Despite a long history of immunotherapeutic approaches to treatment, most genitourinary malignancies are not cured by existing immunotherapy regimens. More recently, cell surface molecules known as immune checkpoints have become the focus of efforts to develop more effective immunotherapies.
Since 2016, five new programmed cell death protein 1/ligand 1 (PD-1/L1) checkpoint inhibitors have been approved for metastatic urothelial carcinoma. This review will summarize the data supporting the widespread use of these agents and highlight areas of ongoing clinical development.
Renal cell carcinoma (RCC) was recognized as an immunologically sensitive cancer over 30 years ago. The first therapies to affect the course of RCC were cytokines (interferon alfa-2B and interleukin-2).
The treatment of urothelial carcinoma (UC) had remained unchanged for several years until the recent FDA approval of immune checkpoint inhibitors (CPIs) in the salvage setting. Novel dual CPI-CPI and CPI-chemotherapy combinations are now being investigated aggressively as first line therapy for metastatic disease.
Systemic therapy for metastatic urothelial carcinoma has seen minimal progress and no new approved therapies in the past 20 years. However, with the approval of the checkpoint inhibitor atezolizumab in May 2016, immunotherapy inserted itself into the standard clinical dogma.
Immuno-oncological therapy with checkpoint inhibition (CI) has become a new standard treatment in metastatic renal cell carcinoma (RCC), but the prognostic value of the expression of CI therapy target molecules is still controversial.
Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), agents that provide durable disease control and long-term survival are still needed. It is a fact that a tumor-induced immunosuppressive status (mediated by aberrant activation of inhibitory immune checkpoint pathways as a mechanism to evade host immune surveillance) plays a crucial role in the pathogenesis of cancer, including prostate cancer (PC), making CRPC patients suitable candidates for immunotherapy.
Bladder cancer is the sixth most common cancer in the US and most tumors have urothelial (transitional cell) histology. Platinum-based chemotherapy has long been the standard of care in advanced disease, but long-term outcomes have largely remained poor.
Immunotherapy for the treatment of cancer has made significant progresses over the last 20 years. Multiple efforts have been attempted to restore immune-mediated tumor elimination, leading to the development of several targeted immunotherapies.
Treatment of cancer patients involves a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Traditionally, patients with metastatic disease are treated with combination chemotherapies or targeted agents.
Immunotherapy is rapidly transforming cancer care across a range of tumor types. Although Sipuleucel-T represented the first successful vaccine for the treatment of established cancer, other immunotherapeutic approaches for prostate cancer such as checkpoint inhibitors have been relatively disappointing to date.
Renal cell carcinoma (RCC) is a highly immunogenic neoplasm, and cytokine-based immunotherapies have been used for decades with limited success. In recent years, antibody-based immunotherapies targeting immune checkpoint receptors PD-1 and CTLA-4 have demonstrated clinical efficacy in metastatic RCC (mRCC) patients, leading to regulatory approval of the combination of nivolumab and ipilimumab in treatment-naïve patients with intermediate- or poor-risk disease in April 2018.
The impairment of immunological surveillance caused by aberrant T cell activation can lead to an inadequate anti-tumor response. Therefore, deregulation in co-stimulatory pathway might be associated with cancer susceptibility.
The advent of immunotherapy has heralded a number of significant advances in the treatment of particular malignancies associated with poor prognosis (melanoma, non-small-cell lung, renal and head/neck cancers).
Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4, that has been shown to significantly improve survival in patients with metastatic melanoma. Blocking cytotoxic T-lymphocyte antigen-4 elicits T cell activation, proliferation and anti-tumor response, but can also trigger immune-related adverse events.
Clinical value and utility of checkpoint inhibitors, a drug class targeting adaptive immune suppression pathways (PD-1, PDL-1, and CTLA-4), is growing rapidly and maintains status of a landmark achievement in oncology.
Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Smith 353, Boston, MA, 02215, United States.
Checkpoint inhibitors (CPIs) are established as a standard therapy option for metastatic bladder cancer; however, their role in earlier-stage disease remains undefined.
To summarize the preclinical and clinical evidence forming the rationale for multiple ongoing investigations of CPIs in patients with localized bladder cancer defined by non-muscle-invasive or muscle-invasive stages.
Systemic therapy for bladder cancer, both localized muscle-invasive disease and metastatic disease, has seen minimal progress over the past two decades. Current approaches rely upon cytotoxic chemotherapy combinations aimed at increasing cure rates or achieving palliation and disease control, but these regimens are fraught with short- and long-term toxicities and outcomes remain suboptimal.
Prostate cancer exists in a clinical continuum of hormone-sensitive to castration-resistant disease. Despite the use of chemotherapy and androgen synthesis inhibitors in the castration-resistant setting, this remains a lethal disease.
Immune biomarkers encompass a wide range of blood-borne and cell-associated molecules whose detection or expression may change in response to an immune therapy. These immune therapies encompass a range of platforms including autologous cellular products, in other words, dendritic cells, prime boost DNA vaccines, chimeric antigen receptor (CAR) T cells and checkpoint inhibitors.
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