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In this White Paper, we discuss the current state of microbial cancer therapy. This paper resulted from a meeting (‘Microbial Based Cancer Therapy’) at the US National Cancer Institute in the summer of 2017. Here, we define ‘Microbial Therapy’ to include both oncolytic viral therapy and bacterial anticancer therapy. Both of these fields exploit tumor-specific infectious microbes to treat cancer, have similar mechanisms of action, and are facing similar challenges to commercialization. We designed this paper to nucleate this growing field of microbial therapeutics and increase interactions between researchers in it and related fields. The authors of this paper include many primary researchers in this field. In this paper, we discuss the potential, status and opportunities for microbial therapy as well as strategies attempted to date and important questions that need to be addressed. The main areas that we think will have the greatest impact are immune stimulation, control of efficacy, control of delivery, and safety. There is much excitement about the potential of this field to treat currently intractable cancer. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other biological or small molecule drugs. By better understanding and controlling these mechanisms, we will create new therapies that will become integral components of cancer care.

Current ulcerative colitis (UC) treatments are focused on symptom management primarily via immune suppression. Despite the current arsenal of immunosuppressant treatments, the majority of patients with UC still experience disease progression. Importantly, aggressive long-term inhibition of immune function comes with consequent risk, such as serious infections and malignancy. There is thus a recognized need for new, safe and effective treatment strategies for people living with UC that work upstream of managing the symptoms of the disease. The objective of this study was to evaluate a microbial-based treatment, QBECO, that functions to productively activate rather than suppress mucosal immune function as a novel approach to treat UC. Two established models of experimental colitis, namely chemically-induced DSS colitis and the spontaneous colitis that develops in deficient mice, were used to assess whether QBECO treatment could ameliorate gastrointestinal disease. A small exploratory 16-week QBECO open-label trial was subsequently conducted to test the safety and tolerability of this approach and also to determine whether similar improvements in clinical disease and histopathology could be demonstrated in patients with moderate-to-severe UC. QBECO treatment successfully reduced inflammation and promoted mucosal and histological healing in both experimental models and in UC patients. The preclinical models of colitis showed that QBECO ameliorated mucosal pathology, in part by reducing inflammatory cell infiltration, primarily that induced by neutrophils and inflammatory T cells. The most rapid and noticeable change observed in QBECO treated UC patients was a marked reduction in rectal bleeding. Collectively, this work demonstrates for the first time that strategically activating immune function rather than suppressing it, not only does not worsen colitis induced-damage, but may lead to an objective reduction in UC disease pathology.

Background Cigarette smoke exposure is the major risk factor for developing COPD. Presently, available COPD treatments focus on suppressing inflammation and providing bronchodilation. However, these options have varying efficacy in controlling symptoms and do not reverse or limit the progression of COPD. Treatments strategies using bacterial-derived products have shown promise in diseases characterized by inflammation and immune dysfunction. This study investigated for the first time whether a novel immunotherapy produced from inactivated Klebsiella (hereafter referred to as KB) containing all the major Klebsiella macromolecules, could attenuate cigarette smoke exposure-induced immune responses. We hypothesized that KB, by re-directing damaging immune responses, would attenuate cigarette smoke-induced lung inflammation and bronchoalveolar (BAL) cytokine and chemokine production. Methods KB was administered via a subcutaneous injection prophylactically before initiating a 3-week acute nose-only cigarette smoke exposure protocol. Control mice received placebo injection and room air. Total BAL and differential cell numbers were enumerated. BAL and serum were analysed for 31 cytokines, chemokines, and growth factors. Lung tissue and blood were analysed for Ly6C HI monocytes/macrophages and neutrophils. Body weight and clinical scores were recorded throughout the experiment. Results We demonstrate that KB treatment attenuated cigarette smoke-induced lung inflammation as shown by reductions in levels of BAL IFNγ, CXCL9, CXCL10, CCL5, IL-6, G-CSF, and IL-17. KB additionally attenuated the quantity of BAL lymphocytes and macrophages. In parallel to the attenuation of lung inflammation, KB induced a systemic immune activation with increases in Ly6C HI monocytes/macrophages and neutrophils. Conclusions This is the first demonstration that subcutaneous administration of a microbial-based immunotherapy can attenuate cigarette smoke-induced lung inflammation, and modulate BAL lymphocyte and macrophage levels, while inducing a systemic immune activation and mobilization. These data provide a foundation for future studies exploring how KB may be used to either reverse or prevent progression of established emphysema and small airways disease associated with chronic cigarette smoke exposure. The data suggest the intriguing possibility that KB, which stimulates rather than suppresses systemic immune responses, might be a novel means by which the course of COPD pathogenesis may be altered.

