Immuno-Oncology Approaches to Salvage Treatment for Non-muscle invasive Bladder Cancer

This article provides a comprehensive review of the available data for immunotherapy being used as a salvage treatment in non–muscle-invasive bladder cancer. The literature demonstrates that the immune system has an important role in bladder cancer progression. Initial results from studies using checkpoint inhibitors, recombinant interferon-α2b protein, and oncolytic adenoviruses have shown promising responses with acceptable toxicities. However, the majority of the current data arises from small trials with limited follow-up. There are currently several ongoing studies in this setting, which we await completion, to increase our understanding of immunotherapy as a salvage treatment in non–muscle-invasive bladder cancer.

Key points

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There is a complex interplay between bladder cancer and immune cells such as myeloid-derived suppressor cells, neutrophils, tumor-associated macrophages, and T lymphocytes that can be harnessed as targets for therapy.
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Early results show promise for checkpoint inhibitors, recombinant interferon-α2b protein and oncolytic adenoviruses to be used as a salvage treatment after bacillus Calmette-Guérin in non–muscle-invasive disease.
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The currently available data are in early stages and maturation is awaited to improve understanding of the optimal immunotherapy agent to be used as salvage treatment in non–muscle-invasive disease.

Approximately three-quarters of all newly diagnosed bladder cancers are nonmuscle invasive. The gold standard management option for non–muscle-invasive bladder cancer (NMIBC) is transurethral resection followed by intravesical chemotherapy or immunotherapy to decrease the risk of recurrence. Chemotherapeutic agents, such as mitomycin C and gemcitabine, are used for low-risk NMIBC; whereas bacillus Calmette-Guérin (BCG) immunotherapy is used for intermediate- and high-risk disease. Although these agents have been demonstrated to decrease the risk of recurrence in large phase III randomized trials, a large proportion of patients still experience recurrent disease. The management of chemorefractory and BCG-refractory disease is an important area of research in the NMIBC domain. As with other malignancies refractory or unresponsive to traditional therapies, systemic therapy with a new generation of immuno-oncology agents have or are being investigated for used as salvage therapy in this setting. We provide a comprehensive review of the current evidence in this area and provide a window into what lies ahead in the future.

Bladder cancer and the immune system

The relationship between cancer processes and the immune system is incredibly complex and cannot be fully explored in this limited space, but we aim to provide a overview of this interplay.

Bladder cancer often causes local inflammation and consequently attracts inflammatory cells to the site. However, the local immunosuppression caused by neoplastic processes results in these cells being unable to combat the cancer. Myeloid-derived suppressor cell are a cell type that has been implicated in cancer-associated immunosuppression. Several preclinical studies have demonstrated that the increased concentration of myeloid-derived suppressor cells in peripheral blood and tumor tissue potentiates cancer progression through immune suppression and stimulation of angiogenesis. Eruslanov and colleagues found an increased number of granulocyte-type CD15 ^high CD33 ^low cells in peripheral blood and tumor tissue in patients with bladder cancer compared with healthy controls. Monocyte-type CD15 ^low CD33 ^high cells were also found in these patients but their concentration was not markedly higher than in controls. However, both the aforementioned cell types were highly activated and produced considerable amounts of proinflammatory chemokines and cytokines. These findings can be potential targets of immunotherapies to induce quiescence of the overactivated states of myeloid-derived suppressor cells and their immunosuppressive effects.

Neutrophils have also been implicated in promoting bladder cancer growth. Human neutrophil proteins (HNP)-1, -2, and -3 have been shown to promote tumor cell growth through the recruitment of leukocytes across a range of malignancies. They may have additional roles, such as the inhibition of angiogenesis and immunomodulation, which may all contribute to tumor invasion. Higher levels of HNPs have been found in the urine and serum of patients with bladder cancer compared with controls. ^, Furthermore, Gunes and colleagues demonstrated that plasma levels of HNPs were greater in patients with more aggressive cancers such as patients with metastatic disease and nodal involvement. The method in which HNPs exert their tumorigenic effects are not completely clear and need further research to be understood.

The role of tumor-associated macrophages (TAMs) in cancer development and progress has been extensively studied. Several studies have reported that the presence of TAMs in malignant tissue is associated with a poorer prognosis. The role of TAMs in potentiating tumor growth is all encompassing and has been reported to involve inhibiting the T-cell–mediated immune response and stimulating angiogenesis, cell proliferation, and metastasis. As can be seen with their many functions, TAMs are complex cells and are involved with various immune pathways. To simplify it, we can consider TAMS as having 2 phenotypical forms: M1 and M2. M1 phenotype has antitumor effects by slowing cell proliferation and causes tissue damage. In contrast, the M2 phenotype promotes tumor growth by causing immunosuppression, angiogenesis, and promoting invasion. Lima and colleagues demonstrated that patients who experienced BCG failure had higher concentration of M2 TAMs in their stroma relative to tumor tissue compared with those who had a successful response to BCG. This pattern of TAMs was associated with poorer prognosis as patients with higher M2 TAMs in their stroma had decreased recurrence-free survival. Ajili and colleagues also found that TAMs were associated with BCG failure. These findings have been validated in further studies, which found that CD163 ⁺ TAM infiltration was associated with increased vascular invasion and distant metastasis. Although Xu and colleagues did not find that TAMs were directly associated with worse overall survival and recurrence-free survival, they did find a positive correlation between CD163 ⁺ TAM infiltration and B7-H3 expression; the latter conferred worse survival. Hanada and colleagues reported that higher TAM counts are associated with muscle-invasive disease and higher rates of radical cystectomy in addition to worse 5-year survival.

