Improving lung cancer immunotherapy using epigenetic approaches

Immunotherapy of cancer has advanced in leaps and bounds in recent years. In this guest blog, Anne Marie-Baird provides an update on some of the most important lung cancer immunotherapy clinical trials using epigenetic drugs.

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.

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