A new age for vaccine therapy in renal cell carcinoma

Abstract

Over the past several years, the dominant paradigm in drug development for metastatic renal cell carcinoma (mRCC) has been to more selectively and potently target moieties such as the vascular endothelial growth factor receptor. The effectiveness of this strategy appears to be nearing a plateau, however, underscoring the need for novel approaches. Vaccine-based therapies represent one such approach. Several distinct vaccines are currently being examined in mRCC, each using a distinct mechanism of action. For instance, the autologous dendritic cell vaccine AGS-003 uses patient-specific antigens derived from primary tumor tissue. In contrast, the poxvirus vaccine TG4010 produces an antigenic response to MUC1, a cell surface glycoprotein that reduces cell-cell interactions and thereby precludes contact inhibition. Other vaccines elicit a response to a broader spectrum of antigens-for instance, the vaccine IMA901 is based on 9 tumor-associated peptides identified from a novel biotechnology platform combining mass spectroscopy, microarray analysis of RNA expression, and immunogenicity assays. Herein, the current status of vaccine-based therapies for mRCC is described in detail. Furthermore, challenges to clinical implementation (eg, cost, optimal pairing with targeted agents, appropriate sequencing) are presented.

Figure 1

Schema showing the randomization employed in the phase III assessment of IMA901. Note that cyclophosphamide (Cy) is offered as a single pulse dose of 300 mg/m² prior to initiation of IMA901. IMA901, given with GM-CSF, is delivered over a total of 4 months with a series of 10 consecutive vaccinations. Sunitinib is given on the approved schedule, namely 50 mg daily (4 weeks on, 2 weeks off).

Figure 2

Schema showing the randomization employed in the phase III assessment of AGS-003. AGS-003 is delivered every six weeks for a total of 48 weeks. Patients with stable disease or better at 48 weeks may continue AGS-003 injections quarterly until progressive disease is noted.

Figure 3

Schema outlining the proposed mechanisms of action of sunitinib. Although sunitinib is well known to inhibit angiogenesis, abrogation of MDSC recruitment to tumor sites by sunitinib may promote the antitumor immune response, suggesting an alternative mechanism of action.