How SSIs Work
“After decades of research, the concept that bacteria can be used to activate and train our immune system to fight cancer and other diseases, such as Crohn’s, is coming to fruition… and Qu is leading the way.”
Qu Biologics has developed a platform of immunotherapies called Site Specific Immunomodulators (SSIs). SSIs are derived from components of inactivated bacteria, designed to restore the body’s normal immune function to treat cancer and other immune-related diseases, such as inflammatory bowel disease (IBD). In the context of cancer, Qu Biologics’ SSIs are designed to restore immune function and activate the patient’s own immune cells to clear cancer cells. In IBD, unlike current treatments that suppress the immune system, SSIs are designed to restore the body’s innate immune system and correct the dysfunctional immune response.
Restoring our body’s normal healthy immune function
For millions of years, acute infection was the major selective force for the evolution of the immune system. Our immune system is remarkably adept at responding to acute infection, and our body’s response to acute infection helps us preserve and maintain optimal immune function. A lack of immune system stimulation by acute infection can lead to chronic immune system dysregulation, resulting in an increased risk of cancer and other chronic inflammatory diseases. This concept is commonly referred to as the ‘hygiene hypothesis’ –that we may be living in ‘too clean’ a world and our immune system is not getting sufficient stimulation to maintain optimal health.
Qu Biologics has discovered the underlying mechanism of the ‘hygiene hypothesis’ – the mechanism by which our immune system’s response to acute infection helps us fight cancer and other chronic inflammatory diseases. Qu Biologics’ Site Specific Immunomodulators (SSIs), derived from bacterial components, are designed to harness this natural response, restoring normal immune function and our body’s innate capacity to heal.
Cancer and chronic inflammatory disorders, such as Crohn’s disease and ulcerative colitis, stem from and perpetuate chronic immune dysfunction that, if left unchecked, can lead to progressively deteriorating health. Ironically, many current treatments for both cancer and immune-related disorders suppress or disable the immune system rather than acting to restore normal immune function. At Qu Biologics, we recognize that sustainable recovery from diseases is contingent upon restoring healthy immune function and harnessing our body’s natural ability to heal. It is with this central aim that Qu Biologics has developed SSIs that are designed to activate the body’s innate immune system to re-establish balance and normal healthy immune function.
SSIs are designed to restore the body’s normal immune response
In order to understand how SSIs work, it is helpful to know about the two complementary parts of our immune system. Our immune system consists of two main components, referred to as the innate and adaptive immune systems. The adaptive immune system is highly specific – a specific antibody or specific memory T-cell produced to attack a specific antigen – and relies on past exposure to tailor a very specific immune response to a very specific threat. The innate immune system, on the other hand, responds immediately to danger and is very non-specific – when stimulated, cells of the innate immune system clear up whatever is not supposed to be there, including bacteria, cancer cells and dead and dying cells. This makes the innate immune system pivotal as the first line of defence and for guiding a normal healthy immune response against a wide variety of threats.
Cancer is associated with a ‘suppression’ of the adaptive immune system in the tumour – an inability of the adaptive immune system to recognize and clear cancer cells. On the other hand, the symptoms of IBD (Crohn’s disease, ulcerative colitis) and autoimmune disease are due to an ‘overreaction’ of the adaptive immune system, resulting in damage and inflammation. While cancer and inflammatory bowel disease are opposite diseases from the perspective of the adaptive immune system, they share the same underlying pathology – a defect/deficiency/suppression of the innate immune system, specifically, a very important cell of our innate immune system, macrophages, which means ‘big eater’.
Historically, immunotherapy research in cancer, inflammatory bowel disease and autoimmune disease has been focused on the adaptive immune system. Qu Biologics is approaching the treatment of these diseases in an entirely different way – by restoring the innate immune system and our body’s normal immune response and capacity to heal.
