Mycobacteria-Based Vaccines as Immunotherapy for Non-urological Cancers

Abstract

The arsenal against different types of cancers has increased impressively in the last decade. The detailed knowledge of the tumor microenvironment enables it to be manipulated in order to help the immune system fight against tumor cells by using specific checkpoint inhibitors, cell-based treatments, targeted antibodies, and immune stimulants. In fact, it is widely known that the first immunotherapeutic tools as immune stimulants for cancer treatment were bacteria and still are; specifically, the use of Mycobacterium bovis bacillus Calmette-Guérin (BCG) continues to be the treatment of choice for preventing cancer recurrence and progression in non-invasive bladder cancer. BCG and also other mycobacteria or their components are currently under study for the immunotherapeutic treatment of different malignancies. This review focuses on the preclinical and clinical assays using mycobacteria to treat non-urological cancers, providing a wide knowledge of the beneficial applications of these microorganisms to manipulate the tumor microenvironment aiming at tumor clearance.

Keywords: BCG; adjuvant; immunotherapy; mycobacteria antigens; non-tuberculous mycobacteria.

Figure 1

Schematic representation of mycobacterium immunomodulatory molecules. The peptidoglycan–arabinogalactan–mycolic acids complex is covalently linked to the cell membrane and is present in all mycobacteria. Glycopeptidolipids, lipooligosaccharides, phenolglycolipids, phthiocerol dimycocerosates (PDIM), and poliacyl-trehaloses are located in the outer membrane of only some species. Mycolic acids, lipomannan, and trehalose-mycolates are present in all mycobacteria, but the fine structure differs among different species. Neither the cell nor the whole cell wall molecules are drawn to scale.

Figure 2

In vitro and in vivo studies using mycobacteria-derived agents carried out for the treatment of melanoma and lung cancer. ^A, alone or in combination with chemotherapy; ^B, along with MUC1-MBP fusion protein; ^C, B16 cells expressing mycobacterial antigens; ^D, in combination with monosodium urate crystals; ^E, anchored to tumor proteins; ^F, administered together with B16 cell lysates; ^G, co-expressed with herpes simplex thymidine kinase in Salmonella typhimurium; ^H, in combination with chemotherapy and radiotherapy. Ag85—antigen 85 complex, BCG—Mycobacterium bovis bacillus Calmette-Guerin, BEC2—anti-idiotypic antibody mimicking the GD3 ganglioside expressed on most small-cell lung cancer (SCLC) cells, CpG—cytosine-guanosine nucleotide, CWS—cell wall skeleton, HK—heat-killed, HSP—heat-shock proteins, IL-—Interleucin, L-MTP-PE—liposomal muramyl tripeptide phosphatidyl ethanolamine, MBP—maltose binding protein, MIP—Mycobacterium indicus pranii, RelE—toxin of Mycobaterium tuberculosis, SMP-105—CWS-BCG Tokyo 172, SRL 172—M. vaccae commercial preparation, WT1—Wilms’ tumor protein, Z-100—an arabinomannan from M. tuberculosis strain Aoyama B.