TY - JOUR

T1 - Theoretical premises of a "three in one" therapeutic approach to treat immunogenic and nonimmunogenic cancers: a narrative review

AU - Proskurina, Anastasia S.

AU - Ruzanova, Vera S.

AU - Ostanin, Alexandr A.

AU - Chernykh, Elena R.

AU - Bogachev, Sergey S.

N1 - Funding Information: The authors are sincerely grateful to Andrey A. Gorchakov for the brilliant translation of the manuscript. Funding: This work was supported by the Russian Ministry of Science and Higher Education via the Institute of Cytology and Genetics (State Budget Project No. 0259-2021-0013), the Russian Foundation for Basic Research (Project No. 18-29-09045), and “Karanahan” LLC. Publisher Copyright: © 2021 AME Publishing Company. All rights reserved. 2021 Translational Cancer Research. All rights reserved.

PY - 2021/11

Y1 - 2021/11

N2 - Objective: We describe experimental and theoretical premises of a powerful cancer therapy based on the combination of three approaches. These include (I) in situ vaccination (intratumoral injections of CpG oligonucleotides and anti-OX40 antibody); (II) chronometric or metronomic low-dose cyclophosphamide (CMLD CP)-based chemotherapy; (III) cancer stem cell-eradicating therapy referred to as Karanahan (from the Sanskrit karana ["source"] + han ["to kill"]). Background: In murine models, the first two approaches are particularly potent in targeting immunogenic tumors for destruction. In situ vaccination activates a fully fledged anticancer immune response via an intricate network of ligand-receptor-cytokine interactions. CMLD CP-based chemotherapy primarily targets the suppressive tumor microenvironment and activates tumor-infiltrating effectors. In contrast, Karanahan technology, being aimed at replicative machinery of tumor cells (both stem-like and committed), does not depend on tumor immunogenicity. With this technology, mice engrafted with ascites and/or solid tumors can be successfully cured. There is a significant degree of mechanistic and therapeutic overlap between these three approaches. For instance, the similarities shared between in situ vaccination and Karanahan technology include the therapeutic procedure, the cell target [antigen-presenting cells (APC) and dendritic cells (DC)], and the use of DNA-based preparations (CpG and DNAmix). Features shared between CMLD CP-based chemotherapy and Karanahan technology are the timing and the dose of the cytostatic drug administration, which lead to tumor regression. Methods: The following keywords were used to search PubMed for the latest research reporting successful eradication of transplantable cancers in animal models that relied on approaches distinct from those used in the Karanahan technology: Eradication of malignancy, cure cancer, complete tumor regression, permanently eradicating advanced mouse tumor, metronomic chemotherapy, in situ vaccination, immunotherapy, and others. Conclusion: We hypothesize, therefore, that very potent anticancer activity can be achieved once these three therapeutic modalities are combined into a single approach. This multimodal approach is theoretically curative for any type of cancer that depends on the presence of tumor-inducing cancer stem cells, provided that the active therapeutic components are efficiently delivered into the tumor and the specific biological features of a given patient's tumor are properly addressed. We expect this multimodal approach to be primarily applicable to late-stage or terminal cancer patients who have exhausted all treatment options as well as patients with inoperable tumors.

AB - Objective: We describe experimental and theoretical premises of a powerful cancer therapy based on the combination of three approaches. These include (I) in situ vaccination (intratumoral injections of CpG oligonucleotides and anti-OX40 antibody); (II) chronometric or metronomic low-dose cyclophosphamide (CMLD CP)-based chemotherapy; (III) cancer stem cell-eradicating therapy referred to as Karanahan (from the Sanskrit karana ["source"] + han ["to kill"]). Background: In murine models, the first two approaches are particularly potent in targeting immunogenic tumors for destruction. In situ vaccination activates a fully fledged anticancer immune response via an intricate network of ligand-receptor-cytokine interactions. CMLD CP-based chemotherapy primarily targets the suppressive tumor microenvironment and activates tumor-infiltrating effectors. In contrast, Karanahan technology, being aimed at replicative machinery of tumor cells (both stem-like and committed), does not depend on tumor immunogenicity. With this technology, mice engrafted with ascites and/or solid tumors can be successfully cured. There is a significant degree of mechanistic and therapeutic overlap between these three approaches. For instance, the similarities shared between in situ vaccination and Karanahan technology include the therapeutic procedure, the cell target [antigen-presenting cells (APC) and dendritic cells (DC)], and the use of DNA-based preparations (CpG and DNAmix). Features shared between CMLD CP-based chemotherapy and Karanahan technology are the timing and the dose of the cytostatic drug administration, which lead to tumor regression. Methods: The following keywords were used to search PubMed for the latest research reporting successful eradication of transplantable cancers in animal models that relied on approaches distinct from those used in the Karanahan technology: Eradication of malignancy, cure cancer, complete tumor regression, permanently eradicating advanced mouse tumor, metronomic chemotherapy, in situ vaccination, immunotherapy, and others. Conclusion: We hypothesize, therefore, that very potent anticancer activity can be achieved once these three therapeutic modalities are combined into a single approach. This multimodal approach is theoretically curative for any type of cancer that depends on the presence of tumor-inducing cancer stem cells, provided that the active therapeutic components are efficiently delivered into the tumor and the specific biological features of a given patient's tumor are properly addressed. We expect this multimodal approach to be primarily applicable to late-stage or terminal cancer patients who have exhausted all treatment options as well as patients with inoperable tumors.

KW - In situ vaccination

KW - chronometric

KW - metronome low-dose chemotherapy

KW - Karanahan technology

KW - immunity

KW - cancer stem cells

KW - IN-SITU VACCINATION

KW - CELLS ERADICATION STRATEGY

KW - STEM-CELLS

KW - DENDRITIC CELLS

KW - METRONOMIC CYCLOPHOSPHAMIDE

KW - SCHEDULE-DEPENDENCE

KW - ANTITUMOR IMMUNITY

KW - SUPPRESSOR-CELLS

KW - TUMOR-REGRESSION

KW - INNATE IMMUNITY

KW - Immunity

KW - Chronometric/metronome low-dose chemotherapy

KW - Cancer stem cells

UR - http://www.scopus.com/inward/record.url?scp=85120412948&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/03c429d1-d092-3cf1-a9bc-e4f3fcc4e808/

U2 - 10.21037/tcr-21-919

DO - 10.21037/tcr-21-919

M3 - Review article

C2 - 35116346

VL - 10

SP - 4958

EP - 4972

JO - Translational cancer research

JF - Translational cancer research

SN - 2218-676X

IS - 11

ER -