Cancer and chronic inflammatory disorders are linked to defective macrophage function
Macrophages, important sentinel cells of the innate immune system, are derived from a type of white blood cell called monocytes, which circulate through the body in search of ‘trouble’. When they receive a danger signal from a specific organ or tissue, monocytes move into that tissue where they undergo a series of changes to become tissue-associated resident macrophages, which allow them to ingest (or “phagocytose”) invading pathogens or cancer cells and remove dead or damaged cells that cause inflammation. Resident macrophages stay on guard for months monitoring the environment to make sure that the proper barriers are working and that there is nothing out of line disturbing normal tissue function. By playing these important roles, macrophages are essential in ensuring tissue health and normal immune function. There is growing evidence that disruption of proper macrophage function may underlie cancer and other immune related diseases such as Crohn’s disease, ulcerative colitis, and autoimmune disease.
The role of macrophages in cancer
Macrophages have two important and distinct roles in the body – tissue repair (M2) and immune defence (M1). M2 macrophages function in the tissue repair role, stimulating tissue growth and wound repair, including stimulating blood vessel growth and the growth of new cells. When functioning in this tissue repair role (for example, in the healing of a wound), M2 macrophages suppress the immunological function of both the innate and adaptive immune systems to prevent the immune system from reacting against the newly growing cells. In the context of wound repair, M2 macrophages play an essential role in repairing damaged tissue. However, in the context of cancer, M2 macrophages perceive cancer as a ‘wound’ in need of repair and stimulate the growth of cancer cells while suppressing immune function, leading to unbridled growth uncontrolled by the immune system. While our immune system is normally capable of killing cancer cells, in the context of M2 macrophage dominance in the tumour, the immune system is suppressed and M2 macrophages drive cancer growth.
However, macrophages have another important role in the body, their immunological M1 role. M1 macrophages are highly immune competent and immunostimulative, stimulating both the adaptive and innate immune systems to respond against any threat, including cancer (illustrated below).
The strongest driver of M1 macrophage recruitment is acute infection. SSIs are designed to mimic acute infection and stimulate organ specific recruitment of activated M1 macrophages to the site in which the cancer is growing. This shift to M1 macrophage dominance in the tumour is designed to relieve the immunosuppression caused by M2 macrophages and, since M1 macrophages are highly immunostimulative, stimulate the body’s own capacity to mount an anti-cancer immune response, by both the innate and adaptive immune systems, restoring normal immune function.
M2 macrophages in tumours are associated with a poor prognosis, while M1 macrophages in tumours, which drive a strong innate and adaptive immune response, are associated with a good prognosis1,2,3. In simple terms, the greater the density of M1 macrophages, the better the prognosis. For example, in a study in lung cancer patients conducted by Ma and colleagues, a high density of M1 macrophages was found to correlate with a 5-fold increase in five year survival4. Similar results have been published for patients with melanoma (skin cancer)5, ovarian cancer6,7, pancreatic cancer8, gastric cancer9, colorectal cancer10, prostate cancer11,and Hodgkin’s lymphoma12.
Preclinical studies demonstrate SSIs reduce tumour burden and improve survival
Qu Biologics has demonstrated in cancer mouse models that SSI treatment drives site specific recruitment of M1 activated macrophages to the targeted organ or tissue, shifting macrophage dominance in the tumour from M2 to M1, reducing tumour burden and improving survival. Read more about these preclinical studies and efficacy data. This research suggests that SSI therapy, with the resultant recruitment of activated M1 macrophages to the targeted organ and the restoration of immune function, may be a promising new approach to treating cancer.
