Antitumor efficacy of multi-target <i>in situ</i> vaccinations with CpG oligodeoxynucleotides, anti-OX40, anti-PD1 antibodies, and aptamers

Anastasia S. Proskurina; Vera S. Ruzanova; Genrikh S. Ritter; Yaroslav R. Efremov; Zakhar S. Mustafin; Sergey A. Lashin; Ekaterina A. Burakova; Alesya A. Fokina; Timofei S. Zatsepin; Dmitry A. Stetsenko; Olga Y. Leplina; Alexandr A. Ostanin; Elena R. Chernykh; Sergey S. Bogachev

doi:10.7555/JBR.36.20220052

Volume 37 Issue 3

May 2023

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Article Navigation > The Journal of Biomedical Research > 2023 > 37(3): 194-212

Anastasia S. Proskurina, Vera S. Ruzanova, Genrikh S. Ritter, Yaroslav R. Efremov, Zakhar S. Mustafin, Sergey A. Lashin, Ekaterina A. Burakova, Alesya A. Fokina, Timofei S. Zatsepin, Dmitry A. Stetsenko, Olga Y. Leplina, Alexandr A. Ostanin, Elena R. Chernykh, Sergey S. Bogachev. Antitumor efficacy of multi-target in situ vaccinations with CpG oligodeoxynucleotides, anti-OX40, anti-PD1 antibodies, and aptamers[J]. The Journal of Biomedical Research, 2023, 37(3): 194-212. doi: 10.7555/JBR.36.20220052

Citation:

Anastasia S. Proskurina, Vera S. Ruzanova, Genrikh S. Ritter, Yaroslav R. Efremov, Zakhar S. Mustafin, Sergey A. Lashin, Ekaterina A. Burakova, Alesya A. Fokina, Timofei S. Zatsepin, Dmitry A. Stetsenko, Olga Y. Leplina, Alexandr A. Ostanin, Elena R. Chernykh, Sergey S. Bogachev. Antitumor efficacy of multi-target in situ vaccinations with CpG oligodeoxynucleotides, anti-OX40, anti-PD1 antibodies, and aptamers[J]. The Journal of Biomedical Research, 2023, 37(3): 194-212. doi: 10.7555/JBR.36.20220052

Citation:

Anastasia S. Proskurina, Vera S. Ruzanova, Genrikh S. Ritter, Yaroslav R. Efremov, Zakhar S. Mustafin, Sergey A. Lashin, Ekaterina A. Burakova, Alesya A. Fokina, Timofei S. Zatsepin, Dmitry A. Stetsenko, Olga Y. Leplina, Alexandr A. Ostanin, Elena R. Chernykh, Sergey S. Bogachev. Antitumor efficacy of multi-target in situ vaccinations with CpG oligodeoxynucleotides, anti-OX40, anti-PD1 antibodies, and aptamers[J]. The Journal of Biomedical Research, 2023, 37(3): 194-212. doi: 10.7555/JBR.36.20220052

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Antitumor efficacy of multi-target in situ vaccinations with CpG oligodeoxynucleotides, anti-OX40, anti-PD1 antibodies, and aptamers

doi: 10.7555/JBR.36.20220052

1.
Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia
2.
Department of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia
3.
Department of Physics, Novosibirsk State University, Novosibirsk 630090, Russia
4.
Department of Chemistry, Moscow State University, Moscow 119991, Russia
5.
Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia

More Information

Corresponding author: Sergey S. Bogachev, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentiev ave., Novosibirsk 630090, Russia. Tel: +7-383-363-49-63 ext. 3411, E-mail: labmolbiol@mail.ru
Received: 2022-03-14
Revised: 2022-07-04
Accepted: 2022-07-22

