**10. Perspective**

The advent of immunotherapy has brought about a paradigm shift in the treatment of advanced RCC. Properly integrating immunotherapy into the present treatment is challenging. Preclinical research has demonstrated the role of VEGF in suppressing tumor immune responses—an attractive strategy to combine with ICIs [117–119]. This successful synergy has been confirmed in phase 1 and 2 studies with axitinib-pembrolizumab [84], axitinib-avelumab [120], lenvatinib-pembrolizumab [121], and bevacizumab-atezolizumab [122, 123]. The ORR ranged between 32% and 67%, and AEs were manageable in all these studies, in contrast to studies in other combinations as TKIs (pazopanib/sunitinib) plus immunotherapy, which did not move forward because of unacceptable toxicity [83, 124, 125]. Although preliminary, the abovementioned results are encouraging and have led to larger, confirmatory, phase 3 trials, which are now actively accruing patients.

The evaluation of responses to immunotherapeutic agents represents a challenge in the clinic. Specific tumor response patterns with ICI treatment sometimes differ from those with chemotherapeutic and targeted agents. Due to immune-mediated mechanisms, tumor flare, which shows enlarged size of baseline lesions or increased total tumor burden, may occur before cellular immune responses have a chance to affect the actual tumor size [103]. Additionally, transient immune cell infiltration at the tumor site may boost the appearance of tumor growth [103, 104]. Therefore, tumor flare can confuse tumor response interpretation by appearing as disease progression, hence the term pseudoprogression, and may result in inappropriately switching therapy before ongoing clinical benefits manifest on imaging [105]. While pseudoprogression is relatively uncommon (occurring in <10% of patients) versus true progression, it sometimes presents a challenge for patients and for clinicians in determining when to stop and/or switch therapy [105]. Recently updated guidelines for the use of modified RECIST (iRECIST) in trials of immunotherapies were published in an effort to standardize and validate

Response to ICI has been associated with specific intrinsic and extrinsic properties of tumors or of the host that have been recently classified as the elements of the cancer-immune set point [107]. Intrinsic properties reflect the degree of tumor foreignness [108], linked to the mutational burden and the presence of neoantigens that can be recognized by the immune system, as shown in NSCLC and melanoma [109, 110]. Foreignness of RCC might vary by molecular subtype and a higher number of mutations [111]. In addition, the general individual immune status, mirrored by the levels of circulating lymphocytes and the neutrophil to lymphocyte ratio (NLR), the increase of the C reactive protein, the erythrocyte sedimentation rate PD-L1 expression (although controversial), and LDH were shown to influence the response to ICI. In addition to the intrinsic properties of the tumors, extrinsic factors, such as exposure to sunlight and to cigarette smoke, the presence of viral infections, and the composition of the gut microbiota, were classified as elements of the cancer-immune set point [107]. The exposure to sunlight and cigarette smoke was relevant for melanoma and NSCLC, respectively, while the presence of viral infections might impact the response to ICI in human papilloma virus positive tumors and Epstein-Barr virus related tumors. Preclinical evidence showed that several bacteroides and bifidobacterium species influenced the efficacy of ICI with anti-CTLA-4 and anti-PD-L1 mAb in mice [112–114]. The role of the gut microbiota in patients with renal cancer

Taken together, these data suggest that multiple parameters should be taken into account to identify ideal candidates for immunotherapy in RCC. The genomic landscape likely has a role in determining the putative immunogenicity of the tumor [115]; TIL, PD-L1 expression, and immune gene signatures could detect tumors with an inflamed phenotype, which have higher

The advent of immunotherapy has brought about a paradigm shift in the treatment of advanced RCC. Properly integrating immunotherapy into the present treatment is challenging.

these criteria and harmonize the interpretation of the results [106].

treated with ICB requires further investigations.

chances of response to ICB [107, 116].

**10. Perspective**

58 Evolving Trends in Kidney Cancer

In addition, different novel immunotherapies beyond ICIs are being investigated, including adoptive T-cell therapy and T-cell agonists.

Adoptive T-cell transfer therapy refers to the autologous or allogeneic infusion of T-cells. One such therapy involves the generation and infusion of chimeric antigen receptor (CAR) T-cells—T cells that have been genetically modified to express a receptor specific to tumor epitopes independent of HLA. The promising efficacy of anti-CD19 CAR T cells in hematological malignancies has inspired further investigations in solid tumors [126]. One of the key aspects of designing effective CAR T cells is finding a tumor-associated antigen that is uniformly expressed in tumor cells but not in the normal tissue. Carbonic anhydrase 9 (CAIX) is an enzyme that is overexpressed in clear-cell RCC but minimally expressed in normal tissue [127]. Early efforts in using CAIX as a tumor-associated antigen for CAR resulted in liver enzyme elevations that limited its use, likely owing to the therapy also targeting CAIX expressed in the liver bile duct epithelium [128]. Cor H.J. Lamers and his colleagues gave patients a CAIX monoclonal antibody before infusion of CAR T cells to reduce this off-target toxicity [129]. However, in the study, no clinical responses were observed, and the efficacy of CAIX CAR T cells is yet to be proven.

Another form of adoptive immune cell therapy tested in RCC is autologous cytokine-induced killer (CIK) cell immunotherapy. CIK cells are created in vitro by harvesting peripheral mononuclear cells in the blood using an anti-CD3 antibody. The resulting phenotype by IL-1, IFNγ, and IL-2 shares features of effector T-cells and natural killer cells [130]. A phase II trial randomly assigned 148 patients with mRCC to CIK cell immunotherapy or IL-2 combined with IFNα [131]. PFS and OS at 3 years in the CIK cell therapy arm were 18% and 61%, respectively, compared with 12% and 23% in the IL-2 plus IFNα arm (p = 0.031 and p < 0.001, respectively). This therapy is being further investigated in conjunction with DC vaccines and early results show that therapy is well tolerated and might have activity against RCC [132].

Stimulatory molecules expressed on immune cells can also be targeted with agonist antibodies. CD137 is a co-stimulatory molecule for T-cells that increases T-cell effector activity and survival. Its use in combination with anti-DR5 and anti-CD40 antibodies in mouse models of RCC has shown to improve survival compared with control mice (p < 0.001) [133]. The CD137 agonist PF-05082566 is currently being tested in combination with pembrolizumab in a phase I trial of advanced solid tumors, including RCC (NCT02179918). Varlilumab is an agonist antibody targeting CD27, another co-stimulatory molecule for T-cell activation. In a phase I trial in solid tumors, including 11 patients with RCC, of the six evaluable RCC patients, two had stable diseases [134]. This antibody is currently being studied in combination with sunitinib and in combination with atezolizumab in phase I/II trials in RCC (NCT02386111).

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 immunomodulatory agents [135, 136].

needed to optimize patient selection. To date, nivolumab has been approved in the secondline setting, and randomized phase III trials with novel immunotherapy combinations are challenging the first-line standard of care in RCC—in the near future, immunotherapy will

Immunotherapy for Renal Cell Carcinoma http://dx.doi.org/10.5772/intechopen.77377 61

, Ding Wu1†, Haowei He1†, Xiaofeng Xu1† and Cheng Chen2

1 Department of Urology, Jinling Hospital, Clinical School of Medical College,

2 Department of Medical Oncology, Jinling Hospital, Clinical School of Medical College,

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Nanjing University, Nanjing, China

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**Author details**

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

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 moving toward precision medicine [142].

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.
