Trial watch: intratumoral immunotherapy

Juliette Humeau, Julie Le Naour, Lorenzo Galluzzi, Guido Kroemer, Jonathan G Pol, Juliette Humeau, Julie Le Naour, Lorenzo Galluzzi, Guido Kroemer, Jonathan G Pol

Abstract

While chemotherapy and radiotherapy remain the first-line approaches for the management of most unresectable tumors, immunotherapy has emerged in the past two decades as a game-changing treatment, notably with the clinical success of immune checkpoint inhibitors. Immunotherapies aim at (re)activating anticancer immune responses which occur in two main steps: (1) the activation and expansion of tumor-specific T cells following cross-presentation of tumor antigens by specialized myeloid cells (priming phase); and (2) the immunological clearance of malignant cells by these antitumor T lymphocytes (effector phase). Therapeutic vaccines, adjuvants, monoclonal antibodies, cytokines, immunogenic cell death-inducing agents including oncolytic viruses, anthracycline-based chemotherapy and radiotherapy, as well as adoptive cell transfer, all act at different levels of this cascade to (re)instate cancer immunosurveillance. Intratumoral delivery of these immunotherapeutics is being tested in clinical trials to promote superior antitumor immune activity in the context of limited systemic toxicity.

Keywords: Antitumor immunity; cancer immunosurveillance; immunotherapy; in situ vaccination; intralesional injection.

Conflict of interest statement

JGP is named as inventor on patents for cancer vaccination involving an oncolytic rhabdovirus. These patents have been licensed to Turnstone Biologics of which JGP is shareholder. GK is a cofounder of Samsara Therapeutics, everImmune and Therafast Bio. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Samsara, Sanofi, Sotio, Vascage and Vasculox/Tioma. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Samsara Therapeutics and Therafast Bio.L.G. has received research funding from Lytix Biopharma and Phosplatin, as well as consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, and the Luke Heller TECPR2 Foundation. The other author(s) declare no conflicts of interest. As per standard operations at Oncoimmunology, LG has been excluded from the editorial evaluation of the present article.

© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.

Figures

Figure 1.
Figure 1.
Types of immunotherapies and their targets in the cancer-immunity cycle. Upon immunogenic cell death of cancer cells, dendritic cells (DCs) are recruited to the lesion where they uptake and present tumor antigens to naïve CD8+ T cells, triggering their differentiation into cytotoxic CD8+ T cells which, together with natural killer (NK) cells, eliminate cancer cells. Memory T cells are also generated during this process. Cancer cells may express immune checkpoint ligands contributing to T cell exhaustion. Immunotherapeutics (in red) can act at different levels of the (re)establishment of this anticancer immune response. DAMP, damage-associated molecular pattern; DC, dendritic cell; ICD, immunogenic cell death; ICI, immune checkpoint inhibitor; IFN, interferon; IFN-I, type 1 interferons; IL, interleukin; mAb, monoclonal antibody; TNF, tumor necrosis factor
Figure 2.
Figure 2.
Types of intratumoral immunotherapy across recently initiated clinical trials. Pie chart depicting the proportion of each type of immunotherapeutic interventions in recently initiated clinical investigations. ICD, immunogenic cell death

