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Home / Equine Research Bank / J Immunother Cancer / Simple and effective bacterial-based intratumoral cancer imm...
Journal for immunotherapy of cancer2021; 9(9); doi: 10.1136/jitc-2021-002688

Simple and effective bacterial-based intratumoral cancer immunotherapy.

Abstract: We describe intratumoral injection of a slow-release emulsion of killed mycobacteria (complete Freund's adjuvant (CFA)) in three preclinical species and in human cancer patients. Efficacy and safety were tested in mammary tumors in mice, in mastocytomas in mice and dogs, and in equine melanomas. In mice, survival, tumor growth, and tumor infiltration by six immune cell subsets (by flow cytometry) were investigated and analyzed using Cox proportional hazards, a random slopes model, and a full factorial model, respectively. Tumor growth and histology were investigated in dogs and horses, as well as survival and tumor immunohistochemistry in dogs. Tumor biopsies were taken from human cancer patients on day 5 (all patients) and day 28 (some patients) of treatment and analyzed by histology. CT scans are provided from one patient. Significantly extended survival was observed in mouse P815 and 4T1 tumor models. Complete tumor regressions were observed in all three non-human species (6/186 (3%) of mouse mastocytomas; 3/14 (21%) of canine mastocytomas and 2/11 (18%) of equine melanomas). Evidence of systemic immune responses (regression of non-injected metastases) was also observed. Analysis of immune cells infiltrating mastocytoma tumors in mice showed that early neutrophil infiltration was predictive of treatment benefit. Analysis of the site of mastocytoma regression in dogs weeks or months after treatment demonstrated increased B and T cell infiltrates. Thus, activation of the innate immune system alone may be sufficient for regression of some injected tumors, followed by activation of the acquired immune system which can mediate regression of non-injected metastases. Finally, we report on the use of CFA in 12 human cancer patients. Treatment was well tolerated. CT scans showing tumor regression in a patient with late-stage renal cancer are provided. Our data demonstrate that intratumoral injection of CFA has major antitumor effects in a proportion of treated animals and is safe for use in human cancer patients. Further trials in human cancer patients are therefore warranted. Our novel treatment provides a simple and inexpensive cancer immunotherapy, immediately applicable to a wide range of solid tumors, and is suitable to patients in developing countries and advanced care settings.
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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Publication Date: 2021-09-18 PubMed ID: 34531247PubMed Central: PMC8449973DOI: 10.1136/jitc-2021-002688Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research study details the effectiveness of using killed mycobacteria, in the form of complete Freund’s adjuvant (CFA), for intratumoral injections in various species and human cancer patients. The researchers found that the treatment can lead to tumor regression, survival extension, and is safe for human use.

Study Design and Methodology

  • The researchers conducted their study using three different preclinical animal species and human cancer patients. The animal models used were mice with mammary tumors and mastocytomas, dogs with mastocytomas, and horses with melanomas.
  • Essentially, the killed mycobacteria were prepared in a slow-release emulsion form called complete Freund’s adjuvant (CFA) and injected directly into the tumors.
  • The treatment’s effectiveness was assessed by watching for changes in survival rates, tumor growth, and the infiltration of immune cells in the tumor in mice. In dogs and horses, tumor growth, histology, and survival rates were examined.
  • Human cancer patients underwent tumor biopsies on the 5th and 28th day of treatment, after which the biopsies were analyzed histologically. One patient’s CT scans were also reviewed.

Findings in Animal Models

  • The treatment application extended survival in mice tumor models significantly.
  • There was a complete regression of tumors across all three animal models, albeit with varying success rates. Mouse mastocytomas had 3% regression, canine mastocytomas had 21%, and equine melanomas had 18% regression.
  • The researchers also noted evidence of systemic immune responses by observing the regression of non-injected metastases.
  • Analysis of immune cell infiltration hinted that early infiltration of neutrophils might predict positive treatment outcomes. Further analysis showed increased B and T cell infiltration weeks or months after treatment at the site of canine mastocytoma regression.

