Safety evaluation of immune-based combinations in patients with advanced renal cell carcinoma: a systematic review and meta-analysis

Massari, Francesco; Mollica, Veronica; Rizzo, Alessandro; Cosmai, Laura; Rizzo, Mimma; Porta, Camillo

doi:10.1080/14740338.2020.1811226

Cited by 71 publications

(40 citation statements)

References 47 publications

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“…Novel treatment strategies combining targeted therapy and immunotherapy have been introduced [5][6][7]. However, even with combined drug application resistance occurs and adverse side effects are common [5,8,9].…”

Section: Introductionmentioning

confidence: 99%

Artesunate Inhibits Growth of Sunitinib-Resistant Renal Cell Carcinoma Cells through Cell Cycle Arrest and Induction of Ferroptosis

Markowitsch

Schupp

Lauckner

et al. 2020

Cancers

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Although innovative therapeutic concepts have led to better treatment of advanced renal cell carcinoma (RCC), efficacy is still limited due to the tumor developing resistance to applied drugs. Artesunate (ART) has demonstrated anti-tumor effects in different tumor entities. This study was designed to investigate the impact of ART (1–100 µM) on the sunitinib-resistant RCC cell lines, Caki-1, 786-O, KTCTL26, and A-498. Therapy-sensitive (parental) and untreated cells served as controls. ART’s impact on tumor cell growth, proliferation, clonogenic growth, apoptosis, necrosis, ferroptosis, and metabolic activity was evaluated. Cell cycle distribution, the expression of cell cycle regulating proteins, p53, and the occurrence of reactive oxygen species (ROS) were investigated. ART significantly increased cytotoxicity and inhibited proliferation and clonogenic growth in both parental and sunitinib-resistant RCC cells. In Caki-1, 786-O, and A-498 cell lines growth inhibition was associated with G0/G1 phase arrest and distinct modulation of cell cycle regulating proteins. KTCTL-26 cells were mainly affected by ART through ROS generation, ferroptosis, and decreased metabolism. p53 exclusively appeared in the KTCTL-26 cells, indicating that p53 might be predictive for ART-dependent ferroptosis. Thus, ART may hold promise for treating selected patients with advanced and even therapy-resistant RCC.

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Section: Introductionmentioning

confidence: 99%

Artesunate Inhibits Growth of Sunitinib-Resistant Renal Cell Carcinoma Cells through Cell Cycle Arrest and Induction of Ferroptosis

Markowitsch

Schupp

Lauckner

et al. 2020

Cancers

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“…As known, several studies assessing the combination of PD-1/PD-L1 inhibitors and targeted therapies have been recently published or presented (7,8). In metastatic setting, the CheckMate214, the KEYNOTE-426 and the JAVELIN Renal 101 have shown important clinical benefits compared to sunitinib alone, shaping the-novel -outlook of firstline setting.…”

Section: Discussionmentioning

confidence: 99%

“…Radical surgical resection is the standard of care for patients with localized disease, and although the 70% of all RCC cases are diagnosed with early-stage or locally advanced disease, approximately the 20-40% of patients progress toward metastatic disease following radical surgery (3,4). Recent years have witnessed remarkable changes in the therapeutic landscape of RCC, with the advent of several targeted agents and immune checkpoint inhibitors (ICIs), as single-agents or as part of immune-based combinations in the metastatic setting (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Adjuvant therapy in renal cell carcinoma: is it the right strategy to inhibit VEGF?

et al. 2021

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Despite several clinical trials have assessed different agents in the adjuvant setting, renal cell carcinoma (RCC) still remains a disease orphan of an effective adjuvant treatment. In fact, systemic therapies targeting angiogenesis that have been observed to be effective in metastatic setting failed to show an improvement in terms of clinical outcomes when used ad adjuvant treatments. In this study, we performed a meta-analysis of 5 randomized clinical trials to assess the impact of tyrosine kinase inhibitors (TKIs) targeting angiogenesis after surgery: ASSURE, S-TRAC, PROTECT, ATLAS, SORCE. Among the 6,531 patients assessed, we confirmed the lack of efficacy of adjuvant treatments in terms of diseasefree survival (DFS) (pooled-HR 0.93, 95% CI, 0.84-1.02, P=0.16) and overall survival (OS) (pooled-HR 0.98, 95% CI, 0.88-1.09, P=0.54). To the best of our knowledge, we still ignore why some treatments active in the metastatic setting do not show similar efficacy as adjuvant treatment. Exploring possible reasons of this apparently conflicting results is important as it may offer new insights that should be evaluated in next generation adjuvant trials. Immune checkpoint inhibitors (ICIs) have reported significant results-as monotherapy or in combinations with other anticancer agents-in metastatic setting, and the results of trials evaluating these agents in the adjuvant setting are awaited.

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“…RCC is characterized by great high immunogenicity, with a tremendous infiltration of immune cells, notably in T cells, NK cells, dendritic cells, macrophages and so on [ 5 ]. Remarkably, therapies targeting tumor immune microenvironment such as non-specific immunomodulators, vaccine gene therapy, monoclonal antibodies, colony stimulating factors, interleukins, and interferons have become the mainstays for the immune treatment of RCC in recent years [ 6 ]. Nowadays, with the growing understanding of escape mechanisms over the last decade, significant improvements have been made.…”

Section: Introductionmentioning

confidence: 99%

Accumulation of CD45RO+CD8+ T cells is a diagnostic and prognostic biomarker for clear cell renal cell carcinoma

Zheng

Yao

et al. 2021

Aging

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Renal cell carcinoma is characterized by high immunogenicity and infiltration of immune cells. CD45RO+CD8+ T cells are well known as a critical role in host defense of the immune environment. However, their role in clear cell renal carcinoma (ccRCC) remains unknown. To elucidate the clinical importance of CD45RO+CD8+ T cells in ccRCC as well as its underlying mechanism, we analyzed several types of peripheral immune cells from 274 patients with ccRCC who have received radical or partial nephrectomy and 350 healthy people. Flow cytomety assays showed there was no significant difference in the proportions of CD8+ T cells and its subtypes other than CD45RO+/CD45RA+CD8+ cells. Both gene and protein expression levels of CD45RO in ccRCC tissues were decreased. CD45RO+CD8+ T cells showed increased proliferative abilities but decreased apoptotic abilities through MAPK signaling activation in ccRCC. High expression level of CD45RO+CD8+ T cells inhibited ccRCC progression, including proliferation, invasion, as well as autophagy of ccRCC through many signaling pathways. Bioinformatics and immunohistochemical chip analysis measured gene and protein levels of CD45RO and other related proteins. The combination of UCHL1, HMGB3, and CD36 has diagnostic value in ccRCC and is able to predict prognosis. Collectively, CD45RO+CD8+ T cells play a critical role in ccRCC progression and may be regarded as clinical indicators.

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Safety evaluation of immune-based combinations in patients with advanced renal cell carcinoma: a systematic review and meta-analysis

Cited by 71 publications

References 47 publications

Artesunate Inhibits Growth of Sunitinib-Resistant Renal Cell Carcinoma Cells through Cell Cycle Arrest and Induction of Ferroptosis

Artesunate Inhibits Growth of Sunitinib-Resistant Renal Cell Carcinoma Cells through Cell Cycle Arrest and Induction of Ferroptosis

Adjuvant therapy in renal cell carcinoma: is it the right strategy to inhibit VEGF?

Accumulation of CD45RO+CD8+ T cells is a diagnostic and prognostic biomarker for clear cell renal cell carcinoma

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