**Author details**

In addition to CD137 and CD27, other co-stimulatory molecules such as OX40 and GITR are also promising therapeutic targets. Trials of monotherapy with the OX40 agonist MEDI0562, and with the GITR agonists MK-4166 and TRX518, are under way in solid tumor malignancies (NCT02318394, NCT02132754, and NCT02628574). Like combination checkpoint blockade strategies, much enthusiasm exists for combined treatment strategies with other immuno-

Owing to the unique antitumor mechanisms elicited by immunotherapy, patients treated with these agents can have tumor response patterns that are different from conventional tumorresponse criteria, such as the WHO criteria [137, 138]. A subset of patients receiving ICI therapy develop pseudoprogression, in which tumor burden decreases after an initial increase or during or after the appearance of new lesions. The evaluation of pseudoprogression provides new challenges in treatment monitoring and therapeutic decision-making because it cannot be evaluated with the existing response-evaluation criteria. The establishment of a standardized strategy to evaluate immune-related responses in patients receiving ICIs is extremely important. However, advances in the knowledge of immune-related responses have been challenged by the fact that only a few clinical trials have used the immune-related response criteria (irRC) [103] or immune-related response evaluation criteria in solid tumors (irRE-

In addition, the development of robust biomarkers to assist prediction of response and clinical benefits of immunotherapy is essential to further advance the field as precision immunooncology. Despite the remarkable success of clinical applications of immunotherapy reported in the past decade, the effectiveness of these therapies varies greatly across individual patients and among different tumor types. A substantial unmet need is the development of biomarkers of response to immunotherapeutic agents, in order to identify, before the initiation of treatment, which patients are likely to experience clinical benefit from such treatments. This aspect is particularly important in the management of tumors with low response rates, such as NSCLC (response rate ≤ 20%), RCC, and urothelial carcinoma (UCC) [141]. The growing knowledge of molecular subtypes of RCC with next-generation sequencing is the first step toward developing RCC-specific genomic signatures and guiding therapy selection, thereby

Taken together, the therapeutic activity of immunotherapy is the result of a complex interplay between multiple factors in the tumor, tumor microenvironment, and immune system, requiring a collaborative approach to translate the emerging knowledge into the clinical context.

Novel immune therapies are emerging as an important addition to targeted therapies in the treatment of RCC. Many questions regarding their use remain to be optimized including dose, schedule, AEs, and adjuvant or neoadjuvant application. An investigation of the rational combination of different treatment modalities is also critical in maximizing the potential of immunotherapy. Additional investigations into predictive biomarkers or resistance mechanisms are

CIST) [139] as the primary criteria to define their end points [77, 104, 140].

modulatory agents [135, 136].

60 Evolving Trends in Kidney Cancer

moving toward precision medicine [142].

**11. Conclusions**

Le Qu1 \*† , Ding Wu1†, Haowei He1†, Xiaofeng Xu1† and Cheng Chen2

\*Address all correspondence to: septsoul@hotmail.com

1 Department of Urology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, China

2 Department of Medical Oncology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, China

† These authors contributed equally to this paper.