Findings in Human Patients

  • The researchers moved to test the adequacy of CFA in 12 human cancer patients, primarily they were looking at the safety of the treatment. The treatment was well tolerated among the patients.
  • CT scans from one patient with late-stage renal cancer showed tumor regression, demonstrating the efficacy of the treatment in humans alongside its safety.

Implications and Future Directions

  • The success of this study thus shows that CFA could potentially play a significant role in intratumoral cancer immunotherapy. However, more trials involving human patients are necessary to solidify this notion.
  • CFA’s success as a simple, cheap, and effective cancer treatment can greatly benefit many patients, particularly in regions with underdeveloped healthcare systems or advanced care settings.

Cite This Article

APA
Carroll CSE, Andrew ER, Malik L, Elliott KF, Brennan M, Meyer J, Hintze A, Almonte AA, Lappin C, MacPherson P, Schulte KM, Dahlstrom JE, Tamhane R, Neeman T, Herbert EW, Orange M, Yip D, Allavena R, Fahrer AM. (2021). Simple and effective bacterial-based intratumoral cancer immunotherapy. J Immunother Cancer, 9(9). https://doi.org/10.1136/jitc-2021-002688

Publication

Journal for immunotherapy of cancer
ISSN: 2051-1426
NlmUniqueID: 101620585
Country: England
Language: English
Volume: 9
Issue: 9

Researcher Affiliations

Carroll, Christina S E
  • Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia.
Andrew, Erin R
  • Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia.
Malik, Laeeq
  • Department of Medical Oncology, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
  • Medical School, Australian National University, Canberra, Australian Capital Territory, Australia.
Elliott, Kathryn F
  • School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
Brennan, Moira
  • School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
Meyer, James
  • Adelaide Plains Equine Clinic, Gawler, South Australia, Australia.
Hintze, Alexander
  • Klinik Arlesheim, Haus Wegman, Arlseheim, Switzerland.
Almonte, Andrew A
  • Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia.
Lappin, Cassandra
  • School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
MacPherson, Philip
  • School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
Schulte, Klaus-Martin
  • Medical School, Australian National University, Canberra, Australian Capital Territory, Australia.
Dahlstrom, Jane E
  • Medical School, Australian National University, Canberra, Australian Capital Territory, Australia.
  • ACT Pathology, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
Tamhane, Rohit
  • Canberra Imaging Group, Canberra, Australian Capital Territory, Australia.
Neeman, Teresa
  • Biological Data Science Institute, Australian National University, Canberra, Australian Capital Territory, Australia.
Herbert, Elizabeth W
  • Adelaide Plains Equine Clinic, Gawler, South Australia, Australia.
Orange, Maurice
  • Klinik Arlesheim, Haus Wegman, Arlseheim, Switzerland.
Yip, Desmond
  • Department of Medical Oncology, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
  • Medical School, Australian National University, Canberra, Australian Capital Territory, Australia.
Allavena, Rachel
  • School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
Fahrer, Aude M
  • Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia aude.fahrer@anu.edu.au.

MeSH Terms

  • Animals
  • Cell Line, Tumor
  • Dogs
  • Female
  • Horses
  • Humans
  • Immunotherapy / methods
  • Male
  • Mice
  • Neoplasms / drug therapy

Conflict of Interest Statement

Competing interests: None declared.

