Knocking Out Cancer With a One-Two Punch
Immunotherapy - Knocking Out Cancer With a One-Two Punch

Immunotherapy - Knocking Out Cancer With a One-Two Punch

By Dr Mark Chao, et al.
Spring 2019

New immunotherapies that integrate innate and adaptive immune responses may increase efficacy against many cancers, and have the potential to expand the range of tumours and patients that can be treated with immunotherapy.

Over the past decade, insights into the molecular mechanisms that cancer cells use to evade T-cells, antibodies/B cells and other adaptive immune defences have revolutionised oncology therapies. New understandings of how cancer evades innate immune defences – including macrophages, dendritic cells (DC) and Natural Killer (NK) cells – suggest a second, and perhaps even more significant, immunotherapy revolution may be at hand.

Recent preclinical and early clinical studies demonstrate that targeting molecular mechanisms that many cancer cells use to block macrophages and other innate immune cells from attacking may be effective against a wide range of cancers. Moreover, research suggests that therapies, which mobilise innate and adaptive immune responses, may be more effective when combined rather than used separately.

It is as though we have been fighting cancer with one hand tied behind our backs. Much as in boxing, where quick left-hand jabs open space for a decisive right-cross knockout, these studies suggest that a treatment plan that combines the two halves of the immune system work better than they do individually.

The opportunities for addressing unmet patient needs are profound, as are the commercial prospects for pioneers exploring this new immunotherapy frontier.

Cancer in the corner: broadening immunotherapy targets

The first wave of immunotherapies developed to treat cancer were monoclonal antibodies. These antibodies bind to antigens on the surface of tumour cells, such as HER2 on breast cancer, therefore inhibiting receptor signalling and marking cancer cells to be destroyed by the innate immune system. However, antibody therapy only works against cancers that display specific antigens, limiting their effectiveness.

The second wave of immunotherapies were Tcell checkpoint inhibitors that bind to molecules, such as PD-L1, and are responsible for creating an immunosuppressive microenvironment in tumours. Inhibiting these effects restores the responsiveness of tumours to T-cells. In doing so, T-cell checkpoint inhibitors can induce long-term responses in some patients with difficult-to-treat cancers, including melanoma, bladder cancer and nonsmall cell lung cancer.

However, T-cell checkpoint inhibitors do not work in all tumours. Also, since T-cell checkpoint inhibitors work by ‘taking the brakes off’ T-cells, they are only effective in patients who have a preexisting activated T-cell response.

We are now in the third wave of immunotherapies, where treatments in development seek to integrate the innate and adaptive immune systems. Research shows that macrophages and other cells of the innate immune system help fight cancer in two major ways – and both potentially broaden and strengthen the body’s overall anti-cancer immune response.

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