Advances in Bacterial Lysate Immunotherapy for Infectious Diseases and Cancer

Abstract

Antigenic cell fragments, pathogen-associated molecular patterns, and other immunostimulants in bacterial lysates or extracts may induce local and systemic immune responses in specific and nonspecific paradigms. Based on current knowledge, this review aimed to determine whether bacterial lysate has comparable functions in infectious diseases and cancer treatment. In infectious diseases, including respiratory and urinary tract infections, immune system activation by bacterial lysate can identify and combat pathogens. Commercially available bacterial lysates, including OM-85, Ismigen, Lantigen B, and LW 50020, were effective in children and adults in treating respiratory tract infections, chronic obstructive pulmonary disease, rhinitis, and rhinosinusitis with varying degrees of success. Moreover, OM-89, Uromune, Urovac, Urivac, and ExPEC4V showed therapeutic benefits in controlling urinary tract infections in adults, especially women. Bacterial lysate-based therapeutics are safe, well-tolerated, and have few side effects, making them a good alternative for infectious disease management. Furthermore, a nonspecific immunomodulation by bacterial lysates may stimulate innate immunity, benefiting cancer treatment. "Coley's vaccine" has been used to treat sarcomas, carcinomas, lymphomas, melanomas, and myelomas with varying outcomes. Later, several similar bacterial lysate-based therapeutics have been developed to treat cancers, including bladder cancer, non-small cell lung cancer, and myeloma; among them, BCG for in situ bladder cancer is well-known. Proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, may activate bacterial antigen-specific adaptive responses that could restore tumor antigen recognition and response by tumor-specific type 1 helper cells and cytotoxic T cells; therefore, bacterial lysates are worth investigating as a vaccination adjuvants or add-on therapies for several cancers.

Figure 1

Mechanisms of action of the most studied bacterial lysate OM-85. In humans, pathogen-associated molecular patterns (PAMPs) of OM-85 stimulate the Toll-like receptors of the immune cells and activate monocytes, macrophages, dendritic cells (DCs), and natural killer cells, activating the immune system to fight infections. OM-85 also stimulates the production of secretory immunoglobulin A (sIgA) (1a). In sinonasal immunity, OM-85 activates bitter taste receptors (T2R), resulting in increases in ciliary beat frequency (CBF) (indicating improved lung functions), and other local immune defenses such as the release of nitric oxide (NO) and secretion of antimicrobial compounds lead to the killing of pathogens. Moreover, OM-85 also activates polyclonal B cells, increasing IgG levels in serum and IgA and IgG levels in bronchoalveolar lavage. IgA neutralizes viruses and controls secondary bacterial infections (1b). An effect on the expansion of type 1 helper T (Th1) cells, regulatory T cells (Treg), and CD8+ T cells has also been observed with the administration of OM-85. Th1 cells produce inflammatory cytokines, which send signals to immune cells to destroy pathogens, whereas the cytotoxic activity of CD8+ T cells also does the same. Treg cells downregulate the Th2 cells and restore Th/Th1 balance, improving overall mucosal immunity (1c). In a mice study, OM-85 increased the production of IL-6 and TNF-α in bronchoalveolar lavage fluid, contributing to reduced viral load (2a). Also, nonspecific maturation of B cells and DCs by OM-85 leads to increased surface expression of antigen-presenting molecules (MHC II, CD86, and CD40) and helps to neutralize pathogens, and a decrease in inducible T-cell costimulator ligand (ICOSL) provides protection against allergic responses (2b). In vitro, data showed that OM-85 could activate T2R (downstream processes are like in human studies) and NF-kB and MAPK in monocyte-derived DCs from COPD patients, resulting in the upregulation of chemokines (CXCL8, CXCL6, CCL3, CCL20, and CCL22), and B-cell-activating cytokines (IL-6, BAFF, and IL-10) may impact in fighting against pathogens (3a). OM-85 also increased the expression of virus-interacting proteins such as C1q-R and β-defensin, essential for antigen presentation and phagocytosis, and significantly reduced rhinovirus-induced expression of intracellular adhesion molecule (ICAM)-1, resulting reduced viral load (3b).

Figure 2

Mode of actions of bacterial lysate-based cancer immunotherapy. Pathogen recognition receptors (PRR) in immune cells such as natural killer cells, macrophages, T cells, and dendritic cells (DCs) interact with the pathogen-associated molecular pattern (PAMPs), activating the immune cells (1). This activation creates a cytokine milieu (IL-1, IL-6, IL-12, and TNF-α), ultimately leading to type 1 immunity. Activating type 1 immunity helps to restore the ability of tumor-specific type 1 helper T cells (Th1) and cytotoxic T cells, which then recognize cancer antigens and destroy cancer cells (2). In addition, PAMP-activated DCs gained the ability to present antigens to CD4+ T cells and CD8+ T cells. This nonspecific immune activation could also play a role in destroying cancer cells (3) (PFN, perforin; GzmB, granzyme B).