References

This article includes 38 references
  1. Fahrer AM. A proposal for a simple and inexpensive therapeutic cancer vaccine. Immunol Cell Biol 2012;90:310–3.
    doi: 10.1038/icb.2011.42pubmed: 21606943google scholar: lookup
  2. Sagiv-Barfi I, Czerwinski DK, Levy S. Eradication of spontaneous malignancy by local immunotherapy. Sci Transl Med 2018;10.
    doi: 10.1126/scitranslmed.aan4488pmc: PMC5997264pubmed: 29386357google scholar: lookup
  3. Nauts HC, Swift WE, Coley BL. The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M.D., reviewed in the light of modern research. Cancer Res 1946;6:205–16.
    pubmed: 21018724
  4. Nauts HC, McLaren JR. Coley toxins-the first century. Adv Exp Med Biol 1990;267:483–500.
    doi: 10.1007/978-1-4684-5766-7_52pubmed: 2088067google scholar: lookup
  5. Sedighi M, Zahedi Bialvaei A, Hamblin MR. Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities. Cancer Med 2019;8:3167–81.
    doi: 10.1002/cam4.2148pmc: PMC6558487pubmed: 30950210google scholar: lookup
  6. Zhou S, Gravekamp C, Bermudes D. Tumour-targeting bacteria engineered to fight cancer. Nat Rev Cancer 2018;18:727–43.
    doi: 10.1038/s41568-018-0070-zpmc: PMC6902869pubmed: 30405213google scholar: lookup
  7. Twumasi-Boateng K, Pettigrew JL, Kwok YYE. Oncolytic viruses as engineering platforms for combination immunotherapy. Nat Rev Cancer 2018;18:419–32.
    doi: 10.1038/s41568-018-0009-4pubmed: 29695749google scholar: lookup
  8. Hernández-Luna MA, Luria-Pérez R. Cancer Immunotherapy: priming the Host Immune Response with Live Attenuated Salmonella enterica. J Immunol Res 2018;2018:1–15.
    doi: 10.1155/2018/2984247pmc: PMC6158935pubmed: 30302344google scholar: lookup
  9. Lee S-Y, Yang S-B, Choi Y-M. Heat-Killed Mycobacterium paragordonae therapy exerts an anti-cancer immune response via enhanced immune cell mediated oncolytic activity in xenograft mice model. Cancer Lett 2020;472:142–50.
    doi: 10.1016/j.canlet.2019.12.028pubmed: 31874244google scholar: lookup
  10. Mathé G, Florentin I, Bruley-Rosset M. Heat-Killed Pseudomonas aeruginosa as a systemic adjuvant in cancer immunotherapy. Biomedicine 1977;27:368–73.
    pubmed: 414800
  11. Viaud S, Saccheri F, Mignot G. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013;342:971–6.
    doi: 10.1126/science.1240537pmc: PMC4048947pubmed: 24264990google scholar: lookup
  12. Iida N, Dzutsev A, Stewart CA. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 2013;342:967–70.
    doi: 10.1126/science.1240527pmc: PMC6709532pubmed: 24264989google scholar: lookup
  13. Yu T, Guo F, Yu Y. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 2017;170:548–63.
    doi: 10.1016/j.cell.2017.07.008pmc: PMC5767127pubmed: 28753429google scholar: lookup
  14. Routy B, Le Chatelier E, Derosa L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91–7.
    doi: 10.1126/science.aan3706pubmed: 29097494google scholar: lookup
  15. Baruch EN, Youngster I, Ben-Betzalel G. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 2021;371:602–9.
    doi: 10.1126/science.abb5920pubmed: 33303685google scholar: lookup
  16. Matson V, Fessler J, Bao R. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359:104–8.
    doi: 10.1126/science.aao3290pmc: PMC6707353pubmed: 29302014google scholar: lookup
  17. Almonte AA, Rangarajan H, Yip D. How does the gut microbiome influence immune checkpoint blockade therapy?. Immunol Cell Biol 2021;99:361–72.
    doi: 10.1111/imcb.12423pubmed: 33147357google scholar: lookup
  18. Marchesi JR, Dutilh BE, Hall N. Towards the human colorectal cancer microbiome. PLoS One 2011;6:e20447.
    doi: 10.1371/journal.pone.0020447pmc: PMC3101260pubmed: 21647227google scholar: lookup
  19. Geller LT, Barzily-Rokni M, Danino T. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 2017;357:1156–60.
    doi: 10.1126/science.aah5043pmc: PMC5727343pubmed: 28912244google scholar: lookup