Published: 2022-11-28

Issue Date: 2023-05-28

Abstract

Abstract

To overcome immune tolerance to cancer, the immune system needs to be exposed to a multi-target action intervention. Here, we investigated the activating effect of CpG oligodeoxynucleotides (ODNs), mesyl phosphoramidate CpG ODNs, anti-OX40 antibodies, and OX40 RNA aptamers on major populations of immunocompetent cells ex vivo. Comparative analysis of the antitumor effects of in situ vaccination with CpG ODNs and anti-OX40 antibodies, as well as several other combinations, such as mesyl phosphoramidate CpG ODNs and OX40 RNA aptamers, was conducted. Antibodies against programmed death 1 (PD1) checkpoint inhibitors or their corresponding PD1 DNA aptamers were also added to vaccination regimens for analytical purposes. Four scenarios were considered: a weakly immunogenic Krebs-2 carcinoma grafted in CBA mice; a moderately immunogenic Lewis carcinoma grafted in C57Black/6 mice; and an immunogenic A20 B cell lymphoma or an Ehrlich carcinoma grafted in BALB/c mice. Adding anti-PD1 antibodies (CpG+αOX40+αPD1) to in situ vaccinations boosts the antitumor effect. When to be used instead of antibodies, aptamers also possess antitumor activity, although this effect was less pronounced. The strongest effect across all the tumors was observed in highly immunogenic A20 B cell lymphoma and Ehrlich carcinoma.
- immunogenicity,
- Krebs-2 carcinoma,
- Lewis carcinoma,
- Ehrlich carcinoma,
- A20 B cell lymphoma,
- mesyl phosphoramidate

CLC number: R730.5, Document code: A
The authors reported no conflict of interests.
△These authors contributed equally to this work.

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References(60)

