Targeted therapy in renal cell carcinoma: moving from molecular agents to specific immunotherapy

Bedke, Jens; Gouttefangeas, Cécile; Singh‐Jasuja, Harpreet; Stevanović, Stefan; Behnes, Carl-Ludwig; Stenzl, Arnulf

doi:10.1007/s00345-013-1033-3

Cited by 28 publications

(15 citation statements)

References 53 publications

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“…8 Recent understanding of these host-tumor immune interactions has given rise to novel antibodies directed against immune checkpoint proteins. 9,10 …”

Section: Introductionmentioning

confidence: 99%

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial

Motzer

Rini

McDermott

et al. 2015

JCO

961

689

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Purpose Nivolumab is a fully human immunoglobulin G4 programmed death–1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC). Patients and Methods Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety. Results A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs. Conclusion Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting.

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“…8 Recent understanding of these host-tumor immune interactions has given rise to novel antibodies directed against immune checkpoint proteins. 9,10 …”

Section: Introductionmentioning

confidence: 99%

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial

Motzer

Rini

McDermott

et al. 2015

JCO

961

689

View full text Add to dashboard Cite

show abstract

“…The use of SA-4-1BBL in combination with targeted therapies, such as sunitinib, which blocks suppressive functions of both MDSCs and Tregs, presents another attractive treatment modality. Consistent with this notion, sunitinib has been shown to work in synergy with an agonistic 4-1BB mAb for the treatment of gastrointestinal stromal tumors [76] and metastatic renal cell carcinoma [77] in preclinical tumor models.…”

Section: Prospect Of Sa-4-1bbl Use In Combinatorial Cancer Therapiesmentioning

confidence: 94%

SA-4-1BBL as a novel adjuvant for the development of therapeutic cancer vaccines

Sharma

Yolcu

Shirwan

2014

Expert Review of Vaccines

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Tumor associated antigen (TAA)-based therapeutic vaccines have great potential as a safe, practical, and cost-efficient alternative to standard treatments for cancer. Clinical efficacy of TAA-based vaccines, however, has yet to be realized and will require adjuvants with pleiotropic functions on immune cells. Such adjuvants need not only to generate/boost T cell responses, but also reverse intrinsic/extrinsic tumor immune evasion mechanisms for therapeutic efficacy. This review focuses on a novel agonistic ligand, SA-4-1BBL, for 4-1BB costimulatory receptor as an adjuvant of choice because of its ability to: i) serve as a vehicle to deliver TAAs to dendritic cells (DCs) for antigen uptake and cross-presentation to CD8+ T cells; ii) augment adaptive Th1 and innate immune responses; and iii) overcome various immune evasion mechanisms, cumulatively translating into therapeutic efficacy in preclinical tumor models.

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“…27,28 This phenomenon termed peripheral tolerance is influenced by the antigen-specific tolerogenic role of DCs. 22,27,28 CD152 -CTLA-4…”

Section: Immunosurveillance and Immunoeditingmentioning

confidence: 99%

“…21 Theses tumor-driven mechanisms of immune suppression includes the downregulation of HLA molecules and/or tumor associated antigens (TAA), which leads to a decreased immunogenicity or the induction of suppressive cytokines like IL-10 or TGF-b. 22 These cytokines can lead to recruitment of regulatory T cells (T regs ), myeloid derived suppressor cells (MDCS) or tumor-associated M2 macrophages which can act as immunosuppressors. 21,23,24 Therefore, agents called immunomodulators or checkpoint inhibitors, which counteract tumor-induced immunosuppression are an external editing of the immune system to potentially shift tumor growth from the escape phase to the equilibrium state or toward tumor elimination.…”

Section: Immunosurveillance and Immunoeditingmentioning

confidence: 99%

Checkpoint modulation - A new way to direct the immune system against renal cell carcinoma

Bedke

Kruck

Gakis

et al. 2015

Human Vaccines & Immunotherapeutics

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The introduction of targeted therapies like the tyrosine kinase (TKI) and mammalian target of rapamycin (mTOR) inhibitors has improved patients´ survival in general. Nevertheless the prognosis remains limited. Therapies with a new mode of action are urgently warranted, especially those who would provoke long-term responders or long-lasting complete remissions as observed with unspecific immunotherapy with the cytokines interleukin-2 and interferon-α. In the recent years a deeper understanding of the underlying immunology of T cell activation led to the development of checkpoint inhibitors, which are mainly monocloncal antibodies and which enhances the presence of the co-stimulatory signals needed for T cell activation or priming. This review discusses the clinical data and ongoing studies available for the inhibition of the PD-1 (CD279) and CTLA-4 (CD152) axis in mRCC. In addition, potential future immunological targets are discussed. This approach of T-cell activation or re-activation by immunological checkpoint inhibition holds the inherent promise to directly affect the tumor cell and thereby to potentially cure a subset of patients with mRCC.

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Targeted therapy in renal cell carcinoma: moving from molecular agents to specific immunotherapy

Cited by 28 publications

References 53 publications

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial

SA-4-1BBL as a novel adjuvant for the development of therapeutic cancer vaccines

Checkpoint modulation - A new way to direct the immune system against renal cell carcinoma

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