Synergistic effects of SSI treatment and chemotherapy
Chemotherapy kills cancer cells, resulting in the release of tumour antigens. Due to the suppression of immune function caused by M2 macrophage dominance within the tumour, the immune system is not able to respond optimally to the released tumour antigens. SSI treatment is designed to recruit activated macrophages to the tumour, relieving immunosuppression and activating immune function. Qu Biologics’ scientists hypothesize that SSI therapy may work synergistically with chemotherapy to enhance its effectiveness. When tumour antigens are released due to chemotherapy treatment, the activated immune system due to SSI therapy may enable a more effective response to the released tumour antigens, enhancing the effectiveness of chemotherapy. In mouse models, Qu Biologics’ scientific team have demonstrated this synergy, suggesting that, in addition to their potential as individual cancer treatments, SSIs may be important adjuncts to standard cancer treatments. Read more about the preclinical data showing SSIs enhance the effectiveness of chemotherapy. Qu is currently assessing the capacity of SSIs to augment the activity of other standard therapies and novel immunotherapeutics.
Promising compassionate use clinical data (cancer)
Qu Biologics’ SSIs were first used clinically in a compassionate use program in patients with advanced cancer. From 2008 to 2012, more than 250 patients with advanced cancer (including breast, prostate, lung, colon, liver, skin, bone and ovarian cancer) were treated with one or more SSIs. Read more about the safety profile and promising clinical data in Qu Biologics’ compassionate use program in advanced cancer.
The role of macrophages in inflammatory bowel disease
In parallel with the growing recognition of the important role of M2 macrophages in driving cancer growth, there is a growing recognition that macrophage defect / deficiency / immunosuppression plays an important underlying role in IBD, including Crohn’s disease and ulcerative colitis. There are several hundred gene abnormalities associated with inflammatory bowel disease that increase the risk for these diseases, many of which are associated with reduced macrophage function13 and, specifically, reduced ability of macrophages to optimally clear bacterial infection14. While most people with these gene abnormalities never develop Crohn’s disease or ulcerative colitis, it is thought that an environmental trigger in genetically susceptible individuals with reduced macrophage function may set up a chronic inflammatory stimulus that results in sustained immune dysfunction, including an over-reactive adaptive immune response that causes further ongoing inflammation and damage.
People with active Crohn’s disease have monocytes that are unproductively immunosuppressive15–17, broadly characterized as having an “M2-like” phenotype. This immunosuppressive M2 phenotype results in an inability to clear bacterial infection in the gastrointestinal tract, which may lead to dysbiosis (i.e., reduction in healthy commensal bacteria in the GI tract and an overgrowth of pathogenic bacterial species) and invasion of the mucosal lining of the GI tract with multiple pathogenic species. Without the support of immunostimulatory M1 macrophages, it is hypothesized that these immunosuppressed M2 macrophages (depicted in orange in illustration below) are unable to clear the bacterial infection (depicted in blue in illustration below), resulting in chronic inflammation and tissue damage. The adaptive immune system reacts against the chronic infection, resulting in further inflammation, tissue damage and symptoms, but without the support of M1 macrophages, this overreactive adaptive immune response is unable to clear the chronic infection/dysbiosis.
Current treatments for Crohn’s disease and ulcerative colitis (e.g., prednisone, Imuran®, Remicade®, Humira®, etc.) suppress this overreactive adaptive immune response. In the portion of patients in whom these treatments are effective, these treatments reduce the inflammation and symptoms of the disease, but these treatments do not treat what may be the underlying cause of the disease (i.e., innate immune system dysfunction, dysbiosis, and chronic bacterial infection), so not surprisingly, when these treatments are discontinued, symptoms typically recur. Suppressing the adaptive immune system is also associated with significant potential side effects.
Restoring immunocompetent macrophage function may be central for resetting productive immune responses
SSI treatment for Crohn’s disease and ulcerative colitis is designed to recruit activated M1 macrophages (depicted in green in illustration below) to the gastrointestinal tract, resulting in the clearance of dysbiosis and the resolution of chronic bacterial infection. Once this underlying trigger is removed, there is no longer any pathology for the adaptive immune system to respond against, resolving the chronic inflammation and restoring normal immune function and health. In other words, Qu’s SSIs are specifically designed to reboot normal macrophage function in the diseased organ, re-instating the normal innate immune response required to restore health.
