There is no doubt that immunotherapy lies in the spotlight of current cancer research and clinical trials. However, there are still limitations in the treatment response in certain types of tumors largely due to the presence of the complex network of immunomodulatory and immunosuppressive pathways. These limitations are not likely to be overcome by current immunotherapeutic options, which often target isolated steps in immune pathways preferentially involved in adaptive immunity. Recently, we have developed an innovative anti-cancer immunotherapeutic strategy that initially elicits a strong innate immune response with subsequent activation of adaptive immunity in mouse models. Robust primary innate immune response against tumor cells is induced by toll-like receptor ligands and anti-CD40 agonistic antibodies combined with the phagocytosis-stimulating ligand mannan, anchored to a tumor cell membrane by biocompatible anchor for membrane. This immunotherapeutic approach results in a dramatic therapeutic response in large established murine subcutaneous tumors including melanoma, sarcoma, pancreatic adenocarcinoma, and pheochromocytoma. Additionally, eradication of metastases and/or long-lasting resistance to subsequent re-challenge with tumor cells was also accomplished. Current and future advantages of this immunotherapeutic approach and its possible combinations with other available therapies are discussed in this review.

Department of Medical Biology Faculty of Science University of South Bohemia Ceske Budejovice 37005 Czech Republic

Immunoaction LLC Charlotte Vermont VT 05445 USA

Neuro Oncology Branch National Cancer Institute National Institutes of Health Bethesda Maryland MD 20814 USA

Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda Maryland MD 20814 USA

Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda Maryland MD 20814 USA; Department of Medical Biology Faculty of Science University of South Bohemia Ceske Budejovice 37005 Czech Republic

Zobrazit více v PubMed

Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350–5. PubMed PMC

Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12(4):278–87. PubMed

Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res. 1991(262):3–11. PubMed

Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801. PubMed

Wang RF. Tumor antigens discovery: perspectives for cancer therapy. Mol Med. 1997;3(11):716–31. PubMed PMC

Kudrin A Cancer vaccines: what do we need to measure in clinical trials? Hum Vaccin Immunother. 2014;10(11):3236–40. PubMed PMC

Jacobs JJ, Snackey C, Geldof AA, et al. Inefficacy of therapeutic cancer vaccines and proposed improvements. Casus of prostate cancer. Anticancer Res. 2014;34(6):2689–700. PubMed

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. PubMed

Russell M, Huang X, Vuzman D, et al. Characterization of biomarkers to immune checkpoint blockade therapy across solid tumors. J Clin Oncol. 2018;36(5).

Dempke WCM, Fenchel K, Uciechowski P, Dale SP. Second- and third-generation drugs for immune-oncology treatment-The more the better? Eur J Cancer. 2017;74:55–72. PubMed

Thallinger C, Fureder T, Preusser M, et al. Review of cancer treatment with immune checkpoint inhibitors : Current concepts, expectations, limitations and pitfalls. Wien Klin Wochenschr. 2018;130(3–4):85–91. PubMed PMC

Kaiser J Too much of a good thing? Science. 2018;359(6382):1346–7. PubMed

Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur j Cancer. 2016;54:139–48. PubMed

Chaplin DD. Overview of the immune response. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S3–23. PubMed PMC

Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60. PubMed

Schreiber RD, Old Lj, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70. PubMed

Smyth MJ, Godfrey DI, Trapani JA. A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol. 2001;2(4):293–9. PubMed

Reis ES, Mastellos DC, Ricklin D, Mantovani A, Lambris JD. Complement in cancer: untangling an intricate relationship. Nat Rev Immunol. 2018;18(1):5–18. PubMed PMC

Kourtzelis I, Rafail S. The dual role of complement in cancer and its implication in anti-tumor therapy. Ann Transl Med. 2016;4(14):265. PubMed PMC

Roumenina LT, Daugan MV, Noe R, et al. Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth. Cancer Immunol Res. 2019;7(7):1091–105. PubMed

Smyth MJ, Sullivan LC, Brooks AG, Andrews DM. Non-classical MHC Class I molecules regulating natural killer cell function. Oncoimmunology. 2013;2(3):e23336. PubMed PMC

Waldhauer I, Steinle A. NK cells and cancer immunosurveillance. Oncogene. 2008;27(45):5932–43. PubMed

Wang X, Qiu L, Li Z, Wang XY, Yi H. Understanding the Multifaceted Role of Neutrophils in Cancer and Autoimmune Diseases. Front Immunol. 2018;9:2456. PubMed PMC

Yan J, Kloecker G, Fleming C, et al. Human polymorphonuclear neutrophils specifically recognize and kill cancerous cells. Oncoimmunology. 2014;3(7):e950163. PubMed PMC

