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Contains fulltext : 218672.pdf (Publisher’s version ) (Open Access) 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.

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: only adaptive immunity confers immunological memory and innate immunity lacks specificity. This work describes the novel observation that innate immune effector cells can be recruited to specific tissues of the body where pathology is present by using a microbial-based immune stimulus that consists of an inactivated pathogen that typically resides or causes infection in that target tissue site. We demonstrate this principle using experimental models of cancer and infection for which different subcutaneously delivered microbial-based treatments were shown to induce the recruitment of immune effector cells to specific diseased organs. Amelioration of disease in a given organ niche was dependent on matching the correct microbial stimulus for the affected organ site but was independent of the nature of the pathology. This observation intriguingly suggests that the immune system, upon pathogen recognition, tends to direct its resources to the compartment in which the pathogen has previously been encountered and would be the most likely source of infection. Importantly, this phenomenon provides a novel means to therapeutically target innate immune effector cells to sites of specific disease localization to potentially treat a wide spectrum of pathologies, including cancer, infection, and chronic inflammatory disorders.AUTHOR SUMMARYVaccines that target adaptive immune memory have revolutionized medicine. This study describes a novel strategy that works as a modified innate immune “vaccine” that exploits the trained response of innate immune effector cells to clear pathology in a specific tissue site. Unlike memory of the adaptive immune system, which functions like a lock and key, innate immune memory is more akin to a reflex response – like experienced muscle or neural cells that are changed by a stimulus to respond more efficiently upon re-exposure. This change in behavior through experience is the definition of learning. Our study suggests that this innate immune learning occurs at different levels. Emergency hematopoiesis trains new innate immune cells in the bone marrow to respond quickly and effectively to a non-specific threat; whereas, pathogen-specific training occurs at sites where cells making up the immunologic niche have had interactions with a particular pathogen and have been trained to respond more robustly to it upon re-presentation in the context of a danger signal. The speed with which new immune cells are trained in the bone marrow in response to an imminent microbial threat and their subsequent recruitment to the target organ site where that microbe typically resides suggests there are ways the immune system communicates to coordinate this rapid response that are yet to be fully delineated. These findings provide a novel highly proficient way to harness the potent effector functions of the innate immune system to address a wide range of immune-based diseases.

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 bacteriaE. 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.

Acute infection is known to induce strong anti-tumor immune responses, but clinical translation has been hindered by the lack of an effective strategy to safely and consistently provoke a therapeutic response. These limitations are overcome with a novel treatment approach involving repeated subcutaneous delivery of a Klebsiella-derived investigational immunotherapeutic, QBKPN. In preclinical models of lung cancer, QBKPN administration consistently showed anti-cancer efficacy, which was dependent on Klebsiella pre-exposure, but was independent of adaptive immunity. Rather, QBKPN induced anti-tumor innate immunity that required NK cells and NKG2D engagement. QBKPN increased NK cells and macrophages in the lungs, altered macrophage polarization, and augmented the production of cytotoxic molecules. An exploratory trial in patients with non-small cell lung cancer demonstrated QBKPN was well tolerated, safe, and induced peripheral immune changes suggestive of macrophage polarization and reduction of PD-1 and PD-L1 expression on leukocytes. These data demonstrate preclinical efficacy, and clinical safety and tolerability, for this cancer immunotherapy strategy that exploits innate anti-tumor immune mechanisms.

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 Ly6CHI 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 Ly6CHI 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.

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 TH2 cytokines including IL-4, IL-13 and IL-5. Treatment with KB attenuated HDM-mediated airway eosinophilia, total bronchoalveolar lavage (BAL) cell numbers, BAL TH2 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.

