The spontaneous remission of cancer: Current insights and therapeutic significance

Abstract

Many diseases heal spontaneously. The common cold, for example, remedies itself within a few days in people with an uncompromised immune system. If a disease with a poor prognosis heals in the absence of a targeted therapeutic, many even call it a miracle cure. Such is the case with the spontaneous regression (SR) of malignant neoplasms, a rare but well-documented phenomenon that finds its first mention in the Ebers Papyrus of 1550 BCE. Given the challenges associated with current cancer treatment modalities such as rapidly evolving drug resistance mechanisms, dose-limiting side effects, and a failure to completely eliminate cancer cells, knowledge of how a tumour heals itself would be immensely helpful in developing more effective therapeutic modalities. Although the intricate mechanisms of SR have yet to be fully elucidated, it has been shown that infection-mediated immune system activation, biopsy procedures, and disruptions of the tumour microenvironment play pivotal roles in the self-healing of many tumours. Bacterial and viral infections are especially well-documented in instances of SR. Insights from these findings are paving the way for novel therapeutic strategies. Inspired by bacteria-mediated SR, Bacillus Calmette-Guérin (BCG) has been used as an approved treatment option for non-muscle-invasive bladder cancer (NMIBC). Similarly, Talimogene laherparepvec (T-VEC), the first engineered oncolytic herpes simplex virus (HSV), has been approved by the United States Food and Drug Administration for the treatment of some forms of advanced melanoma. Here we describe the current understanding of SR, explore its therapeutic significance, and offer perspectives on its future.

Keywords: BCG; Oncolytic virus; Spontaneous regression; T-VEC; Tumour immunology.

Graphical abstract

Fig. 1

Spontaneous remission of cancer as reported over time. From its earliest mention in Ebers Papyrus to the development of nanobodies-delivering designer bacteria are shown.

Fig. 2

Postulated anti-tumour mechanism of BCG in non-muscle invasive bladder cancer. BCG gets internalized in the cancer cells of the urothelium and and in the antigen-presenting cells (APCs). The urothelial cells and the activated APCs present the BCG antigens on their surface, leading to cytokine/chemokine release and granuloma formation. These granulomas, comprising macrophages, dendritic cells (DCs), neutrophils, T cells, B cells, and fibroblasts, trigger innate and adaptive immune responses and destroy the cancer cells.

Fig. 3

Oncolytic viruses. Many OVs selectively replicate in cancer cells (cellular tropism) and lyse the cells. The resultant release of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) recruits and activates dendritic cells (DCs). DCs then migrate to lymph nodes and present the antigens to the T cells. These activated cytotoxic T cells undergo clonal expansion. They induce apoptosis in target cells via the release of perforin and granzymes.

Fig. 4

Possible mechanisms involved in SR of cancers. Factors that stimulate an immune response, including fever and infection, may promote SR. Similarly, disruption in the tumour microenvironment, biopsy and ablation procedures and the induction of cell death by various means, may also induce SR.