References

    1. 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;3:1–31. doi:10.1177/003591571000301601.
    1. Kamat AM, Flaig TW, Grossman HB, Konety B, Lamm D, O’Donnell MA, Uchio E, Efstathiou JA, Taylor JA. Expert consensus document: consensus statement on best practice management regarding the use of intravesical immunotherapy with BCG for bladder cancer. Nat Rev Urol. 2015;12:225–235. doi:10.1038/nrurol.2015.58.
    1. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301–305. doi:10.1126/science.1071059.
    1. Land WG, Messmer K. The danger theory in view of the injury hypothesis: 20 years later. Front Immunol. 2012;3:349. doi:10.3389/fimmu.2012.00349.
    1. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045. doi:10.1146/annurev.iy.12.040194.005015.
    1. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–545. doi:10.1016/S0140-6736(00)04046-0.
    1. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2:301–310. doi:10.1038/nrc780.
    1. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410:1107–1111. doi:10.1038/35074122.
    1. Sprooten J, Garg AD. Type I interferons and endoplasmic reticulum stress in health and disease. Int Rev Cell Mol Biol. 2020;350:63–118.
    1. Sprooten J, Agostinis P, Garg AD. Type I interferons and dendritic cells in cancer immunotherapy. Int Rev Cell Mol Biol. 2019;348:217–262.
    1. Vitale I, Shema E, Loi S, Galluzzi L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat Med. 2021;27(2):212–224. doi:10.1038/s41591-021-01233-9.
    1. Fucikova J, Kline JP, Galluzzi L, Spisek R. Calreticulin arms NK cells against leukemia. Oncoimmunology. 2020;9:1671763. doi:10.1080/2162402X.2019.1671763.
    1. Rodriguez-Ruiz ME, Vitale I, Harrington KJ, Melero I, Galluzzi L. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat Immunol. 2020;21:120–134. doi:10.1038/s41590-019-0561-4.
    1. Buque A, Rodriguez-Ruiz ME, Fucikova J, Galluzzi L. Apoptotic caspases cut down the immunogenicity of radiation. Oncoimmunology. 2019;8:e1655364. doi:10.1080/2162402X.2019.1655364.
    1. Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, Schmitt E, Hamai A, Hervas-Stubbs S, Obeid M, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005;202(12):1691–1701. doi:10.1084/jem.20050915.
    1. Galluzzi L, Humeau J, Buque A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020;17:725–741. doi:10.1038/s41571-020-0413-z.
    1. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20:651–668.
    1. Lopez-Otin C, Kroemer G. Hallmarks of health. Cell. 2021;184:33–63. doi:10.1016/j.cell.2020.11.034.
    1. Coventry BJ. Therapeutic vaccination immunomodulation: forming the basis of all cancer immunotherapy. Ther Adv Vaccines Immunother. 2019;7:2515135519862234.
    1. Dermime S, Armstrong A, Hawkins RE, Stern PL. Cancer vaccines and immunotherapy. Br Med Bull. 2002;62:149–162. doi:10.1093/bmb/62.1.149.
    1. Hu HG, Li YM. Emerging adjuvants for cancer immunotherapy. Front Chem. 2020;8:601. doi:10.3389/fchem.2020.00601.
    1. Le Naour J, Galluzzi L, Zitvogel L, Kroemer G, Vacchelli E. Trial watch: TLR3 agonists in cancer therapy. Oncoimmunology. 2020;9(1):1771143. doi:10.1080/2162402X.2020.1771143.
    1. Weiner LM, Dhodapkar MV, Ferrone S. Monoclonal antibodies for cancer immunotherapy. Lancet. 2009;373:1033–1040. doi:10.1016/S0140-6736(09)60251-8.
    1. Han X, Vesely MD. Stimulating T cells against cancer with agonist immunostimulatory monoclonal antibodies. Int Rev Cell Mol Biol. 2019;342:1–25.
    1. Roy DG, Geoffroy K, Marguerie M, Khan ST, Martin NT, Kmiecik J, Bobbala D, Aitken AS, de Souza Ct, Stephenson KB, et al. Adjuvant oncolytic virotherapy for personalized anti-cancer vaccination. Nat Commun. 2021;12:2626. doi:10.1038/s41467-021-22929-z.
    1. Briukhovetska D, Dorr J, Endres S, Libby P, Dinarello CA, Kobold S. Interleukins in cancer: from biology to therapy. Nat Rev Cancer. 2021;21:481-499.
    1. Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020;17:807–821.
    1. Petroni G, Buque A, Zitvogel L, Kroemer G, Galluzzi L. Immunomodulation by targeted anticancer agents. Cancer Cell. 2021;39:310–345.
    1. Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020;11(1):3801. doi:10.1038/s41467-020-17670-y.
    1. Rakova J, Truxova I, Holicek P, Salek C, Hensler M, Kasikova L, Pasulka J, Holubova M, Kovar M, Lysak D, et al. TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients. Oncoimmunology. 2021;10(1):1889822. doi:10.1080/2162402X.2021.1889822.
