Immune consequences of kinase inhibitors in development, undergoing clinical trials and in current use in melanoma treatment

Abstract

Metastatic malignant melanoma is a frequently fatal cancer. In recent years substantial therapeutic progress has occurred with the development of targeted kinase inhibitors and immunotherapeutics. Targeted therapies often result in rapid clinical benefit however responses are seldom durable. Immune therapies can result in durable disease control but responses may not be immediate. Optimal cancer therapy requires both rapid and durable cancer control and this can likely best be achieved by combining targeted therapies with immunotherapeutics. To achieve this, a detailed understanding of the immune consequences of the various kinase inhibitors, in development, clinical trial and currently used to treat melanoma is required.

Keywords::

• combination therapy
• immunotherapy
• kinase inhibition
• MAPK
• melanoma
• PI3K/AKT/mTOR
• RAF
• signaling

Financial & competing interests disclosure

Operational Infrastructure Support Program funding was provided by the Victorian Government of Australia. J Cebon has received honoraria from speakers’ bureau and is a consultant/advisory board member of GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• In order to treat melanoma more effectively, there is a need to widen the range of targets in order to prolong the duration of response, overcome or prevent resistance and to target other oncogenic drivers.

• Combining MEK and BRAF inhibitors results in longer responses and acceptable toxicity, suggesting other combinations may also extend the duration of benefit.

• BRAF inhibition is associated with a variety of immune-related changes in treated melanoma patients, such as an increase in tumor infiltrating lymphocyte counts and tumor antigen expression, providing a rationale for combination therapy.

• Immunotherapies are effective and may induce durable responses. Strategies for combination with targeted therapies are being developed.

• When combining kinase inhibitors, the safety and effects of kinase inhibitors on immune cell function need consideration, since immunotherapy enhances immune cell function and poses the potential for the interaction to enhance both anti-tumor efficacy and toxicity. It will be critical to evaluate schedule and dosing strategies.

• MEK inhibition has variable effects on immune cells and notably suppressive effects on isolated immune cells. On balance, however, clinical experience has shown benefit. Nonetheless, careful evaluation of immune function is warranted in the clinical trial setting.

• In addition to the MAPK pathway, alternate signaling pathways, such as the PI3K/mTOR/AKT pathway are active in malignant melanoma, particularly when resistance to BRAF inhibitors develops. Drugs are being evaluated against components of these signaling pathways. While relevant targets in a subset of malignant melanomas, these pathways are also associated with immune cell signaling. As combinations with these agents are developing, it will be important to evaluate their effects on immune cells, particularly those combinations including immunotherapeutics.