Knocking out cancer with a one-two punch

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.

By Dr Mark Chao,

Dr Ranjana H. Advani and Dr Jens Peter Volkmer


ver 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 revolu- tionised 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 box- ing, 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 mark- ing cancer cells to be destroyed by the innate immune system. However, antibody therapy only works against cancers that display specific anti- gens, limiting their effectiveness. The second wave of immunotherapies were T-

cell 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 check- point inhibitors can induce long-term responses in some patients with difficult-to-treat cancers, including melanoma, bladder cancer and non- small 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 pre- existing activated T-cell response. We are now in the third wave of immunothera-

pies, where treatments in development seek to inte- grate 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. First, innate immune cells recognise general pat-

terns of abnormality and foreignness rather than highly-specific antigens. So they respond to, and

Drug Discovery World Spring 2019

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