T lymphocytes have an important role in tumor development and progression. Regulatory T cells have been shown to be involved in modulating the immune response in maintaining self-tolerance. They have the ability to downregulate the antitumor immune response and therefore potential cancer growth and spread. High concentrations of regulatory T cells in tumor tissue is associated with a worse prognosis. BCG exerts a part of its action against bladder cancer through the regulation of T cells and natural killer cells. Furthermore, IL-2, which is produced by T lymphocytes, has been shown to be associated with higher recurrence of bladder cancer. Although the evidence in bladder cancer is somewhat limited, it is evident that T lymphocytes are intrinsically linked to tumorigenesis in the bladder. Therefore, T lymphocytes could be a target of immunotherapy.

Emerging immunotherapies for salvage treatment of non–muscle-invasive bladder cancer

The use of immuno-oncology in BCG-unresponsive disease is a developing area and the evidence is in its infancy. In an attempt to avoid, or at least, delay surgical removal of the bladder, a number of trials have evaluated using a variety of agents for BCG refractory disease. The majority of trials have shown very little success and, as a result, we continue the search for other therapies to use in this setting. Several of the studies discussed elsewhere in this article did not administer patients with adequate BCG (as defined by the US Food and Drug Administration consensus recommendations) initially which entails at least 5 of 6 weekly instillations of induction therapy, 2 of 3 instillations of maintenance therapy or a re-induction course of at least 5 of 6 instillations. Therefore, we are extrapolating the effect of the below mentioned agents after inadequate BCG to the true BCG refractory setting.

Although there are several ongoing trials, only a limited number have reported their results, which are discussed here.

Checkpoint inhibitors have been a revelation in the field of immunotherapy across several tumors. As mentioned elsewhere in this article, T cells have a role in attenuating the immune response to malignant cells. Checkpoint inhibitors work by counteracting this and reestablishing the ability of the immune system to attack cancer cells ( Fig. 1 ). Programmed death ligand-1 (PD-L1), programmed cell death protein-1, and cytotoxic T-lymphocyte associated protein 4 are 3 of the main targets of checkpoint inhibitors in bladder cancer. Early preclinical studies demonstrated that the binding of PD-L1 to programmed cell death protein-1 on activated T and B cells resulted in immunosuppression. Therefore, it is suggested that inhibition of this ligand and/or protein should reactivate the immune system. Pembrolizumab is an anti–programmed cell death protein-1 antibody that was first shown to have benefit in advanced cancers including melanoma, non-small cell lung cancer, and even urothelial carcinoma. Specifically to NMIBC, BCG interacts with these pathways. Chevalier and colleagues found that the administration of BCG resulted in increased levels of PD-L1 ⁺ regulatory T cells urine and could possibly be an important mechanism in BCG-refractory disease. These findings are supported by a study by Hashizume and colleagues in which tissue microarrays before and after BCG instillation were stained by antibodies against PD-L1, PD-L2, and CD8; and showed that PD-L1 expression was significantly increased on tumor cell, tumor-infiltrating inflammatory cells, and inflammatory cells after BCG therapy. A single-arm phase II trial (KEYNOTE-057, NCT02625961 ) administered pembrolizumab to 101 patients with histologically confirmed high-grade BCG-unresponsive NMIBC and found that the complete response rate at 3 months was 41.2%. Of those patients who experienced a complete response, the mean duration of response was 8.1 months, 85.6% had a response for longer than 6 months, and 57% had a response beyond 12 months. Furthermore, the majority of complete responders had an ongoing response at a median of 21 months of follow-up. No patients experienced progression to muscle-invasive disease. It should be noted that 15.5% of the cohort experienced an immune-mediated side effect, including 2.1% who experienced grade III or IV toxicities. The results of this trial provide encouragement for the use of checkpoint inhibitors in BCG-refractory disease, which are being evaluated in several other studies, which are discussed elsewhere in this article.

Ongoing trials and future directions

There are several ongoing trials that are investigating the role of salvage therapies in patients who have failed to respond to intravesical BCG. Immunotherapy as a treatment category has important presence in the salvage setting as well as in patients who are BCG naïve. Systemic immunotherapy in the form of immune check point inhibitors look most promising with several trials showing benefits in the locally advanced as well as metastatic setting. ^,

Three forms of immunotherapy are being evaluated in current clinical trials. These include systemic immunotherapy agents in the form of immune checkpoint inhibitors, cytokine therapy, and vaccines.

Systemic Immunotherapy Agents

Several phase I/II studies are studying the efficacy of pembrolizumab, atezolizumab, duravulumab, and nivolumab ( Table 1 ). These agents are being studied as a standalone systemic therapy ( NCT02324582 , NCT02625961 /KEYNOTE057, NCT02844816 /SWOG1605), ^, in combination with other systemic agents ( NCT03519256 ) or with intravesical BCG ( NCT02792192 , NCT03519256 , NCT02324582 ), as well as intravesical immunologic agents like vicinium ( NCT03258593 ). Some trials are using these agents for intravesical instillation with or without BCG ( NCT02808143 , NCT03759496 , and NCT02808143 ).