  20. Nejman D, Livyatan I, Fuks G. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 2020;368:973–80.
    doi: 10.1126/science.aay9189pmc: PMC7757858pubmed: 32467386google scholar: lookup
  21. Kalaora S, Nagler A, Nejman D. Identification of bacteria-derived HLA-bound peptides in melanoma. Nature 2021;592:138–43.
    doi: 10.1038/s41586-021-03368-8pmc: PMC9717498pubmed: 33731925google scholar: lookup
  22. Freund J. The mode of action of immunologic adjuvants. Bibl Tuberc 1956;7:130–48.
    pubmed: 13341884
  23. Carroll CSE, Altin JG, Neeman T. Repeated fine-needle aspiration of solid tumours in mice allows the identification of multiple infiltrating immune cell types. J Immunol Methods 2015;425:102–7.
    doi: 10.1016/j.jim.2015.06.015pubmed: 26159390google scholar: lookup
  24. Kiupel M, Webster JD, Bailey KL. Proposal of a 2-tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior. Vet Pathol 2011;48:147–55.
    doi: 10.1177/0300985810386469pmc: PMC8369849pubmed: 21062911google scholar: lookup
  25. Gordon I, Paoloni M, Mazcko C. The comparative oncology trials Consortium: using spontaneously occurring cancers in dogs to inform the cancer drug development pathway. PLoS Med 2009;6:e1000161.
    doi: 10.1371/journal.pmed.1000161pmc: PMC2753665pubmed: 19823573google scholar: lookup
  26. Paoloni M, Khanna C. Translation of new cancer treatments from PET dogs to humans. Nat Rev Cancer 2008;8:147–56.
    doi: 10.1038/nrc2273pubmed: 18202698google scholar: lookup
  27. Roberts NJ, Zhang L, Janku F. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci Transl Med 2014;6:249ra111.
    doi: 10.1126/scitranslmed.3008982pmc: PMC4399712pubmed: 25122639google scholar: lookup
  28. Veterinary cooperative oncology group. Common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Vet Comp Oncol 2011;14:417–46.
    pubmed: 28530307
  29. Rosengren Pielberg G, Golovko A, Sundström E. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse. Nat Genet 2008;40:1004–9.
    doi: 10.1038/ng.185pubmed: 18641652google scholar: lookup
  30. Curik I, Druml T, Seltenhammer M. Complex inheritance of melanoma and pigmentation of coat and skin in grey horses. PLoS Genet 2013;9:e1003248.
    doi: 10.1371/journal.pgen.1003248pmc: PMC3567150pubmed: 23408897google scholar: lookup
  31. Park JS, Withers SS, Modiano JF. Canine cancer immunotherapy studies: linking mouse and human. J Immunother Cancer 2016;4:97.
    doi: 10.1186/s40425-016-0200-7pmc: PMC5171656pubmed: 28031824google scholar: lookup
  32. Guiducci C, Vicari AP, Sangaletti S. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res 2005;65:3437–46.
    doi: 10.1158/0008-5472.CAN-04-4262pubmed: 15833879google scholar: lookup
  33. Coley WB. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med 1910;3:1–48.
    doi: 10.1177/003591571000301601pmc: PMC1961042pubmed: 19974799google scholar: lookup
  34. Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer--a current perspective. Nat Rev Urol 2014;11:153–62.
    doi: 10.1038/nrurol.2014.15pubmed: 24492433google scholar: lookup
  35. Sivan A, Corrales L, Hubert N. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350:1084–9.
    doi: 10.1126/science.aac4255pmc: PMC4873287pubmed: 26541606google scholar: lookup
  36. Vétizou M, Pitt JM, Daillère R. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015;350:1079–84.
    doi: 10.1126/science.aad1329pmc: PMC4721659pubmed: 26541610google scholar: lookup
  37. Soularue E, Lepage P, Colombel JF. Enterocolitis due to immune checkpoint inhibitors: a systematic review. Gut 2018;67:2056–67.
    doi: 10.1136/gutjnl-2018-316948pubmed: 30131322google scholar: lookup
  38. Derosa L, Hellmann MD, Spaziano M. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol 2018;29:1437–44.
    doi: 10.1093/annonc/mdy103pmc: PMC6354674pubmed: 29617710google scholar: lookup
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