Current Crohn's disease (CD) therapies focus on suppressing immune function and come with consequent risk, such as infection and cancer. Notwithstanding, most CD patients still experience disease progression. There is a need for new CD treatment strategies that offer better health outcomes for patients. To assess safety, efficacy, and tolerability of a novel microbial-derived immunotherapy, QBECO, that aims to restore rather than suppress immune function in CD. A randomized, double-blind, placebo-controlled trial was conducted in 68 patients with moderate-to-severe CD. Primary endpoints: safety and Week 8 clinical improvement. Secondary endpoints: Week 8 clinical response and remission. Week 8 responders continued blinded treatment through Week 16; non-responders received open-label QBECO from Weeks 9-16. Exploratory analyses included immune biomarker and genotype assessments. QBECO was well-tolerated. Mean reduction in Crohn's Disease Activity Index (CDAI) score was -68 for QBECO vs. -31 for placebo at Week 8. Improvement with QBECO continued through Week 16 (-130 CDAI reduction). Week 8 QBECO clinical response, improvement and remission rates were 41.2%, 32.4%, 29.4% vs. 26.5%, 23.5%, 23.5% for placebo. TNFα inhibitor-naïve subjects achieved higher response rates at Week 8 with QBECO (64%) vs. placebo (26%). Specific immune biomarkers were identified that linked to QBECO response. This proof-of-concept study supports further investigation for the use of QBECO as a novel immunotherapy approach for CD. Biomarker analyses suggests it may be feasible to personalize CD treatment with QBECO. Larger trials are now needed to confirm clinical improvement and the unique biological findings. NCT01809275 (https://clinicaltrials.gov/ct2/show/NCT01809275).

We investigated the mechanism of action, safety, and efficacy of the Site-Specific Immunomodulator (SSI) QBECO, a novel immunotherapy for Crohn’s disease (CD). Using human monocytic THP-1 cells, we demonstrate that SSI QBECO (derived from the common colon bacteria E. coli) activates macrophages to an M1 phenotype (associated with enhanced capacity to eliminate bacteria and activate innate immune responses). We assessed SSI QBECO in a compassionate use protocol of ten adult patients with active CD. Patients with moderate to severe clinical symptoms receiving conventional CD treatments and/or complementary therapies were included, except patients receiving anti-TNF medications. SSI QBECO was self-administered subcutaneously every second day, for a minimum of 2.5 months and a maximum of 11 months. All 10 patients reported improvement of symptoms while on the SSI QBECO treatment. Seven patients reported full resolution of clinical symptoms during a course of SSI QBECO of at least three months. Three patients have experienced ongoing sustained clinical remission after discontinuing all medications, including SSI treatment. The longest case of clinical remission is still ongoing (>4 years). No serious severe adverse clinical events were reported. Collectively, we conclude that treatment with the immunoactive SSI QBECO was well tolerated and effective for treatment of Crohn’s disease in this case series.

Recent developments in understanding how the functional phenotype of the innate immune system is programmed has led to paradigm-shifting views on immunomodulation. These advances have overturned two long-held dogmas: (1) only adaptive immunity confers immunological memory; and, (2) innate immunity lacks specificity. This work describes the observation that innate immune effector cells appear to be differentially recruited to specific pathological sites when mobilized by distinct inactivated bacterial-based stimuli administered subcutaneously. The studies presented suggest that the immune system, upon detecting the first signs of a potential infection by a specific pathogen, tends to direct its resources to the compartment from which that pathogen is most likely originating. The findings from this work puts forth the novel hypothesis that the immunotherapeutic efficacy of a microbial-based stimulus for innate immune mobilization depends on the correct selection of the microbial species used as the stimulant and its relationship to the organ in which the pathology is present.

There is an unmet need for effective new and innovative treatments for asthma. It is becoming increasingly evident that bacterial stimulation can have beneficial effects at attenuating allergic airway disease through immune modulation. Our aim was to test the ability of a novel inactivated microbe-derived therapeutic based on Klebsiella (KB) in a model of allergic airway disease in mice. BALB/c mice were exposed intranasally to house dust mite (HDM) for two weeks. Mice were treated prophylactically via subcutaneous route with either KB or placebo for one week prior to HDM exposure and throughout the two week exposure period. 24 hours after the last exposure, lungs were analysed for inflammatory cell infiltrate, gene expression, cytokine levels, goblet cell metaplasia, and serum was analysed for allergen-specific serum IgE levels. HDM exposed mice developed goblet cell hyperplasia, elevated allergen-specific serum IgE, airway eosinophilia, and a concomitant increase in T H 2 cytokines including IL-4, IL-13 and IL-5. Treatment with KB attenuated HDM-mediated airway eosinophilia, total bronchoalveolar lavage (BAL) cell numbers, BAL T H 2 cytokine production, and goblet cell metaplasia. Our prophylactic intervention study illustrates the potential of subcutaneous treatment with bacterial derived biologics as a promising approach for allergic airway disease treatment.

