Monday, July 21, 2014

Systemic Treatment of Renal Cell Carcinoma: Programmed Death Ligand 1 Inhibitors

Greater than 80% of renal tumors are renal cell carcinoma (RCC), of which about 70% is of clear-cell pathology.[1]   There are about 64,000 new RCC cases and 14,000 deaths from RCC each year, but due to increased imaging it is thought that we are catching these cancers at an earlier stage, when they are still resectable.  Unfortunately, mortality rates have not decreased and the burden of metastatic disease persists.[2]  Twenty to thirty percent of patients present with metastatic cancer and 20-30% of patients who have resectable disease later return with systemic disease following surgical management, whether it be partial or radical nephrectomy.[3,4] This underscores the necessity of management options outside of surgery.

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.[5]  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.[8]

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).
If the T-cell identifies a tumor cell, it will not get the normal signal that it is a healthy cell, the T-cell can initiate processes to kill the tumor cell (Figure 2).
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).[9]
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.[10]    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.[11] 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.

This blog was written by Jason Cohen, Medical Student at Johns Hopkins Medical School.  Jason recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "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.

[1]  Siegel R et al. CA Cancer J Clin 2014; 64:9.
[2]  Hollingsworth et al. J Natl Cancer Inst. 2006; 98:1331
[3]  Curti B et al. J Am Med Assoc 2004; 292: 97
[4]  Levi D et al. J Urol 1998; 159: 1163
[5]  Chung EK et al. Am J Clin Oncol 2011; 34: 150
[6]  Oliver RT et al. Br J Urol 1989; 63: 128
[7]  Vogelzang NJ et al. J Urol 1992; 148: 1247
[8]  Rini BI et al. Lancet 2009; 373: 1119
[9]  Dong H et al. Nat Med 2002; 8: 793
[10]  Thompson RH et al. PNAS 2004; 101: 17174
[11]  Topalian SL et al. N Engl J Med 2012; 366: 2443


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