PD-1/PD-L1 in Chordoma
|Programmed Cell Death Protein 1 (PD-1) and its ligands PD-L1 and PD-L2 are part thought to play a role in suppressing the immune system. Tumor cells can exploit the PD-1 immune checkpoint pathway to evade immune cells that would normally attack them.
PD-1 proteins serve as receptors on the surface of T-cells (key players in immune response). When PD-L1 or PD-L2 binds to PD-1, it inactivates the T-cell and prevents it from attacking tumor cells. Ultimately, the interaction between PD-1 and its ligands serves to inhibit a host’s natural immune response to foreign antigens.
Expression of the PD-1/PD-L1 pathway has been implicated in the progression of a number of cancers, including both central nervous system tumors and solid tumors.1 2 Immune therapy strategies have been devised to break the interaction between the proteins, making cancer cells susceptible to attack by the cells of a host’s immune system. Immune therapy has received national attention as a possible breakthrough in cancer treatment.
Chordoma researchers have begun preliminary investigations of the PD-1/PD-L1 pathway in chordoma. Their findings are summarized below. Additional research is necessary to discern the role of immune inhibition in chordoma pathogenesis, and to explore whether a chordoma patient’s natural immune response could be harnessed to combat chordoma tumor cells.
- Expression of PD-L1 and PD-L2 at the mRNA level has been confirmed in chordoma cell lines U-CH1 and U-CH2. Expression is shown to be up-regulated by exposure to IFN-gamma, an inflammatory cytokine associated with immune response.1
- PD-L1 expression was significantly correlated with TNF-α and TNFR1 gene expression.3
- In one study 6 of 10 chordoma tumor samples analyzed showed infiltration of immune cells into chordoma tumors. In 3 of those 6, immune cells were found to express PD-1, and in 4 of 6 PD-L1 was expressed in membranous areas surrounding areas of tumor infiltration, though none of the samples showed robust expression.1 Another study found PD-1 and PD-L1 expressing tumor infiltrating lymphocytes in 22% and 11% of tumor samples tested, respectively.4
- In another study, 74 of 78 chordoma samples were positive for PD-L1 expression. Twenty-three of the 78 had tumor-infiltrating lymphocytes (TILs), and those samples had significantly higher PD-L1 expression than those without TILs.5 In a more recent study, 37 of 37 samples were positive for expression of both PD-1 and PD-L1, and 12 had TILs. Again, samples that expressed PD-L1 were more likely to have TILs, and PD-L1 was significantly associated with advanced stages of chordoma.6 7
- Chordoma cell lines U-CH1, U-CH2, and JHC7 showed variable, membranous expression of ligands PD-L1 and PD-L2 at basal levels. Exposure to IFN-gamma led to up-regulation of PD-L2 in all three lines but PD-L1 in only 2/3.1 A more recent study confirmed expression in U-CH1 and U-CH2 and demonstrated expression in cell line CH22. In this study, exposure to IFN-gamma led to up-regulation of PD-L1 in U-CH1 and U-CH2.5
- PD-1 and PD-L1 were measured in tumor-infiltrating lymphocytes (TILs) in 54 chordoma cases. PD-1+ TILs density in the tumor interior was associated with surrounding muscle invasion by tumor whereas PD-L1+ TILs were inversely associated with tumor pathological grade and stage. The density of PD-1+ TILs and PD-L1+ TILs in the tumor interior and invasion margin were significantly associated with local recurrence-free survival and overall survival.8
- Avelumab: Co-culture of 4 chordoma cell lines with brachyury-specific CD8+ cells increased PD-L1 expression on chordoma cells through the production of IFN-γ. The increase in PD-L1 expression subsequently increased the cells’ sensitivity to NK-mediated cell lysis via the anti-PD-L1 monoclonal antibody avelumab. This suggests that avelumab is capable of inducing antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing chordoma cells.9
- Pembrolizumab: A patient with fast growing tumors that had failed to respond to standard therapies was treated with the PD-1 targeting antibody Pembrolizumab (200mg), which led to rapid clinical improvement, shrinkage of tumor bulk, and control of disease for 6 months. A subcutaneous metastasis in the patient showed strong up regulation of PD-L1, while PD-1 was negative before and after immunotherapy.10
- Nivolumab: A patient who had undergone multiple surgeries and had been treated with imatinib and pazopanib was treated with the PD-1 targeting antibody Nivolumab (3mg/kg), which resulted in rapid major clinical improvement. The clinical response lasted 9 months before progression.10
Phase I Trial
- M7824 (MSB0011359C): M7824 is a bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to a TGF-β “trap”. Treatment of a chordoma patient with 20mg/kg M7824 resulted in early progression and drug discontinuation on day 85 followed by late-onset tumor shrinkage observed on day 280 despite no further therapeutic interventions after discontinuing M7824.11
Open Clinical Trials
The following clinical trials have been launched to explore whether PD-1 inhibitors are effective in treating chordoma patients. Visit our Clinical Trials page to view a list of other clinical trials available to chordoma patients and to find out who to contact if you wish to participate.
|NCT03173950||Phase II Trial of the Immune Checkpoint Inhibitor Nivolumab in Patients With Select Rare CNS Cancers||National Cancer Institute (Bethesda, MD)|
|NCT02989636||Phase I Study of Stereotactic Radiosurgery With Concurrent and Adjuvant PD-1 Antibody Nivolumab in Subjects With Recurrent or Advanced Chordoma||Johns Hopkins Hospital (Baltimore, MD) and Memorial Sloan Kettering Cancer Center (New York)|
|NCT03623854||A Signal Finding Phase 2 Study of Nivolumab (Anti-PD-1) and Relatlimab (Anti-LAG-3) in Patients With Advanced Chordoma||UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California|