Immunotherapeutic strategies for the treatment of renal cell carcinoma: where are we now?

Abstract

Immunotherapy with cytokines was the first effective treatment in metastatic renal cell carcinoma (mRCC). Long-term responders and complete remissions were observed, but efficacy in the overall population was limited with the consequence that targeted agents replaced cytokines. The discovery of tumor associated antigens as direct targets paved the way from theses rather unspecific to specific immunotherapeutic strategies, which are discussed in this review. Autologous or dendritic cell (DC) based tumor vaccination with vitespen or AGS-003, adoptive T-cell transfer and synthetic peptide vaccination with IMA901 are new and promising approaches. Besides that the more passive strategies of antibody dependent cytotoxicity with the VEGF antibody bevacizumab or the carbonic anhydrase IX antibody girentuximab are discussed. Immunomodulation by cyclophosphamide, tyrosine kinase inhibitors or nivolumab, which targets the PD-1 axis, further promote T-cell activation and combinatory strategies with these agents are outlined.

Keywords::

• IMA901
• immune therapy
• renal cell carcinoma
• tumor associated antigen
• tumor microenvironment
• tyrosine-kinase inhibitor
• vaccination

Financial & competing interests disclosure:

J Bedke is subinvestigator and A Stenzl is principal investigator of IMA901, J Bedke is principal investigator and A Stenzl sub-investigator of a Phase III trial of nivolumab versus everolimus in mRCC patients as a second-line treatment. J Bedke was supported by a grant by the Deutsche Forschungsgemeinschaft (DFG, SFB 685 C5). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Long-term responders and complete remission are observed in metastatic disease (mRCC) patients treated with immunotherapy.

• • The use of tumor-associated antigens as target elements to activate the immune system is a key mechanism in specific immunotherapy approaches.

• • The synthetic peptide vaccine IM901 demonstrated a clear association between the induction of an immune response and a prolonged overall survival (OS) and underlines the importance of an effective T-cell activation.

• • Immunomodulatory agents like cyclophosphamide, the tyrosine-kinase inhibitor (TKI) sunitinib or PD-1 antibodies as checkpoint inhibitors can further activate the immune system and are ideal candidates for combination strategies.

• • Large Phase III trials of combinations with IMA901 and sunitinib and the dendritic cell (DC) based vaccine AGS-003 and sunitinib are ongoing.

• • Antibody dependent mediated cytotoxicity is a passive approach in specific immunotherapy. The VEGF antibody bevacizumab prolonged OS in mRCC, while the carbonic anhydrase IX antibody girentuximab did not improve OS in adjuvant treated high-risk patients.