Initial results from randomized, placebo-controlled Crohn’s disease study
Qu Biologics’ 68-patient, randomized, placebo-controlled clinical study involved the use of investigational treatment QBECO SSI for moderate-to-severe Crohn’s disease.
Based on the Week 8 and preliminary Week 16 results, QBECO SSI appears safe and well-tolerated and demonstrates consistently positive trends throughout the treatment period of the trial, successfully establishing proof-of-concept in Crohn’s disease and supporting continued development of QBECO SSI in inflammatory bowel disease.
Promising compassionate use clinical data (IBD)
Qu Biologics’ SSIs were first used clinically in inflammatory bowel disease in a compassionate use program. From 2010 – 2013, 10 patients with moderate to severe Crohn’s disease and 2 patients with moderate to severe ulcerative colitis, unresponsive to standard treatment, were treated with SSI in this program. Read about the safety profile and promising clinical data in Qu Biologics’ compassionate use program in Crohn’s disease and ulcerative colitis.
The role of macrophages in autoimmune disease
As in cancer and inflammatory bowel disease, there is a growing recognition that macrophage defect or deficiency may play an important underlying role in autoimmune disease18. Autoimmune disease is characterized by an over-reactive adaptive immune system, in which the adaptive immune system is reacting against the body’s own cells, creating inflammation and damage. Historically, autoimmune diseases have been treated with medications that suppress this over-reactive adaptive immune system, including Remicade®, prednisone and Imuran® and Humira®.
There is growing evidence that an important factor underlying many autoimmune diseases may be a defect or deficiency of macrophage function, leading to an inability to effectively clear dead and dying cells19,20. Our body’s cells have a natural life cycle, measured in days, weeks or months, depending on the tissue. When cells reach the end of their natural life cycle, they undergo a natural process of apoptosis (i.e., programmed cell death), in which they signal to macrophages that they are dying. Macrophages respond to this signal and engulf (phagocytose) the dying cell, sending out anti-inflammatory ‘tolerance’ signals to signal to the adaptive immune system not to respond against the dying cell. In the context of normal macrophage function, the contents of the dead cell are recycled by macrophages, and a healthy tissue is maintained. However, in the context of macrophage defect / deficiency, especially if there is an environmental insult that overwhelms macrophage function, not all dead and dying cells are cleared by macrophages. If dying cells are not engulfed by macrophages, the dying cells necrose and break apart, releasing their internal antigens, against which the adaptive immune system responds, creating further damage and cell death, resulting in the vicious cycle of autoimmune disease as the adaptive immune system continues to react against the dead and dying cells.
SSIs are designed to restore innate immune function in the targeted organ or tissue, resulting in the clearance of dead and dying cells in the affected organ or tissue, and thus, the clearance of the underlying trigger for the autoimmune response, restoring normal immune function and health. The preclinical study, illustrated below, demonstrated that M1 macrophages are much better than M2 macrophages at clearing necrotic (i.e., dead) cells.
In Qu’s compassionate use program, five patients with autoimmune arthritis were treated with SSI. Learn more about the results from our compassionate use program.
SSIs Stimulate Immune Function in the Targeted Organ or Tissue
Through experience, the immune system has learned the tissue specificity of common bacterial pathogens. Qu’s SSIs utilize this built-in knowledge to direct an activated innate immune response to specific organs or tissues to restore normal macrophage function. Each SSI contains components from a single inactivated bacterial species that the immune system recognizes as a common cause of infection in a specific organ or tissue. By utilizing the organ specificity of the innate immune response, SSIs are designed to recruit activated macrophages to the targeted organ/tissue in which the bacterial species commonly causes infection, restoring normal innate immune system function (illustration below).
