Melanoma was one of the first cancers to benefit from the surge in immunotherapy research, however a number of other solid tumours are now also reaping the rewards.
The efficacy of immunotherapy drugs may be further enhanced through combining with epigenetic agents”
A huge step forward in the treatment of metastatic squamous non-small cell lung cancer (NSCLC) came with the FDA’s approval of Opdivo (nivolumab). Opdivo is a human IgG4 monoclonal antibody targeting PD-1 (programmed death receptor-1). The ligand for this receptor, PD-L1 (programmed cell death ligand 1) is overexpressed in approximately 20–65% of NSCLC cases and is associated with poorer overall survival. This receptor plays a key role in immune regulation and tumor immunity.
The efficacy of immunotherapy drugs may be further enhanced either through combining with epigenetic agents or pre-treating patients prior to the addition of an immunotherapy drug. In NSCLC, azacytidine (DNA methyltransferase inhibitor) can alter the expression of a number of immune-modulatory mediators in both the innate and adaptive immune systems, including PD-L1, and may be utilised as a basis for ‘priming’ for more effective checkpoint inhibitor treatment. This study followed from a trial by Juergens and colleagues which used azacytidine and entinostat (a synthetic benzamide derivative, which is a selective Class I HDAC inhibitor) in refractory advanced NSCLC. Six patients from this trial were enrolled in an additional trial with immune checkpoint inhibitors, with five patients developing responses.
A recent study by Kim et al. demonstrated that a combination of entinostat and 5-azacytidine with PD-1 and CTLA-4 (cytotoxic T-lymphocyte associated antigen 4; immune suppressor) cured 80% of mice in a metastatic breast cancer model. In fact, HDAC inhibition alone in combination with PD-1 and CTLA-4 antibodies resulted in 100% inhibition of both primary tumours and metastases (colorectal and breast murine model). The epigenetic mechanism involved the suppression of myeloid derived cells.
A phase II trial is now recruiting in lung cancer (NCT01928576) using azacytidine alone or in combination with entinostat prior to nivolumab (https://clinicaltrials.gov/ct2/show/NCT01928576). A number of other clinical trials are planned in lung cancer with various epigenetic agents and immunotherapies.