References

[1]	Ferlay J, Colombet M, Soerjomataram I, et al. Cancer statistics for the year 2020: an overview[J]. Int J Cancer, 2021, 149(4): 778–789. doi: 10.1002/ijc.33588
[2]	Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age[J]. Nature, 2011, 480(7378): 480–489. doi: 10.1038/nature10673
[3]	Makkouk A, Weiner GJ. Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge[J]. Cancer Res, 2015, 75(1): 5–10. doi: 10.1158/0008-5472.CAN-14-2538
[4]	Vinay DS, Ryan EP, Pawelec G, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies[J]. Semin Cancer Biol, 2015, 35 Suppl 1: S185–S198. doi: 10.1016/j.semcancer.2015.03.004
[5]	Mittal D, Gubin MM, Schreiber RD, et al. New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape[J]. Curr Opin Immunol, 2014, 27(1): 16–25. doi: 10.1016/j.coi.2014.01.004
[6]	Wang J, Xu Y, Huang Z, et al. T cell exhaustion in cancer: mechanisms and clinical implications[J]. J Cell Biochem, 2018, 119(6): 4279–4286. doi: 10.1002/jcb.26645
[7]	Dine J, Gordon R, Shames Y, et al. Immune checkpoint inhibitors: an innovation in immunotherapy for the treatment and management of patients with cancer[J]. Asia Pac J Oncol Nurs, 2017, 4(2): 127–135. doi: 10.4103/apjon.apjon_4_17
[8]	Alizadeh D, Larmonier N. Chemotherapeutic targeting of cancer-induced immunosuppressive cells[J]. Cancer Res, 2014, 74(10): 2663–2668. doi: 10.1158/0008-5472.CAN-14-0301
[9]	Shirota Y, Shirota H, Klinman DM. Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells[J]. J Immunol, 2012, 188(4): 1592–1599. doi: 10.4049/jimmunol.1101304
[10]	Marabelle A, Tselikas L, de Baere T, et al. Intratumoral immunotherapy: using the tumor as the remedy[J]. Ann Oncol, 2017, 28(S12): xii33–xii43. doi: 10.1093/annonc/mdx683
[11]	Sagiv-Barfi I, Lu H, Hewitt J, et al. Intratumoral injection of TLR4 agonist (G100) leads to tumor regression of A20 lymphoma and induces abscopal responses[J]. Blood, 2015, 126(23): 820. doi: 10.1182/blood.V126.23.820.820
[12]	Sagiv-Barfi I, Czerwinski DK, Levy S, et al. Eradication of spontaneous malignancy by local immunotherapy[J]. Sci Transl Med, 2018, 10(426): eaan4488. doi: 10.1126/scitranslmed.aan4488
[13]	Mildner A, Jung S. Development and function of dendritic cell subsets[J]. Immunity, 2014, 40(5): 642–656. doi: 10.1016/j.immuni.2014.04.016
[14]	Gardner A, Ruffell B. Dendritic cells and cancer immunity[J]. Trends Immunol, 2016, 37(12): 855–865. doi: 10.1016/j.it.2016.09.006
[15]	Bayik D, Tross D, Klinman DM. Factors influencing the differentiation of human monocytic myeloid-derived suppressor cells into inflammatory macrophages[J]. Front Immunol, 2018, 9: 608. doi: 10.3389/fimmu.2018.00608
[16]	Tyrinova TV, Leplina OY, Mishinov SV, et al. Cytotoxic activity of ex-vivo generated IFNα-induced monocyte-derived dendritic cells in brain glioma patients[J]. Cell Immunol, 2013, 284(1-2): 146–153. doi: 10.1016/j.cellimm.2013.07.013
[17]	Zong JB, Keskinov AA, Shurin GV, et al. Tumor-derived factors modulating dendritic cell function[J]. Cancer Immunol Immunother, 2016, 65(7): 821–833. doi: 10.1007/s00262-016-1820-y
[18]	Behboudi S, Chao D, Klenerman P, et al. The effects of DNA containing CpG motif on dendritic cells[J]. Immunology, 2000, 99(3): 361–366. doi: 10.1046/j.1365-2567.2000.00979.x
[19]	Scheiermann J, Klinman DM. Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer[J]. Vaccine, 2014, 32(48): 6377–6389. doi: 10.1016/j.vaccine.2014.06.065
[20]	Shirota H, Klinman DM. Recent progress concerning CpG DNA and its use as a vaccine adjuvant[J]. Expert Rev Vaccines, 2014, 13(2): 299–312. doi: 10.1586/14760584.2014.863715
[21]	Shirota H, Tross D, Klinman DM. CpG oligonucleotides as cancer vaccine adjuvants[J]. Vaccines, 2015, 3(2): 390–407. doi: 10.3390/vaccines3020390