In our current placebo-controlled randomized clinical trial in Crohn’s disease and our clinical trial in ulcerative colitis, the SSI study drug is derived from components of an inactivated enteropathic (i.e., gastrointestinal infection) strain of E. coli, a common gastrointestinal pathogen, and is designed to restore innate immune function in the gastrointestinal tract. In our Phase 2a clinical trial in recurrent lung cancer, the SSI is derived from K. pneumoniae, a common lung pathogen, designed to restore a normal anti-cancer immune response in the lungs.
By restoring normal functioning of the innate immune system, SSIs are designed to restore and effectively mobilize the natural healing abilities of the body – an approach that we believe best serves long-term sustainable health.
- Mills, Charles et al. A Breakthrough: Macrophage-Directed Cancer Immunotherapy. Cancer Research, January 15, 2016; doi: 10.1158/0008-5472.CAN-15-1737 (2016).
- Hao, N.-B. et al. Macrophages in tumor microenvironments and the progression of tumors. Clin. Dev. Immunol.2012, 948098 (2012).
- Quatromoni, J. G. & Eruslanov, E. Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. Am. J. Transl. Res.4, 376–89 (2012).
- Ma, J. et al. The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer10, 112 (2010).
- Jensen, T. O. et al. Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. J. Clin. Oncol.27, 3330–7 (2009).
- He, Y. et al. High MUC2 expression in ovarian cancer is inversely associated with the M1/M2 ratio of tumor-associated macrophages and patient survival time. PLoS One8, e79769 (2013).
- Zhang, M. et al. A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J. Ovarian Res.7, 19 (2014).
- Kamper, P. et al. Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin’s lymphoma. Haematologica96, 269–76 (2011).
- Pantano, F. et al. The role of macrophages polarization in predicting prognosis of radically resected gastric cancer patients. J. Cell. Mol. Med.17, 1415–21 (2013).
- Edin, S. et al. The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One7, e47045 (2012).
- Lanciotti, M. et al. The role of M1 and M2 macrophages in prostate cancer in relation to extracapsular tumor extension and biochemical recurrence after radical prostatectomy. Biomed Res. Int.2014, 486798 (2014).
- Kurahara, H. et al. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J. Surg. Res.167, e211–9 (2011).
- Mokry, M. et al. Many inflammatory bowel disease risk loci include regions that regulate gene expression in immune cells and the intestinal epithelium. Gastroenterology146, 1040–7 (2014).
- Vavricka, S. R. & Rogler, G. New insights into the pathogenesis of Crohn’s disease: are they relevant for therapeutic options? Swiss Med. Wkly.139, 527–34 (2009).
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Other Scientific Literature
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- Jensen TO, Schmidt H, Moller HJ, et al. Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. J ClinOncol 2009;27(20):3330-7.
- Ma J, Liu L, Che G, Yu N, Dai F, You Z. The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC cancer 2010;10:112.
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Immune-related disease (Crohn’s disease, ulcerative colitis)
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- Korzenik JR. Is Crohn’s disease due to defective immunity? Gut 2007;56(1):2-5.
- Marks DJ. Defective innate immunity in inflammatory bowel disease: a Crohn’s disease exclusivity? Current opinion in gastroenterology 2011;27(4):328-34.
- Marks DJ, Harbord MW, MacAllister R, et al. Defective acute inflammation in Crohn’s disease: a clinical investigation. Lancet 2006;367(9511):668-78.
- Marks DJ, Rahman FZ, Sewell GW, Segal AW. Crohn’s disease: an immune deficiency state. Clinical reviews in allergy & immunology 2010;38(1):20-31.
Autoimmune disease (rheumatoid arthritis)
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- Nagata S. Rheumatoid polyarthritis caused by a defect in DNA degradation. Cytokine & growth factor reviews 2008;19(3-4):295-302.
- Sumida T, Hasunuma T, Asahara H, Maeda T, Nishioka K. Rheumatoid arthritis and apoptosis. Internal medicine (Tokyo, Japan) 1998;37(2):184-8.