Gardner A, Ruffell B. Dendritic Cells and Cancer Immunity. Trends Immunol. 2016;37(12):855–65. PubMed PMC

Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124(2):263–6. PubMed

Balkwill F, Montfort A, Capasso M. B regulatory cells in cancer. Trends Immunol. 2013;34(4):169–73. PubMed

Ribas A Adaptive Immune Resistance: How Cancer Protects from Immune Attack. Cancer Discov. 2015;5(9):915–9. PubMed PMC

Zou W Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer. 2005;5(4):263–74. PubMed

Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-Based Cell-Cell Communication in the Tumor Microenvironment. Front Cell Dev Biol. 2018;6:18. PubMed PMC

Seager RJ, Hajal C, Spill F, Kamm RD, Zaman MH. Dynamic interplay between tumour, stroma and immune system can drive or prevent tumour progression. Converg Sci phys Oncol. 2017;3. PubMed PMC

Cui Z, Willingham MC, Hicks AM, et al. Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice. Proc Natl Acad Sci U S A. 2003;100(11):6682–7. PubMed PMC

Janotova T, Jalovecka M, Auerova M, et al. The use of anchored agonists of phagocytic receptors for cancer immunotherapy: B16-F10 murine melanoma model. PLoS One. 2014;9(1):e85222. PubMed PMC

Waldmannova E, Caisova V, Faberova J, et al. The use of Zymosan A and bacteria anchored to tumor cells for effective cancer immunotherapy: B16-F10 murine melanoma model. Int Immunopharmacol. 2016;39:295–306. PubMed

Caisova V, Uher O, Nedbalova P, et al. Effective cancer immunotherapy based on combination of TLR agonists with stimulation of phagocytosis. Int Immunopharmacol. 2018;59:86–96. PubMed

Caisova V, Li L, Gupta G, et al. The Significant Reduction or Complete Eradication of Subcutaneous and Metastatic Lesions in a Pheochromocytoma Mouse Model after Immunotherapy Using Mannan-BAM, TLR Ligands, and Anti-CD40. Cancers (Basel). 2019;11(5). PubMed PMC

Marabelle A, Kohrt H, Caux C, Levy R. Intratumoral immunization: a new paradigm for cancer therapy. Clin Cancer Res. 2014;20(7):1747–56. PubMed PMC

Nelson D, Fisher S, Robinson B. The “Trojan Horse” approach to tumor immunotherapy: targeting the tumor microenvironment. J Immunol Res. 2014;2014:789069. PubMed PMC

van den Boorn JG, Hartmann G. Turning tumors into vaccines: co-opting the innate immune system. Immunity. 2013;39(1):27–37. PubMed

Underhill DM, Gantner B. Integration of Toll-like receptor and phagocytic signaling for tailored immunity. Microbes Infect. 2004;6(15):1368–73. PubMed

Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol. 2007;7(3):179–90. PubMed

Bourquin C, Hotz C, Noerenberg D, et al. Systemic cancer therapy with a small molecule agonist of toll-like receptor 7 can be improved by circumventing TLR tolerance. Cancer Res. 2011;71(15):5123–33. PubMed

Oberstein PE, Olive KP. Pancreatic cancer: why is it so hard to treat? Therap Adv Gastroenterol. 2013;6(4):321–37. PubMed PMC

Crona J, Taieb D, Pacak K. New Perspectives on Pheochromocytoma and Paraganglioma: Toward a Molecular Classification. Endocr Rev. 2017;38(6):489–515. PubMed PMC

Wang X, Li M. Correlate tumor mutation burden with immune signatures in human cancers. BMC Immunol. 2019;20(1):4. PubMed PMC

Wood MA, Paralkar M, Paralkar MP, et al. Population-level distribution and putative immunogenicity of cancer neoepitopes. BMC Cancer. 2018;18(1):414. PubMed PMC

Liyanage UK, Goedegebuure PS, Moore TT, et al. Increased prevalence of regulatory T cells (Treg) is induced by pancreas adenocarcinoma. J Immunother. 2006;29(4):416–24. PubMed

Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Front Oncol. 2018;8:86. PubMed PMC

Soares KC, Rucki AA, Wu AA, et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother. 2015;38(1):1–11. PubMed PMC

Rakhmilevich AL, Alderson KL, Sondel PM. T-cell-independent antitumor effects of CD40 ligation. Int Rev Immunol. 2012;31(4):267–78. PubMed PMC

Khong A, Nelson DJ, Nowak AK, Lake RA, Robinson BWS the Use of Agonistic Anti-CD40 Therapy in Treatments for Cancer. International Reviews of Immunology. 2012;31(4):246–66. PubMed

Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013;19(5):1035–43. PubMed PMC

