Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma

Wallin, Jeffrey J.; Bendell, Johanna C.; Funke, Roel; Sznol, Mario; Korski, Konstanty; Jones, Suzanne F.; Hernandez, Genevive; Mier, James W.; He, Xian; Hodi, F. Stephen; Denker, Mitchell; Lévêque, Vincent; Cañamero, Marta; Babitski, Galina; Koeppen, Hartmut; Ziai, James; Sharma, Neeraj; Gaire, Fabien; Chen, Daniel S.; Waterkamp, Daniel; Hegde, Priti S.; McDermott, David F.

doi:10.1038/ncomms12624

Cited by 583 publications

(445 citation statements)

References 28 publications

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“…T-cell infiltrates have been interrogated for biomarkers of immunotherapy response in a variety of solid tumors (34, 53-55). The location, abundance, and characteristics of CD8 + T cells in PDA have not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma

Stromnes

Hulbert

Pierce

et al. 2017

Cancer Immunology Research

164

131

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Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to most therapies, including immune checkpoint blockade. To elucidate mechanisms of immunotherapy resistance, we assessed immune parameters in resected human PDA. We demonstrate significant interpatient variability in T-cell number, localization, and phenotype. CD8+ T cells, Foxp3+ regulatory T cells and PD-1+ and PD-L1+ cells were preferentially enriched in tertiary lymphoid structures that were found in most tumors compared to stroma and tumor cell nests. Tumors containing more CD8+ T cells also had increased granulocytes, CD163+ (M2 immunosuppressive phenotype) macrophages, and FoxP3+ regulatory T cells. PD-L1 was rare on tumor cells, but was expressed by CD163+ macrophages and an additional stromal cell subset commonly found clustered together adjacent to tumor epithelium. The majority of tumoral CD8+ T cells did not express molecules suggestive of recent T-cell receptor (TCR) signaling. However, 41BB+PD-1+ T cells were still significantly enriched in tumors compared to circulation. Tumoral PD-1+ CD8+ T cells commonly expressed additional inhibitory receptors, yet were mostly T-bethi and Eomeslo, consistent with a less terminally exhausted state. Analysis of gene expression and rearranged TCR genes by deep sequencing suggested most patients have a limited tumor-reactive T-cell response. Multiplex immunohistochemistry revealed variable T-cell infiltration based on abundance and location, which may result in different mechanisms of immunotherapy resistance. Overall, the data support the need for therapies that either induce endogenous, or provide engineered, tumor-specific T-cell responses and concurrently relieve suppressive mechanisms operative at the tumor site.

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Section: Discussionmentioning

confidence: 99%

T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma

Stromnes

Hulbert

Pierce

et al. 2017

Cancer Immunology Research

164

131

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“…For example, pre-treatment with sunitinib increased the ability of the investigators to expand TILs from the tumor ex-vivo [320]. In a phase 1 clinical trial, the anti-angiogenic drug bevacizumab increased immune cell infiltration and Th1 gene expression when combined with atezolizumab in metastatic renal cell carcinoma [321]. Data on the potential predictive value of TILs in this setting are limited, however in one study, higher intra-tumor CD8 + T cell counts were independently associated with shorter overall survival in patients receiving tyrosine kinase inhibitor therapy [322].…”

Section: Tils In Genitourinary Carcinomasmentioning

confidence: 99%

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

Hendry

Salgado

Gevaert

et al. 2017

Advances in Anatomic Pathology

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571

366

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Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecological system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

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“…65 Moreover, a clinical study in patients with renal cell carcinoma observed synergistic therapeutic effects for ICB with bevacizumab. 66 In HER2-negative metastatic BC, a pilot study is currently investigating the combination of durvalumab with bevacizumab in patients that progressed after treatment with bevacizumab alone (NCT02802098) (online supplementary table s1).…”

Section: Combination With Targeted Monoclonal Antibodiesmentioning

confidence: 99%

Targeting immune checkpoints in breast cancer: an update of early results

et al. 2017

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The immune tumour microenvironment has been shown to play a crucial role in the development and progression of cancer. Expression of gene signatures, reflecting immune activation, and the presence of tumour-infiltrating lymphocytes were associated with favourable outcomes in HER2-positive and triple-negative breast cancer. Recently, immunotherapy with immune checkpoint blockade induced long-lasting responses and improved survival in hard-to-treat malignancies (ie, melanoma and non-small cell lung cancer) and are changing treatment paradigms in a variety of neoplastic diseases. Immune checkpoint blockade has been evaluated in breast cancer, particularly in the triple-negative subtype, with promising results observed in monotherapy or in combination with chemotherapy in the metastatic and neoadjuvant settings. However, identification of patients who are most likely to benefit from immune checkpoint blockade remains challenging, with many patients not responding to treatments and a significant financial cost. The combination of immune checkpoint blockade with conventional cancer treatments such as chemotherapy, radiotherapy, targeted therapies or with other immunotherapies is a promising strategy to potentiate its efficacy in breast cancer although further research is required to effectively identify who will respond to these immunotherapies. In this review we report the most recent results that emerged from trials testing immune checkpoint blockade and potential predictive biomarkers and emphasise the new strategies that are under clinical development in breast cancer.

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Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma

Cited by 583 publications

References 28 publications

T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma

T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma

Targeting immune checkpoints in breast cancer: an update of early results

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