dose concept to low dose intermittent (‘metronomic’) therapy, whilst in radiation therapy, highly accurate stereotactic targeting enables ablative, antigen-releasing (immunogenic) doses of radiation to be delivered to the tumor with sparing of surrounding normal tissues. Coupled with emerging immunotherapeutic procedures, the future of cancer treatment may well lie in repositioned chemotherapy, radiotherapy, and more localized debulking surgery.

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Section: Reviewmentioning

confidence: 99%

The Concept of Hormesis in Cancer Therapy – Is Less More?

Gaya

Akle

Mudan

et al. 2015

Cureus

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“…MTOR inhibitors are widely used to suppress a rejection response by the immune system in organ transplantation [ 12 ]. Paradoxically, mTOR inhibitor was recently shown to potentiate immune response by generating memory CD8+ T-cells in a dose- and duration-dependent manner [ 13 – 16 ]. Li et al [ 17 ] reported that a short course of high-dose, instead of low-dose rapamycin, generated memory CD8+ T-cell responses, and afforded more durable protection against tumor compared with persistent administration of either low or high dose.…”

Section: Introductionmentioning

confidence: 99%

Harness the synergy between targeted therapy and immunotherapy: what have we learned and where are we headed?

Liu

Zhou

et al. 2017

Oncotarget

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Since the introduction of imatinib for the treatment of chronic myelogenous leukemia, several oncogenic mutations have been identified in various malignancies that can serve as targets for therapy. More recently, a deeper insight into the mechanism of antitumor immunity and tumor immunoevasion have facilitated the development of novel immunotherapy agents. Certain targeted agents have the ability of inhibiting tumor growth without causing severe lymphocytopenia and amplifying antitumor immune response by increasing tumor antigenicity, enhancing intratumoral T cell infiltration, and altering the tumor immune microenvironment, which provides a rationale for combining targeted therapy with immunotherapy. Targeted therapy can elicit dramatic responses in selected patients by interfering with the tumor-intrinsic driver mutations. But in most cases, resistance will occur over a relatively short period of time. In contrast, immunotherapy can yield durable, albeit generally mild, responses in several tumor types via unleashing host antitumor immunity. Thus, combination approaches might be able to induce a rapid tumor regression and a prolonged duration of response. We examine the available evidence regarding immune effects of targeted therapy, and review preclinical and clinical studies on the combination of targeted therapy and immunotherapy for cancer treatment. Furthermore, we discuss challenges of the combined therapy and highlight the need for continued translational research.

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“…Ovalbumin-specific αβ T lymphocytes exposed to microspheres coated with an ovalbumin-derived peptide plus co-stimulatory CD80 molecules (or with anti-CD3/anti-CD28 antibodies) in the presence of rapamycin exhibited improved memory and antitumor functions in vivo than T cells of the same type activated in the presence of interleukin (IL)-12 [85-87]. Along similar lines, rapamycin has been shown to enhance tumor-targeting CD8 + T-cell memory responses elicited by a poxviral anticancer vaccine in mice [88, 89]. Such an immunostimulatory activity was observed only when rapamycin was administered in a high-dose short therapeutic course, as opposed to both a single, low-dose course as well as prolonged treatment schedules [88, 89].…”

mentioning

confidence: 99%

“…Along similar lines, rapamycin has been shown to enhance tumor-targeting CD8 + T-cell memory responses elicited by a poxviral anticancer vaccine in mice [88, 89]. Such an immunostimulatory activity was observed only when rapamycin was administered in a high-dose short therapeutic course, as opposed to both a single, low-dose course as well as prolonged treatment schedules [88, 89]. Of note, rapamycin has also been shown to increase the yield and effector functions of human γδ T cells activated in vitro with isopentenyl pyrophosphate plus recombinant IL-2 [90].…”

mentioning

confidence: 99%

Immunostimulatory activity of lifespan-extending agents

Pedro

Senovilla

2013

Aging

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During the past two decades, several interventions have been shown to increase the healthy lifespan of model organisms as evolutionarily distant from each other as yeast, worms, flies and mammals. These anti-aging maneuvers include (but are not limited to) cycles of caloric restriction, physical exercise as well as the administration of multiple, chemically unrelated agents, such as resveratrol, spermidine and various rapamycin-like compounds collectively known as rapalogs. Most, if not all, lifespan-extending agents promote macroautophagy (hereafter referred to as autophagy), an evolutionarily old mechanism that contributes to the maintenance of intracellular homeostasis and plays a critical role in the adaptive response of cells to stress. In line with this notion, the activation of autophagy appears to mediate significant anti-ageing effects in several organisms, including mice. Here, we focus on rapalogs to discuss the possibility that part of the beneficial activity of lifespan-extending agents stems from their ability to exert immunostimulatory effects. Accumulating evidence indicates indeed that the immune system can recognize and eliminate not only cells that are prone to undergo malignant transformation, but also senescent cells, thus playing a significant role in the control of organismal aging. In addition, it has recently become clear that rapamycin and other rapalogs, which for a long time have been viewed (and used in the clinic) as pure immunosuppressants, can mediate robust immunostimulatory functions, at least in some circumstances.

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Rapamycin

Cited by 12 publications

References 10 publications

The Concept of Hormesis in Cancer Therapy – Is Less More?

The Concept of Hormesis in Cancer Therapy – Is Less More?

Harness the synergy between targeted therapy and immunotherapy: what have we learned and where are we headed?

Immunostimulatory activity of lifespan-extending agents

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