RCC has largely been termed “chemoresistant,” meaning response to existing cytotoxic chemotherapeutic agents has been limited. Therefore, cancer doctors and researchers continue to search for different forms of systemic treatments. In the early 1990s, immunotherapy was successfully used as systemic treatment for RCC. The idea for this treatment came from the wide range in prognoses among patients with seemingly similar disease burden -- for example, among patients with similarly sized tumors (whether small or large), some were cured with surgery alone while patients with very similar tumors developed metastatic cancer and died. In addition, a significant proportion of patients would have spontaneous regression of metastatic disease once the primary tumor was surgically removed. Both of these observations suggest an interaction between the immune system and disease.[6,7] Ultimately, immunotherapies (like IFN-alpha and IL-2) were found to be more effective than previously attempted chemotherapies. More recently, targeted therapies were developed to interrupt specific portions of the cell-cycle and endothelial attachment processes in clear-cell RCC.
The idea of targeted therapy and theories of the immunoresponsive nature of clear cell RCC were combined to focus on specific parts of the immune interaction. Among others, one important interaction is the Programmed Death Ligand 1 (PD-L1) interaction between the tumor cells and the immune cells. T-cells are immune cells that target “foreign” cells in the body and trigger an immune response to kill those cells. T-cells have receptors that have evolved (through genetic mutations and recombinations) to be specific for different surface proteins that may found in the cells of the body. In a normal, healthy person, T-cells will even recognize normal, healthy cells. However there are mechanisms to prevent the T-cell from killing good cells – a process called “anergy” which leads to T-cell death (or apoptosis). One such signaling pathway is the PD-L1 on the healthy cell interacts with the receptor on the healthy cell (Figure 1).
|Figure 1. T-Cell Recognizing Healthy Cell via PD-1-PD-L1 Interaction and Inducing Cell Death (Apoptosis).|
|Figure 2. T-Cell Recognizing Tumor Cell without PD-1-PD-L1 Interaction.|
However, some cancers like kidney cancer, can “trick” the T-cell into thinking the tumor cell is a normal, healthy cell. One mechanism these cancers use is to express PD-L1, allowing tumor cell to escape the immune system and proliferate (Figure 3).
|Figure 3. Tumor Cell Expressing PD-L1 and Avoiding Detection by Immune System.|
It has been noted that patients with tumors that have high expression of PD-L1 have a worse prognosis, which further suggests its involvement in the lifecycle of the disease -- although there is significant heterogeneity in expression of PD-L1 within individuals. Drugs have been developed that target both the PD-L1 on the tumor cells and the PD-1 receptor on the T-cells. Nivolumab is the drug furthest along in the drug approval process that targets PD-1 on the T-cell. There have been significant responses to this agent among about 30% patients who had failed treatment with the targeted therapies and enrolled in the trials. Interestingly, responses were only seen in patients who had clear-cell RCC that expressed PD-L1. This response in patients who had failed the first-line targeted therapy shows promise for these novel agents. The heterogeneity of expression suggests it could play a future role in multimodal therapy.
Programmed Death Ligand 1 Inhibitors: Systemic Treatment of Renal Cell Carcinoma" from which this blog is inspired. Jason is looking forward to a career in urology.
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