Immunotherapy and immune checkpoint inhibition in particular present an exciting opportunity for the treatment of bladder cancer. Over the last 30 years, bladder cancer patients have seen few advances in the treatment of their disease. With an estimated 74,000 new cases and 16,000 deaths from bladder cancer in 2015, the incidence and survival have remained relatively constant. In patients, both with muscle-invasive disease undergoing radical cystectomy as well as those with locally advanced or metastatic disease, there have been no new FDA-approved therapies for those who cannot tolerate or fail to respond to cisplatin-based chemotherapy. However, in the last several years, new insights into tumor immunology have lead to the development of a new class of drugs termed immune checkpoint inhibitors, several of which have demonstrated impressive anti-tumor responses in several malignancies, including melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC).
Currently, these immune checkpoint inhibitors are being actively studied in several treatment settings for bladder cancer, including for non-muscle-invasive disease with BCG (pembrolizumab, NCT02324582) as well as neoadjuvant or adjuvant therapy after cystectomy (atezolizumab, NCT02451423, NCT02450331). In June 2014, the FDA granted the anti-PD-L1 antibody atezolizumab (MPDL3280A) “breakthrough” status for urothelial carcinoma based on promising results of a phase 1a trial in patients with metastatic disease. The purpose of this article is to review the basis for immune checkpoint inhibition in muscle-invasive bladder cancer and discuss the current state of clinical trials to evaluate their safety and efficacy.
Cancer immunotherapy and the role of the immune checkpoint
Human tumors elicit adaptive immune responses, mediated primarily by T lymphocytes. T cells have been the primary focus of cancer immunotherapy primarily due to their ability to organize diverse immune responses via CD4+ helper T cells that have adaptive and innate effector mechanisms. Analysis of immune infiltrates suggests that greater infiltration by T lymphocytes is largely associated with a stronger anti-tumor activity and chemotherapeutic response. Broad cytotoxic CD8+ T cell infiltration in particular has been associated with improved survival through its role of recognizing tumor-associated antigens (TAA) presented by major histocompatibility complex class I (MHC-I) molecules. CD4+ T cells also exhibit effector functions against MHC class II molecule-negative tumors and produce cytokines that mediate these immune responses. These effector T cells are balanced by Foxp3+ regulatory Treg (T) cells, which suppress natural killer cells and the innate immune response as well as effector T cells and the adaptive response. The balance of co-stimulatory and inhibitory responses to cancer is a central tenant of cancer immunology.
The CTLA4 checkpoint
CTLA-4, which is expressed solely on T cells, primarily inactivates T cell activity by competing with the CD28 costimulatory molecule. CD28 and CTLA-4 share the identical ligands of CD80 and CD86 on antigen-presenting cells (APCs), and thus CTLA-4 competes with CD28 function in T cell survival, proliferation, and recruitment. In particular, CTLA-4 down-modulates CD4+ helper T cell activity and enhances Treg immunosuppressive functions. The blockade of CTLA-4 has been in development for sometime, since Allison and colleagues used preclinical models to show that antibody blockade of CTLA-4-enhanced immune-mediated anti-tumor activity. Ipilimumab is a monoclonal antibody targeting CTLA-4 and the first therapy to demonstrate a survival benefit for patients with metastatic melanoma, and it was quickly FDA approved thereafter (see Fig. 1). More impressive was that 18 % of patients survived beyond 2 years, compared with a 5 % survival rate with the previous standard of care. However, the potent immunomodulatory effects of CTLA-4 blockade leads to a significant adverse events (AE), which occur in >70 % of patients treated with ipilimumab. These range from dermatitis, colitis, and hepatitis, to less common uveitis, neuropathy, and lupus nephritis. Essentially with anti-tumor immune suppression comes a component of autoimmune suppression.
It is in the context of CTLA-4’s dramatic anti-tumor activity with a high burden of AEs that propagated interest in the PD-1 pathway. In contrast to CTLA-4, PD-1 expression is induced in peripheral tissues when T cells become activated. This cell-surface molecule is activated by two ligands—PD-L1 and PD-L2, which share 37 % sequence homology and lie within 100 kb of one another in the genome. PD-1 is expressed on many different subtypes of tumor infiltrating leukocytes, and is particularly overexpressed on intra-tumoral Tregs. Similarly, PD-L1 has been shown to have high expression in several solid organ tumors, including melanoma and lung cancer. PD-L2, by contrast, has been less frequently studied but is expressed on different types of APCs (monocytes, macrophages, and dendritic cells) and is also up-regulated during T cell activation in tumor. PD-L1 and PD-L2 expressions can be up-regulated innately via constitutive oncogenic signaling by the tumor cells (via activation of the AKT and STAT3 pathways), or can be induced by an adaptive means as a response to inflammatory signaling. Sustained ligand expression of PD-L1 or PD-L2 on tumor cells leads to proliferation of Tregs and to a state of exhaustion and ultimately T cell anergy and apoptosis. The result is an immunosuppressive state that leads to tumor cell escape and proliferation. Thus far, monoclonal antibodies targeting both PD-1 (nivolumab/pembrolizumab) and PD-L1 (atezolizumab) have been evaluated in human trials. Across multiple histologies, PD-1 and PD-L1 inhibitors have shown tumor regressions and partial and complete responses. In some settings, response was durable beyond 2 years and persisted after drug discontinuation.
Max Kates, Nikolai A. Sopko, Hotaka Matsui. World J Urol (2016) 34:49–55