[22]	Krug A, Towarowski A, Britsch S, et al. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12[J]. Eur J Immunol, 2001, 31(10): 3026–3037. doi: 10.1002/1521-4141(2001010)31:10<3026::AID-IMMU3026>3.0.CO;2-H
[23]	Hoene V, Peiser M, Wanner R. Human monocyte-derived dendritic cells express TLR9 and react directly to the CpG-A oligonucleotide D19[J]. J Leukoc Biol, 2006, 80(6): 1328–1336. doi: 10.1189/jlb.0106011
[24]	Zhu M, Xu W, Su H, et al. Addition of CpG ODN and Poly (I: C) to a standard maturation cocktail generates monocyte-derived dendritic cells and induces a potent Th1 polarization with migratory capacity[J]. Hum Vaccin Immunother, 2015, 11(7): 1596–1605. doi: 10.1080/21645515.2015.1046659
[25]	Krug A, Rothenfusser S, Selinger S, et al. CpG-A oligonucleotides induce a monocyte-derived dendritic cell-like phenotype that preferentially activates CD8 T cells[J]. J Immunol, 2003, 170(7): 3468–3477. doi: 10.4049/jimmunol.170.7.3468
[26]	Croft M. Control of immunity by the TNFR-related molecule OX40 (CD134)[J]. Ann Rev Immunol, 2010, 28(1): 57–78. doi: 10.1146/annurev-immunol-030409-101243
[27]	Piconese S, Valzasina B, Colombo MP. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection[J]. J Exp Med, 2008, 205(4): 825–839. doi: 10.1084/jem.20071341
[28]	Gough MJ, Ruby CE, Redmond WL, et al. OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor[J]. Cancer Res, 2008, 68(13): 5206–5215. doi: 10.1158/0008-5472.CAN-07-6484
[29]	Kitamura N, Murata S, Ueki T, et al. OX40 costimulation can abrogate Foxp3⁺ regulatory T cell-mediated suppression of antitumor immunity[J]. Int J Cancer, 2009, 125(3): 630–638. doi: 10.1002/ijc.24435
[30]	Curti BD, Kovacsovics-Bankowski M, Morris N, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients[J]. Cancer Res, 2013, 73(24): 7189–7198. doi: 10.1158/0008-5472.CAN-12-4174
[31]	Redmond WL, Weinberg AD. Targeting OX40 and OX40L for the treatment of autoimmunity and cancer[J]. Crit Rev Immunol, 2007, 27(5): 415–436. doi: 10.1615/CritRevImmunol.v27.i5.20
[32]	Aspeslagh S, Postel-Vinay S, Rusakiewicz S, et al. Rationale for anti-OX40 cancer immunotherapy[J]. Eur J Cancer, 2016, 52: 50–66. doi: 10.1016/j.ejca.2015.08.021
[33]	Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review[J]. Eur J Cancer, 2016, 54: 139–148. doi: 10.1016/j.ejca.2015.11.016
[34]	Thommen DS, Schumacher TN. T cell dysfunction in cancer[J]. Cancer Cell, 2018, 33(4): 547–562. doi: 10.1016/j.ccell.2018.03.012
[35]	Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer, 2012, 12(4): 252–264. doi: 10.1038/nrc3239
[36]	Merelli B, Massi D, Cattaneo L, et al. Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities[J]. Crit Rev Oncol Hematol, 2014, 89(1): 140–165. doi: 10.1016/j.critrevonc.2013.08.002
[37]	Ross K, Jones RJ. Immune checkpoint inhibitors in renal cell carcinoma[J]. Clin Sci, 2017, 131(21): 2627–2642. doi: 10.1042/CS20160894
[38]	Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients[J]. Clin Cancer Res, 2013, 19(19): 5300–5309. doi: 10.1158/1078-0432.CCR-13-0143
[39]	Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer[J]. Nat Rev Cancer, 2012, 12(4): 278–287. doi: 10.1038/nrc3236
[40]	Melero I, Hervas-Stubbs S, Glennie M, et al. Immunostimulatory monoclonal antibodies for cancer therapy[J]. Nat Rev Cancer, 2007, 7(2): 95–106. doi: 10.1038/nrc2051
[41]	Dillman RO. Cancer immunotherapy[J]. Cancer Biother Radiopharm, 2011, 26(1): 1–64. doi: 10.1089/cbr.2010.0902
[42]	Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma[J]. Clin Ther, 2015, 37(4): 764–782. doi: 10.1016/j.clinthera.2015.02.018
