The failure of radical treatments to cure cancer: can less deliver more?

Abstract

All too often attempts to deliver improved cancer cure rates by increasing the dose of a particular treatment are not successful enough to justify the accompanying increase in toxicity and reduction in quality of life suffered by a significant number of patients. In part, this drive for using higher levels of treatment derives from the nature of the process for testing and incorporation of new protocols. Indeed, new treatment regimens must now consider the key role of immunity in cancer control, a component that has been largely ignored until very recently. The recognition that some drugs developed for cytotoxicity at higher doses can display alternative anticancer activities at lower doses including through modulation of immune responses is prompting a significant re-evaluation of treatment protocol development. Given that tumours are remarkably heterogeneous and with inherent genetic instability it is probably only the adaptive immune response with its flexibility and extensive repertoire that can rise to the challenge of effecting significant control and ultimately elimination of a patient’s cancer. This article discusses some of the elements that have limited higher levels of treatment outcomes and where too much proved less effective. We explore observations that less can often be as effective, if not more effective especially with some chemotherapy regimens, and discuss how this can be exploited in combination with immunotherapies to deliver nontoxic improved tumour responses.

Why do the majority of patients not respond at all, or only partially or transiently, to immunotherapy?

“…Thus, the importance is the sequence of these interventions, as opposed to combinations [17], as well as the doses where more is not always better, a situation that has not been fully explored with CPIs, given that overweight patients seem to do better with CPIs in a number of cancer types, compared to their non-overweight counterparts [18].…”

Harnessing immunity for therapy in human papillomavirus driven cancers

“…Myeloid cells are key players in the orchestration of the immunosuppression blocking effective natural immunity and immunotherapy development [ 57 ]. Likewise, the impact of the current standard of care treatments (radiation and/or chemotherapy), either positive or negative, on natural or therapy induced tumour immunity must also be considered [ 58 ]. It is clearly immensely challenging to document the precise combination of resistance mechanisms for every individual tumour in order to configure the most appropriate immune treatment options.…”

Opportunities to improve immune-based prevention of HPV-associated cancers

“…However, the influences of local and systemic immune suppressive factors remain significant hurdles to efficacy, especially in more advanced disease. Novel strategies for targeting such immunosuppressive components, including a reevaluation of the functions of standard of care treatments in this context, are being investigated to provide for the maximum impact in tandem with therapeutic HPV vaccination [15].…”