Complete clinical responses to cancer therapy caused by multiple divergent approaches: a repeating theme lost in translation

Abstract

Over 50 years of cancer therapy history reveals complete clinical responses (CRs) from remarkably divergent forms of therapies (eg, chemotherapy, radiotherapy, surgery, vaccines, autologous cell transfers, cytokines, monoclonal antibodies) for advanced solid malignancies occur with an approximately similar frequency of 5%–10%. This has remained frustratingly almost static. However, CRs usually underpin strong durable 5-year patient survival. How can this apparent paradox be explained? Over some 20 years, realization that (1) chronic inflammation is intricately associated with cancer, and (2) the immune system is delicately balanced between responsiveness and tolerance of cancer, provides a greatly significant insight into ways cancer might be more effectively treated. In this review, divergent aspects from the largely segmented literature and recent conferences are drawn together to provide observations revealing some emerging reasoning, in terms of “final common pathways” of cancer cell damage, immune stimulation, and auto-vaccination events, ultimately leading to cancer cell destruction. Created from this is a unifying overarching concept to explain why multiple approaches to cancer therapy can provide complete responses at almost equivalent rates. This “missing” aspect provides a reasoned explanation for what has, and is being, increasingly reported in the mainstream literature – that inflammatory and immune responses appear intricately associated with, if not causative of, complete responses induced by divergent forms of cancer therapy. Curiously, whether by chemotherapy, radiation, surgery, or other means, therapy-induced cell injury results, leaving inflammation and immune system stimulation as a final common denominator across all of these mechanisms of cancer therapy. This aspect has been somewhat obscured and has been “lost in translation” to date.

Keywords:

• chemotherapy
• immunotherapy
• immune response
• common pathways
• translational research
• oscillation
• regulatory T-cells
• immune modulation
• complete responses

Acknowledgments

The authors would like to thank Prof S Markovic, Mayo Clinic, MN; Prof A Dalgleish, St George’s Hospital, London; Prof M Lotze, Pittsburgh Cancer Institute, PA; Prof R Hawkins, Christie Hospital, Manchester, UK; Prof D Morton, John Wayne Cancer Institute, Santa Monica, CA; Prof A Cochran, Pathology, UCLA; and Dr R Neves and Dr J Drabick, Hershey Medical Centre, Hershey, PA, for broad and helpful discussions.

Disclosure

The authors declare no conflicts of interest with regard to the content of this paper.