The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial

Huijts, Charlotte M.; Lougheed, Sinéad M.; Bodalal, Zuhir; Herpen, Carla M. van; Hamberg, Paul; Tascilar, Metin; Haanen, John B.A.G.; Verheul, Henk M.W.; Gruijl, Tanja D. de; Vliet, Hans J. van der

doi:10.1007/s00262-018-2288-8

Cited by 27 publications

(21 citation statements)

References 29 publications

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“…For detailed recent reviews on cyclophosphamide as an immune regulator in cancer, read Hughes et al [202] and the phase I clinical trial of metronomic cyclophosphamide and everolimus by Huijts et al [203].…”

Section: Discussionmentioning

confidence: 99%

Synergy Between Low Dose Metronomic Chemotherapy and the pH-Centered Approach Against Cancer

Koltai¹,

Cardone

Reshkin

2019

IJMS

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Low dose metronomic chemotherapy (MC) is becoming a mainstream treatment for cancer in veterinary medicine. Its mechanism of action is anti-angiogenesis by lowering vascular endothelial growth factor (VEGF) and increasing trombospondin-1 (TSP1). It has also been adopted as a compassionate treatment in very advanced human cancer. However, one of the main limitations of this therapy is its short-term effectiveness: 6 to 12 months, after which resistance develops. pH-centered cancer treatment (pHT) has been proposed as a complementary therapy in cancer, but it has not been adopted or tested as a mainstream protocol, in spite of existing evidence of its advantages and benefits. Many of the factors directly or indirectly involved in MC and anti-angiogenic treatment resistance are appropriately antagonized by pHT. This led to the testing of an association between these two treatments. Preliminary evidence indicates that the association of MC and pHT has the ability to reduce anti-angiogenic treatment limitations and develop synergistic anti-cancer effects. This review will describe each of these treatments and will analyze the fundamentals of their synergy.

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Section: Discussionmentioning

confidence: 99%

Synergy Between Low Dose Metronomic Chemotherapy and the pH-Centered Approach Against Cancer

Koltai¹,

Cardone

Reshkin

2019

IJMS

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“…Inhibitors that promote cancer cell death combined with strategies to boost effector functions of T cells while repressing negative regulators of the immune responses could improve therapeutic outcome. In a phase I clinical trial for the treatment of metastatic renal cell cancer, everolimus was combined with low-dose cyclophosphamide [343]. Cyclophosphamide was administered to selectively deplete the immunosuppressive T-regs, which undergo expansion in the presence of rapamycin [344].…”

Section: Immunotherapymentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

165

128

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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“…The combination of cyclophosphamide (50 mg once-daily) and a standard dose of everolimus (10mg once-daily) led to a reduction of T-regs and myeloid-derived suppressor cells. The combination therapy is evaluated in a phase II clinical trial [ 56 ], but the recent approval of new IO-based (immuno-oncology) combinations, as well as new TKI such as cabozantinib, lowered the interest of any everolimus-based combinations.…”

Section: Tme Components As Predictors Of Systemic Treatment Efficamentioning

confidence: 99%

Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC)

Simonaggio

Epaillard

Pobel

et al. 2021

Cancers

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Renal cell carcinoma (RCC) is the seventh most frequently diagnosed malignancy with an increasing incidence in developed countries. Despite a greater understanding of the cancer biology, which has led to an increase of therapeutic options, metastatic clear cell renal cell carcinoma (mccRCC) still have a poor prognosis with a median five-years survival rate lower than 10%. The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies. In the face of these rising therapeutic options, the question of the therapeutic sequences is crucial. Predictive biomarkers are urgently required to provide a personalized treatment for each patient. Disappointingly, the usual ICI biomarkers, PD-L1 expression and Tumor Mutational Burden, approved in melanoma or non-small cell lung cancer (NSCLC) have failed to distinguish good and poor mccRCC responders to ICI. The tumor microenvironment is known to be involved in ICI response. Innovative technologies can be used to explore the immune contexture of tumors and to find predictive and prognostic biomarkers. Recent comprehensive molecular characterization of RCC has led to the development of robust genomic signatures, which could be used as predictive biomarkers. This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures.

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The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial

Cited by 27 publications

References 29 publications

Synergy Between Low Dose Metronomic Chemotherapy and the pH-Centered Approach Against Cancer

Synergy Between Low Dose Metronomic Chemotherapy and the pH-Centered Approach Against Cancer

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC)

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