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

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

Detection of T cell cytokine production as a tool for monitoring immunotherapy

There are many complex relationships between tu- mour cells and effector cells in the immune system. These interactions are controlled predominantly by cy- tokines, either within the tumour environment, or sys- temically where the effector cells may be stimulated as a response to the presence of the tumour. Favourable clinical responses in cancer patients have been shown to be associated with enhanced cell-mediated immunity as well as T cell infiltration in tumours. This status is controlled in part by a predominantly Th1 cytokine profile e.g. IFN γ , TNF α and IL-12. Conversely, pa- tients with advancing cancer may have impaired cell- mediated immunity as a result of an imbalance of Th1 and Th2 cytokines e.g. IL-4 and IL-10 [6,9,15]. Whilst cytokines have long been known to orchestrate the im- mune system by allowing communication between reg- ulatory and effector cells, the pleiotropic nature of these molecules results in a very complex environment in which to study any single molecule’s properties. Several in vitro protocols have been developed,which aim to closely reflect cytokine production and T cell function in vivo. However, these assays have been developed in artificial settings and as such only allow conclusions to be drawn within a defined context [11]. The aim of this report is to outline the basic proto-cols and applications for the detection of intracellular cytokines by flow cytometry, in the context of disease monitoring

Enhanced effect of checkpoint inhibitors when given after or together with IMM-101: significant responses in four advanced melanoma patients with no additional major toxicity

Background The use of checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) has revolutionised the treatment of metastatic melanoma. However still more than the half the patients do not respond to single-agent immunotherapy. This has led to the development of combining these agents in an attempt to enhance the anti-cancer activity. More than 300 different studies with 15 different drug doses are currently ongoing. Combining different checkpoint inhibitors (CPIs) does indeed lead to an increase in response rate, but this is associated with significant toxicity. IMM-101 is a heat killed Mycobacterium preparation which induces marked immune modulation and little systemic toxicity. It has been reported as having activity in melanoma as single agent and in pancreatic cancer in combination with gemcitabine, the latter in a randomised study. Methods Here we report the effect of adding CPIs to 3 patients who had previously been on IMM-101, either as a trial or a named patient programme and a patient who received the IMM-101 together with nivolumab. Results All 4 patients had rapid and very good responses, three of them maintained over 18 months with no significant additional toxicity. Conclusions The rapid and complete clinical responses seen in these patients may suggest that IMM-101 is activating a complementary pathway which is synergistic with CPI treatment

Biovacc-19: A Candidate Vaccine for Covid-19 (SARS-CoV-2) Developed from Analysis of its General Method of Action for Infectivity

This study presents the background, rationale and method of action of Biovacc-19, a candidate vaccine for corona virus disease 2019 (Covid-19), now in advanced preclinical development, which has already passed the first acute toxicity testing. Unlike conventionally developed vaccines, Biovacc-19’s method of operation is upon nonhuman-like (NHL) epitopes in 21.6% of the composition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)’s spike protein, which displays distinct distributed charge including the presence of a charged furin-like cleavage site. The logic of the design of the vaccine is explained, which starts with empirical analysis of the aetiology of SARS-CoV-2. Mistaken assumptions about SARS-CoV-2’s aetiology risk creating ineffective or actively harmful vaccines, including the risk of antibody-dependent enhancement. Such problems in vaccine design are illustrated from past experience in the human immunodeficiency viruses domain. We propose that the dual effect general method of action of this chimeric virus’s spike, including receptor binding domain, includes membrane components other than the angiotensin-converting enzyme 2 receptor, which explains clinical evidence of its infectivity and pathogenicity. We show the nonreceptor dependent phagocytic general method of action to be specifically related to cumulative charge from insertions placed on the SARS-CoV-2 spike surface in positions to bind efficiently by salt bridge formations; and from blasting the spike we display the NHL epitopes from which Biovacc-19 has been down-selected

Development and application of two novel monoclonal antibodies against overexpressed CD26 and integrin α3 in human pancreatic cancer.

