Immune Therapy for Kidney Cancer: A Second Dawn?

McDermott, David F.; Atkins, Michael B.

doi:10.1053/j.seminoncol.2013.05.008

Cited by 17 publications

(14 citation statements)

References 48 publications

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“…The insensitivity to sorafenib could not be compared with the patient's response since he was not treated with this drug. For this patient, the use of alternative tyrosine kinase inhibitors (axitinib, pazopanib, tivozanib) [27]–[30] or immune strategies through the use of antibodies directed against-programmed death 1 (PD-1)/PD-1 ligand [31]–[32] or against cytotoxic T-lymphocyte-associated protein [33]–[35] would have been a better therapeutic strategy if clinicians had taken into account our in vitro results.…”

Section: Resultsmentioning

confidence: 99%

The Relevance of Testing the Efficacy of Anti-Angiogenesis Treatments on Cells Derived from Primary Tumors: A New Method for the Personalized Treatment of Renal Cell Carcinoma

et al. 2014

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Despite the numerous available drugs, the most appropriate treatments for patients affected by common or rare renal cell carcinomas (RCC), like those associated with the Xp11.2 translocation/transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) gene fusion (TFE3 RCC), are not clearly defined. We aimed to make a parallel between the sensitivity to targeted therapies on living patients and on cells derived from the initial tumor. Three patients diagnosed with a metastatic RCC (one clear cell RCC [ccRCC], two TFE3 RCC) were treated with anti-angiogenesis drugs. The concentrations of the different drugs giving 50% inhibition of cell proliferation (IC50) were determined with the Thiazolyl Blue Tetrazolium Bromide (MTT) assay on cells from the primary tumors and a reference sensitive RCC cell line (786-O). We considered the cells to be sensitive if the IC50 was lower or equal to that in 786-O cells, and insensitive if the IC50 was higher to that in 786-O cells (IC 50 of 6±1 µM for sunitinib, 10±1 µM for everolimus and 6±1 µM for sorafenib). Based on this standard, the response in patients and in cells was equivalent. The efficacy of anti-angiogenesis therapies was also tested in cells obtained from five patients with non-metastatic ccRCC, and untreated as recommended by clinical practice in order to determine the best treatment in case of progression toward a metastatic grade. In vitro experiments may represent a method for evaluating the best first-line treatment for personalized management of ccRCC during the period following surgery.

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Section: Resultsmentioning

confidence: 99%

The Relevance of Testing the Efficacy of Anti-Angiogenesis Treatments on Cells Derived from Primary Tumors: A New Method for the Personalized Treatment of Renal Cell Carcinoma

et al. 2014

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“…The PD-1/PD-L1 pathway is known to be activated in many tumor types, including lung, ovarian, colorectal, breast, liver, head and neck, kidney, and bladder cancers and melanoma (9). PD-1 is mainly expressed on tumor-infiltrating lymphocytes, whereas its ligand PD-L1 is expressed on both hematopoietic cells (B, T, myeloid and dendritic cells) and tumor cells (10). There is evidence that similar to epithelial and stromal cells in normal tissues, tumor cells can express PD-L1 on the cell membrane in response to interferon gamma production by activated T cells.…”

Section: Introductionmentioning

confidence: 99%

“…Currently, anti-PD-1 and anti-PD-L1 antibodies are actively being investigated in clinical development for metastatic ccRCC (8,10) and several datasets suggest that primary ccRCC tumors with PD-L1 positivity either on tumor cell membranes or inflammatory cells achieve better response to PD-1/PD-L1 targeting therapies (16–19). Although PD-L1 expression in primary ccRCC tissue increases the likelihood of response to PD-1 pathway inhibition, it fails to identify all responders.…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of PD-L1 between Primary and Metastatic Sites in Clear-Cell Renal Cell Carcinoma

Callea

Albigès

Gupta

et al. 2015

Cancer Immunology Research

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252

170

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PD-L1 expression in primary clear cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti-PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved. Areas with predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti-PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using H-score. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11/53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (p=0.51). Tumor cell PD-L1 positivity was associated with higher T stage (p=0.03) and higher Fuhrman Nuclear Grade (FNG) (p<0.01). Within individual lesions, PD-L1 positivity was heterogeneous and almost exclusively detected in high nuclear grade areas (p<0.001). No difference was found in PD-L1 levels in TIMCs between primary tumors and metastases (p=0.82). Heterogeneity of PD-L1 expression in ccRCC suggests that its assessment as predictive biomarker for PD-1 blockade may require analysis of metastatic lesions. Notably, since PD-L1 expression was mostly detected in high nuclear grade areas, to avoid false negative results, these areas should be specifically selected for assessment.

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“…4 Immunotherapy with high-dose interleukin-2 (HD IL-2) or interferon-alfa was for many years considered the standard treatment for patients with mRCC, but it resulted in only a modest response rate and is associated with significant toxicities. 5 Advances in translational research have led to a major paradigm shift in the management of mRCC over the last decade. With the elucidation of the von HippeleLindau/hypoxia-inducible factor and mammalian target of rapamycin (mTOR) pathways in mRCC, 7 new drugs have been approved by the US Food and Drug Administration (FDA) in the United States since 2005, and many more are in clinical development.…”

Section: Introductionmentioning

confidence: 99%

Treatment Patterns and Costs for Metastatic Renal Cell Carcinoma Patients With Private Insurance in the United States

Geynisman

Liu

et al. 2015

Clinical Genitourinary Cancer

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Immune Therapy for Kidney Cancer: A Second Dawn?

Cited by 17 publications

References 48 publications

The Relevance of Testing the Efficacy of Anti-Angiogenesis Treatments on Cells Derived from Primary Tumors: A New Method for the Personalized Treatment of Renal Cell Carcinoma

The Relevance of Testing the Efficacy of Anti-Angiogenesis Treatments on Cells Derived from Primary Tumors: A New Method for the Personalized Treatment of Renal Cell Carcinoma

Differential Expression of PD-L1 between Primary and Metastatic Sites in Clear-Cell Renal Cell Carcinoma

Treatment Patterns and Costs for Metastatic Renal Cell Carcinoma Patients With Private Insurance in the United States

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