Tumour regression and increased survival has been associated with certain acute microbial infections. Immune dysfunction contributes to the development and progression of lung cancer, and therapies that re-constitute anti-tumor immune responses provide an important means to effectively treat malignancies and improve health outcomes. We hypothesized that stimulating the innate immune system with bacterial-derived immunomodulators could induce protective anti-cancer immune responses. A Klebsiella-derived drug product, QBKPN (Qu Biologics), was used to specifically stimulate the innate immune niche in the lungs in established mouse models of lung cancer. Repeated subcutaneous administration with QBKPN significantly reduced lung tumor burden and increased survival. The protective action of QBKPN required prior exposure to Klebsiella through either environmental exposure or lung infection. However, this QBKPN-mediated anti-tumour response was independent of adaptive immunity, as the protective effect remained in RAG2-knockout mice. QBKPN intervention was characterized by a rapid, acute-like systemic immune response, including increased circulatory inflammatory cytokines and innate immune cells, leading to recruitment of immune effector cells into the lung tissue, including macrophages and natural killer (NK) cells. In addition to recruitment of innate immune cells, QBKPN increased markers of classically activated macrophages and increased production of NK cell effector molecules. Together, these data suggest that QBKPN, a Klebsiella-derived immunomodulator, causes activation and recruitment of macrophages and NK cells into the lungs, reducing cancer tumour burden and improving survival outcomes.

Acute infection in a cancer-bearing organ has been associated with improved prognosis and enhanced survival, although the anti-cancer immune mechanisms remained undefined. In collaboration with Qu Biologics, we hypothesized that stimulating pathogen-specific immunity, using bacteria that have previously infected specific organs, may induce protective anti-cancer immune responses in those target organs. We evaluated Klebsiella-mediated anti-cancer efficacy in metastatic-like B16 melanoma using heat-killed Klebsiella pneumoniae (Qu Biologics’ drug product QBKPN Site Specific Immunomodulator [SSI]). Subcutaneous injection of QBKPN SSI significantly reduced tumor burden. Furthermore, subcutaneous treatment with heat-killed E. coli, (QBECO SSI) reduced lung tumor burden but not as substantially as with QBKPN. This suggests that subcutaneous immune induction using a lung specific-pathogen activates a lung-specific antitumor response. We next asked whether pre-exposure to K. pneumoniae would improve anti-tumor efficacy. We exposed mice to live K. pneumoniae via intratracheal infection prior to subcutaneous injections with QBKPN SSI. Pre-exposure to K. pneumoniae significantly enhanced QBKPN SSI-induced anti-tumor immunity and control of metastatic-like B16 melanoma in the lungs. The anti-tumor efficacy in exposed mice correlated with an influx of monocytes and neutrophils, but did not correlate with an influx of T cells into the lungs. Collectively, these data suggest pre-exposure to K. pneumoniae may induce tissue resident memory cells that mediate tumor cytolysis, and thus explain the lack of T cell infiltration into the lungs.

The immune system recognizes and eliminates malignant cells, and maintains an intricate balance between immune activation and cancer. Historically, spontaneous tumor regression has been observed in some patients experiencing acute microbial infections. Building upon this, it was discovered that repeated subcutaneous injection of novel immunotherapies called Site-Specific Immunomodulators (SSIs), derived from killed bacteria known to cause infection in a particular organ or tissue, may be effective at treating cancer growing in the same site. We hypothesize that SSIs stimulate the body’s immune system to reverse immune suppression and dysfunction in the tumor microenvironment, enabling effective anti-cancer immune responses. To test this hypothesis, we evaluated the efficacy of a lung-specific SSI, QBKPN, in preclinical lung cancer models. Repeated subcutaneous administration of QBKPN significantly reduced lung tumor burden at day 16 post-inoculation (p

We all become ill at some point in our lives – it is a shared human experience. What holds the most meaning during these times? It is not the technology or the treatments: it is the love, kindness and support of others. What do we remember most? Years later, when the specifics of the treatments prescribed by our doctor fade from memory, it is the kind words of compassion, the warm support that helped us face our fear of the unknown, and the hand on our shoulder in assurance that everything was going to be O.K. These are the moments that carry the most meaning.