Ahonen CL, Doxsee CL, McGurran SM, et al. Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN. J Exp Med. 2004;199(6):775–84. PubMed PMC

Vonderheide RH. CD40 Agonist Antibodies in Cancer Immunotherapy. Annu Rev Med. 2019. PubMed

Vacchelli E, Galluzzi L, Eggermont A, et al. Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy. Oncoimmunology. 2012;1(6):894–907. PubMed PMC

Fuge O, Vasdev N, Allchorne P, Green JS. Immunotherapy for bladder cancer. Res Rep Urol. 2015;7:65–79. PubMed PMC

Gandhi NM, Morales A, Lamm DL. Bacillus Calmette-Guerin immunotherapy for genitourinary cancer. BJU Int. 2013;112(3):288–97. PubMed

Agosti JM, Goldie SJ. Introducing HPV vaccine in developing countries--key challenges and issues. N Engl J Med. 2007;356(19):1908–10. PubMed

Mata-Haro V, Cekic C, Martin M, et al. The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science. 2007;316(5831):1628–32. PubMed

Shi M, Chen X, Ye K, Yao Y, Li Y. Application potential of toll-like receptors in cancer immunotherapy: Systematic review. Medicine (Baltimore). 2016;95(25):e3951. PubMed PMC

Anwar MA, Shah M, Kim J, Choi S. Recent clinical trends in Toll-like receptor targeting therapeutics. Med Res Rev. 2019;39(3):1053–90. PubMed PMC

Liu C, Han C, Liu J. The Role of Toll-Like Receptors in Oncotherapy. Oncol Res. 2019;27(8):965–78. PubMed PMC

Mikulandra M, Pavelic J, Glavan TM. Recent Findings on the Application of Toll-like Receptors Agonists in Cancer Therapy. Curr Med Chem. 2017;24(19):2011–32. PubMed

Marsh JC. The effects of cancer chemotherapeutic agents on normal hematopoietic precursor cells: a review. Cancer Res. 1976;36(6):1853–82. PubMed

Mauch P, Constine L, Greenberger J, et al. Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys. 1995;31(5):1319–39. PubMed

Schaue D, McBride WH. T lymphocytes and normal tissue responses to radiation. Front Oncol. 2012;2:119. PubMed PMC

Hanoteau A, Moser M. Chemotherapy and immunotherapy: A close interplay to fight cancer? Oncoimmunology. 2016;5(7):e1190061. PubMed PMC

Turtle CJ, Swanson HM, Fujii N, Estey EH, Riddell SR. A distinct subset of self-renewing human memory CD8+ T cells survives cytotoxic chemotherapy. Immunity. 2009;31(5):834–44. PubMed PMC

Lea NC, Orr SJ, Stoeber K, et al. Commitment point during G0-->G1 that controls entry into the cell cycle. Mol Cell Biol. 2003;23(7):2351–61. PubMed PMC

Schlom J, Arlen PM, Gulley JL. Cancer vaccines: moving beyond current paradigms. Clin Cancer Res. 2007;13(13):3776–82. PubMed PMC

Wheeler CJ, Das A, Liu G, Yu JS, Black KL. Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clin Cancer Res. 2004;10(16):5316–26. PubMed

Fridlender ZG, Sun J, Singhal S, et al. Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms. Mol Ther. 2010;18(11):1947–59. PubMed PMC

Sabel MS. Cryo-immunology: a review of the literature and proposed mechanisms for stimulatory versus suppressive immune responses. Cryobiology. 2009;58(1):1–11. PubMed

Shi J, Li Y, Liang S, et al. Analysis of circulating tumor cells in colorectal cancer liver metastasis patients before and after cryosurgery. Cancer Biol Ther.2016;17(9):935–42. PubMed PMC

Wennerberg E, Lhuillier C, Vanpouille-Box C, et al. Barriers to Radiation-Induced In Situ Tumor Vaccination. Front Immunol. 2017;8:229. PubMed PMC

Engel AL, Holt GE, Lu H. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system. Expert Rev Clin Pharmacol. 2011;4(2):275–89. PubMed PMC

Role of B cells in intratumoral MBTA immunotherapy of murine pheochromocytoma model

The combination of immunotherapy and a glutamine metabolism inhibitor represents an effective therapeutic strategy for advanced and metastatic murine pancreatic adenocarcinoma

Mannan-BAM, TLR ligands, and anti-CD40 immunotherapy in established murine pancreatic adenocarcinoma: understanding therapeutic potentials and limitations

Identification of Immune Cell Infiltration in Murine Pheochromocytoma during Combined Mannan-BAM, TLR Ligand, and Anti-CD40 Antibody-Based Immunotherapy