Immunotherapy for Renal Cell Carcinoma

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Cytokine therapy

Although several cytokines have shown antitumor activity in RCC, the most consistent results have been reported with IL-2 and IFN-α. In contrast to the results seen with molecularly targeted therapies (eg, sorafenib, sunitinib), which lead to tumor shrinkage in most treated patients but do not produce remissions of cancer when therapy is discontinued, the administration of HD IL-2 has consistently produced durable responses in a small percentage of patients with advanced RCC.8, 14, 15 However,

Influence of Histologic Subtype

Responses to immunotherapy are most frequently seen in patients with clear cell RCC.28, 29, 30 This observation was detailed in a retrospective analysis of pathology specimens obtained from 231 patients (163 primary and 68 metastatic tumor specimens) who had received IL-2 therapy in Cytokine Working Group (CWG) clinical trials.30 For patients with primary tumor specimens available for review, the response rate to IL-2 was 21% (30 of 146) for patients with clear cell histologic primary tumors

Current investigation in patient selection

The CWG conducted the high-dose IL-2 Select trial to determine, in a prospective fashion, if the predictive model proposed by Atkins and colleagues32 can identify a group of patients with advanced RCC who are significantly more likely to respond to high-dose IL-2–based therapy (good risk) than a historical, unselected patient population. The preliminary clinical results of this trial revealed a response rate (28%) that was significantly higher that the historical experience with high-dose IL-2.

Combination of immunotherapy and targeted/antiangiogenic therapy

Although the role of low-dose single-agent cytokines is limited, combinations of immunotherapy with vascular endothelial growth factor (VEGF) targeted therapy may have merit. Two recently completed, large phase III trials of IFN plus bevacizumab versus IFN alone have shown superior efficacy with the combination regimen compared with cytokine monotherapy and suggest the potential of an additive effect.

Soon after bevacizumab became the first VEGF targeted agent to show efficacy as monotherapy in

Investigational immunotherapy in RCC tumor vaccines

Metastatic RCC is a setting in which there has been great interest in testing novel immunotherapies. Several such approaches, including vaccination and allogeneic bone marrow transplantation, have been tested over the past 2 decades. The initial reports evaluating allogeneic bone marrow transplantation were encouraging; however, further clinical trials have highlighted the potential toxicity and limited applicability of this approach.6, 42, 43

The use of tumor vaccines has been explored in RCC,

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 satisfactory results. In RCC, obstacles to effective immunotherapy likely include the physiologic downmodulation of the immune response through the increased expression of molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) on the surface of activated T cells, the proliferation of regulatory

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 previous immunotherapy.104 Toxicities associated with CTLA-4 antibodies, including enteritis, skin rash, and hypophysitis, have occasionally been life threatening and have also been associated with tumor response. Combination of cytokines and agents that block immune downregulation may prove particularly effective

PD-1/PD-L1 biology

The PD-1/PD-L1 pathway is an important inhibitory pathway that regulates T-cell activation and mediates T-cell tolerance (Fig. 2).113 The PD-1 receptor is expressed on T cells, B cells, monocytes, and natural killer T cells after activation. PD-L1 (B7-H1) and PD-L2 (B7-dendritic cell), the 2 ligands for PD-1, are expressed on antigen-presenting cells, including dendritic cells and macrophages. In addition, PD-L1 is expressed on nonhematopoietic cells, including pancreatic islet cells,

PD-1 and tumor immunity

There has been increasing interest in exploring the contribution of the PD-1/PD-L1 pathway to tumor evasion of host immunity. Tumor cells secrete inhibitory cytokines, including TGF-β and IL-10, which creates an immunosuppressive milieu and limits effective antitumor immunity.

Recent studies suggest that tumor expression of PD-L1 may play an important role in contributing to tumor-mediated immunosuppression. A variety of tumors have been shown to express PD-L1, including renal, melanoma,

BMS-936558 in phase I trials

Brahmer and colleagues103 reported the first human phase I/II trial of BMS-936558 (MDX-1106, ONO-4538), a fully human IgG4 anti-PD-1 blocking antibody, in patients with selected refractory or relapsed malignancies. This single-dose trial established the maximum tolerated dose (MTD) of BMS-936558 at 10 mg/kg without evidence of serious toxicity (arthritic symptoms: 2 patients; thyroid-stimulating hormone increase: 1 patient). Flow cytometric analysis showed sustained occupancy of most PD-1

Vaccination plus immune checkpoint blockade

To realize the full potential of a vaccine approach in RCC, combinations with immune stimulants (eg, granulocyte macrophage colony-stimulating factor) and inhibitors of natural T-cell regulation pathways (eg, CTLA4 blockade, T-reg depletion) may be necessary.

The PD-1/PD-L1 pathway may play an important role in blunting immune response to tumor vaccines. PD-1 is upregulated on T-cell populations in response to antigenic and nonantigenic stimulation. Study findings suggest that stimulation with

Combination of investigational immunotherapy and targeted/antiangiogenic therapy

Although VEGF pathway targeted therapies (eg, sunitinib, bevacizumab) have significantly improved outcomes for patients with RCC, disease progression is inevitable. Although the mechanisms of treatment resistance are poorly understood, the immunosuppressive effects of increased VEGF levels and MDSC may play an important role in the process.99, 100, 101 Recent preclinical and correlative investigations have provided new insights into the potentially favorable effect that VEGF receptor TKIs (eg,

Summary

RCC has long been considered an immunologically influenced malignancy and thus served as a platform for the clinical testing of anticancer immunotherapy. The nonspecific cytokines, IL-2 and IFN-α, have undergone the most testing and produced only modest benefits for unselected patients. High-dose IL-2 remains the only approach to produce durable responses in patients with metastatic RCC and can thus be considered in appropriately selected patients. For patients unlikely to benefit from, unable

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    Disclosure: Supported in part by the DF/HCC Renal Cancer SPORE: P50 CA101942-01.

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