Integration of Salmonella into Combination Cancer Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Unique Aspects of Salmonella in Cancer Therapy
2.1. Selective Tumor Colonization
2.2. Broad Tumor Specificity
2.3. Intrinsic Oncolytic Capacity
2.4. Immunomodulatory Effects
2.5. Ease of Gene Modification
3. Salmonella in Combination with Other Approaches to Cancer Therapy
3.1. Combination with Chemotherapeutic Agents
3.2. Combination with Radiotherapy
3.3. Combination with Immune Checkpoint Inhibitors
3.4. Combination with Immunomodulatory Cytokines
3.5. Combination with Other Therapies
4. Clinical Application of Salmonella in Combination Cancer Therapy
4.1. Clinical Trials
4.2. Challenges
- Clinical safety. Bacterial pathogens can cause diseases through the action of virulence factors. On the other hand, the attenuation of virulence factors has been correlated with decreased anti-tumor therapeutic effects [183,184]. The optimized balance between reduced virulence and clinical efficacy remains the major challenge in the clinical application of BMCT. Moreover, not all bacterial strains that showed success in pre-clinical models can be used in clinical settings due to their distinct pathologies that differ in animals and humans.
- Route of administration. The systemic administration of bacteria increases the risk of toxicity and potential adverse effects of the infection. The oral administration is considered relatively safer but at the expense of therapeutic efficacy.
- Dose optimization. Since live bacteria proliferate in target tissues, the effective dose does not necessarily mirror the administered dose. The effective dose is dependent on different factors including the route of administration, accessibility to target tissues, level of vascularization, tumor immunogenicity, and the presence of tumor-infiltrating inflammatory cells [21].
- Genetic instability. Live genetically engineered bacteria that carry antibiotic resistance genes or mobile genetic elements are not suitable for clinical use since these recombinant elements can mediate horizontal gene transfer [185]. Other recombinant plasmids can be lost or mutated before reaching tumor tissues, leading to exaggerated infection or therapeutic failure [186].
- Bacterial growth control in vivo. The timely elimination of bacteria using an antibiotic intervention is critical since the early administration of antibiotic may eliminate the infection before an anti-tumor effect has been achieved, whereas a late intervention would result in unpredictable systemic inflammatory response. Microbiota disturbance and the development of antibiotic resistance should be kept in mind when using antibiotics to manage bacterial growth.
- Patient selection. Chemotherapeutic agents suppress the immune system and interfere with delivering the immunomodulatory effects induced by BMCT. Therefore, the risk of bacterial infection is substantially increased in chemotherapy-receiving patients. In addition, brain abscesses, diverticulitis, or recent radiation might enhance the unintentional growth of bacteria in non-target tissues. Live bacteria also have the potential to colonize the foreign bodies in patients with joint replacement, artificial heart valves, and impanated medical devices [22]. Pre-exposure and anti-bacterial immunity should be also taken into account since they might interfere with the anti-tumor immune-stimulatory effects of the bacteria and result in treatment failure.
4.3. Efforts to Overcome Challenges
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
CAR-T | Chimeric antigen receptor T cell therapies |
BMCT | Bacterial-mediated cancer therapy |
TNF-α | Tumor necrosis factor-alpha |
PDOX | Patient-derived orthotopic xenograft |
VEGF | Vascular endothelial growth factor |
p-gp | P-glycoprotein |
MMP-9 | Matrix metalloproteinase 9 |
Tregs | Regulatory T cells |
iNOS | Inducible nitric oxide synthase |
MDSCs | Myeloid-derived suppressor cells |
IDO | Indoleamine 2,3-dioxygenase |
NK | Natural killer |
Cx43 | Connexin 43 |
TILs | Tumor-infiltrating lymphocytes |
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Chemotherapeutic Agent | Salmonella Strain | Route of Salmonella Administration | Cancer Model/ Mouse Strain | Outcome of Combination Treatment | Associated Mechanism | Ref |
---|---|---|---|---|---|---|
CHOP chemotherapy (a cyclophosphamide, doxorubicin, vincristine, and prednisone/steroid combination) | S. typhimurium LVR01 | Intratumoral | B-cell non-Hodgkin lymphoma (murine A20 cell line)/BALB/c mice |
|
| [100] |
Doxorubicin | S. typhimurium DSLpNG | Intravenous | Autochthonous model of breast cancer/BALB/neuT mice |
|
| [101] |
Cisplatin | S. choleraesuis | Intraperitoneal | Lung tumor (murine LL/2 cell line)/C57BL/6 mice and hepatoma (murine ML-1 cell line)/BALB/c mice |
|
| [102] |
Gemcitabine | S. typhimurium A1-R | Intravenous | Pancreatic cancer PDOX mouse model/nude mice |
|
| [103] |
Cyclophosphamide | S. typhimurium VNP20009 | Intraperitoneal | Melanoma model (murine B16F10 cell line)/C57BL/6 mice |
|
| [104] |
Triptolide | S. typhimurium VNP20009 | Intraperitoneal or intratumoral | Melanoma model (murine B16F10 cell line)/C57BL/6 mice |
|
| [67] |
Carboplati-num | S. typhimurium A1-R | Intravenous | Cancer of unknown primary PDOX model/ nude mice |
|
| [105] |
Salmonella Strain | Route of Administration | Cancer Model | Phase | Recruitment Status | Identifier (Nct Number) | Ref |
---|---|---|---|---|---|---|
VNP20009 | Intratumoral | Refractory, superficial solid tumors | I | Completed | NCT00004216 | [175] |
VNP20009 | Intravenous | Advanced or metastatic cancer | I | Completed | NCT00004988 | [176] |
VNP20009 | Intravenous | Metastatic melanoma and metastatic renal cell carcinoma (RCC) | I | Completed | NCT00006254 | [177] |
S. typhimurium SalpIL2 (expresses human IL-2) | Oral | Liver metastasis of solid tumors | I | Completed | NCT01099631 | [178] |
VXM01 vaccine (S. typhimurium Ty21a expresses VEGFR2) | Oral | Advanced pancreatic cancer | I | Completed | NCT01486329 | [179] |
Salmonella CVD908ssb strain (TXSVN vaccine) | Oral | Multiple myeloma | I | Not yet recruiting | NCT03762291 | [180] |
S. typhimurium strain (SS2017) expressing tumor DNA vaccine | Oral | Neuroblastoma | Early phase I | Recruiting | NCT04049864 | [181] |
Saltikva (S. typhimurium expresses human IL-2) | Oral | Metastatic pancreatic cancer | II | Recruiting | NCT04589234 | [182] |
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Al-Saafeen, B.H.; Fernandez-Cabezudo, M.J.; al-Ramadi, B.K. Integration of Salmonella into Combination Cancer Therapy. Cancers 2021, 13, 3228. https://doi.org/10.3390/cancers13133228
Al-Saafeen BH, Fernandez-Cabezudo MJ, al-Ramadi BK. Integration of Salmonella into Combination Cancer Therapy. Cancers. 2021; 13(13):3228. https://doi.org/10.3390/cancers13133228
Chicago/Turabian StyleAl-Saafeen, Besan H., Maria J. Fernandez-Cabezudo, and Basel K. al-Ramadi. 2021. "Integration of Salmonella into Combination Cancer Therapy" Cancers 13, no. 13: 3228. https://doi.org/10.3390/cancers13133228