The mechanisms most-often implicated in driving the spontaneous regression of cancer are thought to be mediated by immune system activation (or reactivation). Sometimes the driving force is an acute intercurrent bacterial or viral infection. Initiated by the work of Dr Lloyd Old, the founder of modern cancer immunology, the US Food and Drug Administration (FDA) in 1990 approved the first bacterial immunotherapy, Bacillus Calmette-Guerin (BCG), for in situ bladder cancer. More recently the FDA approved T-Vec [talimogene laherparepvec], a viral vaccine used to evoke an immune response in patients with advanced melanoma.27-29 

The development of other viral and bacterial vectors is an active area of new drug development, with further success anticipated.30,31 The recent approval of checkpoint inhibitors against an array of cancers and chimeric antigen receptor (CAR)-T cell therapy are testimonies to the power of the immune system, when it awakes from its slumber, to simulate a process historically regarded as “miraculous.”32,33

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The immuno-editing theory proposed by Drs Robert Schreiber, Mark Smyth, and Lloyd Old has helped to refine medical understanding of spontaneous regression, which may be seen as the interplay of cancer undergoing incomplete elimination, equilibrium, and escape.34 Under ideal conditions the innate and adaptive elements of the immune system work in concert to eliminate the cancer (often imperfectly) with regulatory (CD4+) and cytotoxic (CD8+) T cells, dendritic (or antigen presenting cells), natural killer (NK) cells, and macrophages along with a host of immune-activating secreted proteins such as interferon gamma, interleukin 12, and tumor necrosis factor (TNF) all working in harmony. Spontaneous regression may in some cases be a manifestation of this dynamic process, and immunoediting fits well into observations that most cancers that undergo spontaneous regression recur, sometimes years later.

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Another example of this phenomenon can be seen with the so-called abscopal (or out-of-field) effects of radiation therapy, which causes the immune system to mount a systemic response to distant metastases.35

I expect that in the future, as our understanding of cancer immunity matures, the fascinating phenomenon of spontaneous regression will help guide us towards developing the safest and most effective drugs — which may ultimately lead to effective control of this devastating disease.


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