Monoclonal antibody (mAb) technology is an excellent tool for the discovery of overexpressed cell surface tumour antigens and the development of targeting agents. Here, we report the development of two novel mAbs against CFPAC-1 human pancreatic cancer cells. Using ELISA, flow cytometry, immunoprecipitation, mass spectrometry, Western blot and immunohistochemistry, we found that the target antigens recognised by the two novel mAbs KU44.22B and KU44.13A, are integrin α3 and CD26 respectively, with high levels of expression in human pancreatic and other cancer cell lines and human pancreatic cancer tissue microarrays. Treatment with naked anti-CD26 mAb KU44.13A did not have any effect on the growth and migration of cancer cells nor did it induce receptor downregulation. In contrast, treatment with anti-integrin α3 mAb KU44.22B inhibited growth in vitro of Capan-2 cells, increased migration of BxPC-3 and CFPAC-1 cells and induced antibody internalisation. Both novel mAbs are capable of detecting their target antigens by immunohistochemistry but not by Western blot. These antibodies are excellent tools for studying the role of integrin α3 and CD26 in the complex biology of pancreatic cancer, their prognostic and predictive values and the therapeutic potential of their humanised and/or conjugated versions in patients whose tumours overexpress integrin α3 or CD26

Long-term benefit from immune modulation and anti-inflammatory treatment in metastatic mesothelioma.

A 64 year old male heating engineer was investigated for a persistent cough and found to have epithelioid mesothelioma with pleural effusion, lung nodules and increased thoracic lymph nodes. He declined standard of care treatment following his own research and he was enrolled in a named patient programme of IMM-101. He was advised to correct his low vitamin D3 level and to start using anti-inflammatories such as aspirin, bromelain and low dose Naltrexone. At review one year later a CT scan showed no change and he continued on the regimen. Four years after the diagnosis a CT scan showed that there was a modest but definite progression of the left malignant pleural thickening, and a new right-sided effusion, enlargement of several intrathoracic nodes which had been noted on the early scans. The chest wall lump eventually broke down and required local radiotherapy. He then developed abdominal pain and found to have peritoneal disease. Last year he obtained the cannabinoids CBD and THC which slowed down the disease and a CT scan after he had been on this for six months, showed that his disease was fairly stable with marginal progression

Mitigating Coronavirus Induced Dysfunctional Immunity for At-Risk Populations in COVID-19: Trained Immunity, BCG and "New Old Friends".

The novel, highly contagious coronavirus SARS-CoV-2 spreads rapidly throughout the world, leading to a deadly pandemic of a predominantly respiratory illness called COVID-19. Safe and effective anti-SARS-CoV-2 vaccines are urgently needed. However, emerging immunological observations show hallmarks of significant immunopathological characteristics and dysfunctional immune responses in patients with COVID-19. Combined with existing knowledge about immune responses to other closely related and highly pathogenic coronaviruses, this could forebode significant challenges for vaccine development, including the risk of vaccine failure. Animal data from earlier coronavirus vaccine efforts indicate that elderly people, most at risk from severe COVID-19 disease, could be especially at risk from immunopathologic responses to novel coronavirus vaccines. Bacterial "new old friends" such as Bacille Calmette-Guérin (BCG) or Mycobacterium obuense have the ability to elevate basal systemic levels of type 1 cytokines and immune cells, correlating with increased protection against diverse and unrelated infectious agents, called "trained immunity." Here we describe dysfunctional immune responses induced by coronaviruses, representing potentially difficult to overcome obstacles to safe, effective vaccine development for COVID-19, and outline how trained immunity could help protect high risk populations through immunomodulation with BCG and other "new old friends.

Naltrexone at low doses (LDN) and its relevance to cancer therapy.

INTRODUCTION: Naltrexone was designed to inhibit opioid receptors without activating them and hence used to block the stimulatory effects of morphine and heroin. It was noted that in certain patients being treated with naltrexone for an opioid addiction many reported significant secondary benefit when being weaned off naltrexone. This group of patients had chronic inflammatory and autoimmune conditions and reported improvements whilst using the lower dosages of naltrexone. There have also been recent anecdotal reports of cancer resolution following the use of low doses of naltrexone (LDN). However, the mechanism of action is unclear. AREAS COVERED: We review three mechanisms through which LDN can influence cancer progression; namely, (a) antagonism of receptors to which LDN binds, which include toll-like receptors 7-9 that lead to IL-6 suppression b) modulation of immune function in patients; and c) direct inhibition of signaling pathways involved in cancer cell control, including the priming of pro-apoptotic pathways. EXPERT OPINION: Considering the increase in the number of anecdotal reports of activity, there will likely be a bigger drive toward using LDN in the oncological setting. These reports support clinical trials of LDN in cancer, especially when given in combination with certain chemotherapy