Elsevier

Seminars in Oncology

Volume 40, Issue 4, August 2013, Pages 492-498
Seminars in Oncology

Immune Therapy for Kidney Cancer: A Second Dawn?

https://doi.org/10.1053/j.seminoncol.2013.05.008Get rights and content

Agents targeting the immune system have been a historical standard of care in metastatic renal cell carcinoma (RCC), but have largely been supplanted by newer targeted therapy. Recent insights into the regulation of an anti-tumor immune response has led to the development of agents that can activate immune responses primarily within the tumor, enabling the possibility of achieving durable tumor response in the absence of significant systemic toxicity. In addition, a better understanding of tumor immunology has raised the potential of developing predictive biomarkers of response to immunotherapy. Novel approaches including inhibition of immune checkpoints has entered clinical testing in RCC.

Section snippets

Cytokine Therapy

Although a number of cytokines have shown anti-tumor activity in RCC, the most consistent results have been reported with interferon-alfa (IFN-α) and IL-2. Although IFN-α has produced modest benefits in unselected patients, a meta-analysis of randomized clinical trials revealed a 3-month survival benefit with manageable toxic effects when compared with non–IFN-α control arms.11, 12, 13, 14, 15 In the absence of other effective and readily applicable treatments, IFN-α became a de facto standard

Combination of Immunotherapy and Antiangiogenic Therapy

Although the role of single-agent cytokines is limited, combinations of immunotherapy with VEGF-targeted therapy may have merit. Two large phase III trials of IFN plus bevacizumab versus IFN alone have demonstrated superior efficacy for the combination regimen compared with IFN monotherapy and suggest the potential of an additive effect.4, 27 While the AVOREN and Cancer and Leukemia Group B (CALGB) trials led to the regulatory approval of this combination of VEGF pathway inhibition with

Overcoming Obstacles to Effective Immunotherapy in RCC

An improved understanding of the molecular mechanisms that govern the interaction between a tumor and host immune response has provided insight into why immunotherapies too often fail to achieve clinically meaningful results. In RCC, obstacles to effective immunotherapy likely include the physiological down-modulation of the immune response through the increased expression of molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA4) on the surface of activated T cells, the proliferation of

Investigational Targeted Immunotherapy

In a single institution phase II trial, the CTLA-4 antibody ipilimumab produced major tumor regressions but also significant toxicities in patients with metastatic RCC who had failed to respond to prior immunotherapy.37 Toxicities associated with CTLA-4 antibody administration, have included enteritis, rash, hepatitis, and hypophysitis and have typically occurred in 15%–35% of patients.43 These toxicities can be life-threatening if not identified early and managed aggressively. Some reports

PD-1 Blockade in Phase I Trials

Brahmer and colleagues reported the first in human phase I trial of PD-1 blockade with nivolumab (BMS-936558, MDX-1106, nivolumab), a fully human IgG4 anti–PD-1 blocking antibody, in patients with selected refractory or relapsed malignancies.36 This single-dose trial established the maximum tolerated dose (MTD) of nivolumab as 10 mg/kg without evidence of serious toxicity (arthritic symptoms: two patients; thyroid stimulating hormone elevation: one patient). In a dose expansion cohort at the

Combination of Investigational Immunotherapy and Antiangiogenic Therapy

While VEGF pathway-targeted therapies have significantly improved the clinical outcome for patients with advanced RCC, the onset of treatment resistance and disease progression appears inevitable even with continued therapy. While the mechanisms of treatment resistance are poorly understood, the immunosuppressive effects of elevated VEGF levels and the enhanced tumor infiltration of MDSC are hypothesized to play an important role in the process.32, 33, 34, 35 Recent preclinical and correlative

Conclusions

An improved understanding of RCC tumor biology has led to major advancements in the treatment of patients with metastatic RCC over the past decade.1, 2, 3, 4 While agents that target the VEGF and mTOR pathways prolong survival, resistance develops for most patients within the first year of therapy. Agents that can produce complete and durable tumor responses with acceptable toxicity profile even for just a defined subset of patients still remains a critical unmet need for this patient

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    Conflicts of interest: Dr McDermott has served as a consultant for BMS, Genentech, Prometheus, Pfizer, and Curetech. Dr Atkins has served as a consultant for BMS, Genentech, Prometheus, Medimmune, Merck, and Curetech.Supported in part by the DF/HCC Renal Cancer SPORE: P50 CA101942-01.

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