[43]	Niezgoda A, Niezgoda P, Czajkowski R. Novel approaches to treatment of advanced melanoma: a review on targeted therapy and immunotherapy[J]. Biomed Res Int, 2015, 2015: 851387. doi: 10.1155/2015/851387
[44]	Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance[J]. Nat Rev Clin Oncol, 2019, 16(9): 563–580. doi: 10.1038/s41571-019-0218-0
[45]	Adachi T, Nakamura Y. Aptamers: a review of their chemical properties and modifications for therapeutic application[J]. Molecules, 2019, 24(23): 4229. doi: 10.3390/molecules24234229
[46]	Radko SP, Rakhmetova SY, Bodoev NV, et al. Aptamers as affinity reagents for clinical proteomics[J]. Biochem (Moscow) Suppl Ser B:Biomed Chem, 2007, 1(3): 198–209. doi: 10.1134/S1990750807030043
[47]	Bom APDA, da Costa Neves PC, de Almeida CEB, et al. Aptamers as delivery agents of siRNA and chimeric formulations for the treatment of cancer[J]. Pharmaceutics, 2019, 11(12): 684. doi: 10.3390/pharmaceutics11120684
[48]	Nozari A, Berezovski MV. Aptamers for CD antigens: from cell profiling to activity modulation[J]. Mol Ther Nucleic Acids, 2017, 6: 29–44. doi: 10.1016/j.omtn.2016.12.002
[49]	Nimjee SM, Rusconi CP, Sullenger BA. Aptamers: an emerging class of therapeutics[J]. Annu Rev Med, 2005, 56: 555–583. doi: 10.1146/annurev.med.56.062904.144915
[50]	Zhou J, Li H, Li S, et al. Novel dual inhibitory function aptamer–siRNA delivery system for HIV-1 therapy[J]. Mol Ther, 2008, 16(8): 1481–1489. doi: 10.1038/mt.2008.92
[51]	Santulli-Marotto S, Nair SK, Rusconi C, et al. Multivalent RNA aptamers that inhibit CTLA-4 and enhance tumor immunity[J]. Cancer Res, 2003, 63(21): 7483–7489. https://pubmed.ncbi.nlm.nih.gov/14612549/
[52]	Miroshnichenko SK, Patutina OA, Burakova EA, et al. Mesyl phosphoramidate antisense oligonucleotides as an alternative to phosphorothioates with improved biochemical and biological properties[J]. Proc Natl Acad Sci U S A, 2019, 116(4): 1229–1234. doi: 10.1073/pnas.1813376116
[53]	Prakash TP, Mullick AE, Lee RG, et al. Fatty acid conjugation enhances potency of antisense oligonucleotides in muscle[J]. Nucleic Acids Res, 2019, 47(12): 6029–6044. doi: 10.1093/nar/gkz354
[54]	Pratico ED, Sullenger BA, Nair SK. Identification and characterization of an agonistic aptamer against the T cell costimulatory receptor, OX40[J]. Nucleic Acid Ther, 2013, 23(1): 35–43. doi: 10.1089/nat.2012.0388
[55]	Dollins CM, Nair S, Boczkowski D, et al. Assembling OX40 Aptamers on a molecular scaffold to create a receptor-activating aptamer[J]. Chem Biol, 2008, 15(7): 675–682. doi: 10.1016/j.chembiol.2008.05.016
[56]	Prodeus A, Abdul-Wahid A, Fischer NW, et al. Targeting the PD-1/PD-L1 immune evasion axis with DNA aptamers as a novel therapeutic strategy for the treatment of disseminated cancers[J]. Mol Ther Nucleic Acids, 2015, 4: e237. doi: 10.1038/mtna.2015.11
[57]	Ostanin AA, Leplina OY, Burakova EA, et al. Phosphate-modified CpG oligonucleotides induce in vitro maturation of human myeloid dendritic cells[J]. Vavilovskii Zhurnal Genet Selektsii (in Russian), 2020, 24(6): 653–660. doi: 10.18699/VJ20.659
[58]	Ruzanova VS, Proskurina AS, Ritter GS, et al. Experimental comparison of the in vivo efficacy of two novel anticancer therapies[J]. Anticancer Res, 2021, 41(7): 3371–3387. doi: 10.21873/anticanres.15125
[59]	Lai W, Huang BT, Wang J, et al. A novel PD-L1-targeting antagonistic DNA aptamer with antitumor effects[J]. Mol Ther Nucleic Acids, 2016, 5: e397. doi: 10.1038/mtna.2016.102
[60]	Hammond SM, Sergeeva OV, Melnikov PA, et al. Mesyl phosphoramidate oligonucleotides as potential splice-switching agents: impact of backbone structure on activity and intracellular localization[J]. Nucleic Acid Ther, 2021, 31(3): 190–200. doi: 10.1089/nat.2020.0860