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Simple Summary: Earlier diagnosis is often advocated to prevent advanced cancer morbidity and death. Compelling evidence exists where this occurs. A major conundrum is the lack of supportive evidence for some cancers where more sensitive screening and early detection may not translate into reduced morbidity and mortality. Some early cancers do not advance to metastases and death, and thus may not endanger the patient during life, nor require treatment. Biological variants that are non-metastatic and non-lethal may exist. Distinguishing potentially 'fatal' cancers from 'non-fatal' cancers is fundamental for screening to selectively benefit, while avoiding unnecessary treatment. Immune control of cancer has evidential support, and may explain why some cancers progress, while others stay quiescent. The extent of immune system modulation of malignant behaviour could decisively influence cancer outcomes, including lethality. We advance an evidence-based, immune model, worthy of further research, potentially explaining cancer "overdiagnosis" and the susceptibility to recurrence, regression, and lethality. Even though clinically small 'early' cancers represent many millions of cells biologically, when removed surgically, these often never recur or regrow, nor reduce the individual's lifespan. However, some early cancers remain quiescent and indolent; while others grow and metastasize, threatening life. Distinguishing between these different clinical behaviours using clinical/pathological criteria is currently problematic. It is reported that many suspicious lesions and early cancers are being removed surgically that would not threaten the patient's life. This has been termed 'overdiagnosis', especially in the sphere of cancer screening. Although a controversial and emotive topic, it poses clinical and public health policy challenges. The diagnostic differentiation between 'non-lethal' and 'lethal' tumor forms is generally impossible. One perspective gathering evidential support is that a dynamic balance exists between the immune response and malignant processes governing 'lethality', where many more cancers are produced than become clinically significant due to the immune system preventing their progression. Higher medical screening "diagnosis" rates may reflect lead-time effects, with more 'non-progressing' cancers detected when an early immune-cancer interaction is occurring. We present a model for this immune-cancer interaction and review 'excess' or 'overdiagnosis' claims that accompany increasingly sensitive diagnostic and screening technologies. We consider that immune tools should be incorporated into future research, with potential for immune system modulation for some early cancers. [ABSTRACT FROM AUTHOR]

Vaccination, as a public health measure, offers effective protection of populations against infectious diseases. Optimising vaccination efficacy, particularly for higher-risk individuals, like the elderly whose immunocompromised state can prevent the development of robust vaccine responses, is vital. It is now clear that 24-hour circadian rhythms, which govern virtually all aspects of physiology, can generate oscillations in immunological responses. Consequently, vaccine efficacy may depend critically on the time of day of administration(s), including for Covid-19, current vaccines, and any future diseases or pandemics. Published clinical vaccine trials exploring diurnal immune variations suggest this approach could represent a powerful adjunct strategy for optimising immunisation, but important questions remain to be addressed. This review explores the latest insights into diurnal immune variation and the outcomes of circadian timing of vaccination or ‘chronovaccination’. [ABSTRACT FROM AUTHOR]

Background: This year marks the twentieth anniversary of the approval by the US Food and Drug Administration of interleukin-2 (IL2) for use in cancer therapy, initially for renal cell carcinoma and later for melanoma. IL2 therapy for cancer has stood the test of time, with continued widespread use in Europe, parts of Asia, and the US. Clinical complete responses are variably reported at 5%-20% for advanced malignant melanoma and renal cell carcinoma, with strong durable responses and sustained long-term 5-10-year survival being typical if complete responses are generated. Methods: The literature was reviewed for the actions and clinical effects of IL2 on subsets of T cells. The influence of IL2 on clinical efficacy was also sought. Results: The review revealed that IL2 is capable of stimulating different populations of T cells in humans to induce either T effector or T regulatory responses. This apparent "functional paradox" has confounded a clear understanding of the mechanisms behind the clinical effects that are observed during and following administration of IL2 therapy. An average complete response rate of around 7% in small and large clinical trials using IL2 for advanced renal cell carcinoma and malignant melanoma has been shown from a recent review of the literature. Conclusion: This review considers the published literature concerning the actions and emerging clinical effects of IL2 therapy, spanning its 20-year period in clinical use. It further details some of the recently described "bimodal" effects of IL2 to explain the apparent functional paradox, and how IL2 might be harnessed to emerge rapidly as a much more effective and predictable clinical agent in the near future. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]