Margaret A. White1, Marja J. Verhoef2, B.J. Davison3, Hal Gunn4 and Karen Cooke5 1Research Associate, University of Calgary, Calgary, Alberta, Canada. 2Department of Community Health Sciences, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. 3Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. 4InspireHealth, Vancouver, Canada. 5Research Consultant, Vancouver, Canada. Abstract Little is known about men with prostate cancer who decline conventional treatment and use only complementary and alternative medicine (CAM). Objectives: To 1) explore why men decline conventional prostate cancer treatment and use CAM 2) understand the role of holistic healing in their care, and 3) document their recommendations for health care providers. Methods: Semi-structured interviews and follow-up focus groups. Sample: Twenty-nine men diagnosed with prostate cancer who declined all recommended conventional treatments and used CAM. Results: Based on strong beliefs about healing, study participants took control by researching the risks of delaying or declining conventional treatment while using CAM as a first option. Most perceived conventional treatment to have a negative impact on quality of life. Participants sought healing in a broader mind, body, spirit context, developing individualized CAM approaches consistent with their beliefs about the causes of cancer. Most made significant lifestyle changes to improve their health. Spirituality was central to healing for one-third of the sample. Participants recommended a larger role for integrated cancer care. Conclusion: Men who decline conventional prostate cancer treatment and use CAM only may benefit from a whole person approach to care where physicians support them to play an active role in healing while carefully monitoring their disease status.

Abstract Introduction Current therapies for inflammatory bowel disease (IBD) are aimed at immune suppression. These have not prevented disease progression for the majority of IBD patients and come with consequent risk. There is a recognized need for new, safe and effective treatment for IBD. QBECO is a novel microbial-based immunotherapy designed to stimulate the immune response to overcome immune dysfunction in the gastrointestinal tract. QBECO has previously shown promising results in a randomized double-blind placebo controlled phase 2 clinical trials in Crohn's disease (CD; NCT01809275). These findings were followed-up with a phase 2 open-label trial in ulcerative colitis (UC) to assess endoscopic and histological improvement (NCT02426372). Methods An open-label phase 2 trial was conducted with 11 patients with moderate-to-severe UC. QBECO was self-administered subcutaneously every second day throughout the 16 weeks. Endoscopic and histological assessment was measured at screening, week 8 and week 16. QBECO responders were defined as having a decrease in Mayo score (composite of endoscopic healing, rectal bleeding, stool frequency and global physician's assessment) of 3 or more points. Results 7 of 11 patients (63.6%) responded to QBECO and 1 patient (9.1%) was in clinical remission by week 16. For the individual Mayo sub scores, at least a one point improvement was seen in 63.4% of patients for stool frequency, 81.8% for rectal bleeding, 60.0% for endoscopic improvement and 54.5% of patients for global physician's assessment. Histological improvement was seen in 5 of 10 patients (50%) that had week 16 histology samples. Conclusion In this proof-of-concept study, UC patients experienced clinical, endoscopic and histological improvement after 16 weeks of QBECO treatment. This highlights the potential for this novel microbial-based immunotherapeutic strategy to restore gastrointestinal immune function in patients with UC.

Little is known about men with prostate cancer who decline conventional treatment and use only complementary and alternative medicine (CAM). Objectives: To 1) explore why men decline conventional prostate cancer treatment and use CAM 2) understand the role of holistic healing in their care, and 3) document their recommendations for health care providers. Methods: Semi-structured interviews and follow-up focus groups. Sample: Twenty-nine men diagnosed with prostate cancer who declined all recommended conventional treatments and used CAM. Results: Based on strong beliefs about healing, study participants took control by researching the risks of delaying or declining conventional treatment while using CAM as a first option. Most perceived conventional treatment to have a negative impact on quality of life. Participants sought healing in a broader mind, body, spirit context, developing individualized CAM approaches consistent with their beliefs about the causes of cancer. Most made significant lifestyle changes to improve their health. Spirituality was central to healing for one-third of the sample. Participants recommended a larger role for integrated cancer care. Conclusion: Men who decline conventional prostate cancer treatment and use CAM only may benefit from a whole person approach to care where physicians support them to play an active role in healing while carefully monitoring their disease status. Keywords: cancer, complementary and alternative medicine, decision-making, quality of life'