    1. Lesokhin AM, Callahan MK, Postow MA, Wolchok JD. On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. Sci Transl Med. 2015;7:280sr1. doi:10.1126/scitranslmed.3010274.
    1. Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers. 2020;12(3):738. doi:10.3390/cancers12030738.
    1. Pol J, Kroemer G. Anti-CTLA-4 immunotherapy: uncoupling toxicity and efficacy. Cell Res. 2018;28:501–502. doi:10.1038/s41422-018-0031-9.
    1. Mueller MM, Fusenig NE. Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004;4:839–849. doi:10.1038/nrc1477.
    1. Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Perez-Gracia JL, Rodríguez-Ruiz ME, Ponz-Sarvise M, Castañón E, Melero I, et al. Cytokines in clinical cancer immunotherapy. Br J Cancer. 2019;120:6–15. doi:10.1038/s41416-018-0328-y.
    1. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185. doi:10.1155/2014/149185.
    1. Smyth MJ, Godfrey DI, Trapani JA. A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol. 2001;2:293–299. doi:10.1038/86297.
    1. Martinek J, Wu TC, Cadena D, Banchereau J, Palucka K. Interplay between dendritic cells and cancer cells. Int Rev Cell Mol Biol. 2019;348:179–215.
    1. Guerriero JL. Macrophages: their untold story in T cell activation and function. Int Rev Cell Mol Biol. 2019;342:73–93.
    1. Yamamoto T, Kimura T, Ueta E, Tatemoto Y, Osaki T. Characteristic cytokine generation patterns in cancer cells and infiltrating lymphocytes in oral squamous cell carcinomas and the influence of chemoradiation combined with immunotherapy on these patterns. Oncology. 2003;64:407–415. doi:10.1159/000070300.
    1. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–1022. doi:10.1038/ni.2703.
    1. Kotsias F, Cebrian I, Alloatti A. Antigen processing and presentation. Int Rev Cell Mol Biol. 2019;348:69–121.
    1. Buque A, Bloy N, Petroni G, Kroemer G, Galluzzi L. NK cells beat T cells at early breast cancer control. Oncoimmunology. 2020;9:1806010. doi:10.1080/2162402X.2020.1806010.
    1. Buque A, Bloy N, Perez-Lanzon M, Iribarren K, Humeau J, Pol JG, Levesque S, Mondragon L, Yamazaki T, Sato A, et al. Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat Commun. 2020;11:3819. doi:10.1038/s41467-020-17644-0.
    1. Wu Chuang A, Kepp O, Kroemer G, Bezu L. Endoplasmic reticulum stress in the cellular release of damage-associated molecular patterns. Int Rev Cell Mol Biol. 2020;350:1–28.
    1. Khodarev NN. Intracellular RNA sensing in mammalian cells: role in stress response and cancer therapies. Int Rev Cell Mol Biol. 2019;344:31–89.
    1. Audsley KM, McDonnell AM, Waithman J. Cross-presenting XCR1(+) dendritic cells as targets for cancer immunotherapy. Cells. 2020;9:565. doi:10.3390/cells9030565.
    1. Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends Immunol. 2016;37:855–865. doi:10.1016/j.it.2016.09.006.
    1. Schraml BU, Reis e Sousa C. Defining dendritic cells. Curr Opin Immunol. 2015;32:13–20. doi:10.1016/j.coi.2014.11.001.
    1. Balan S, Saxena M, Bhardwaj N. Dendritic cell subsets and locations. Int Rev Cell Mol Biol. 2019;348:1–68.
    1. Lee YS, Radford KJ. The role of dendritic cells in cancer. Int Rev Cell Mol Biol. 2019;348:123–178.
    1. Lhuillier C, Galluzzi L. Preface: dendritic cells: master regulators of innate and adaptive immunity. Int Rev Cell Mol Biol. 2019;349:xi–xvi.
    1. Tanchot C, Terme M, Pere H, Tran T, Benhamouda N, Strioga M, Banissi C, Galluzzi L, Kroemer G, Tartour E, et al. Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. Cancer Microenviron. 2013;6:147–157. doi:10.1007/s12307-012-0122-y.
    1. Rao S, Gharib K, Han A. Cancer immunosurveillance by T cells. Int Rev Cell Mol Biol. 2019;342:149–173.
    1. Mori S, Jewett A, Murakami-Mori K, Cavalcanti M, Bonavida B. The participation of the Fas-mediated cytotoxic pathway by natural killer cells is tumor-cell-dependent. Cancer Immunology, Immunotherapy: CII. 1997;44:282–290. doi:10.1007/s002620050384.
    1. Takeda K, Smyth MJ, Cretney E, Hayakawa Y, Yamaguchi N, Yagita H, Okumura K. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in NK cell-mediated and IFN-gamma-dependent suppression of subcutaneous tumor growth. Cell Immunol. 2001;214:194–200. doi:10.1006/cimm.2001.1896.
    1. Falschlehner C, Schaefer U, Walczak H. Following TRAIL’s path in the immune system. Immunology. 2009;127:145–154. doi:10.1111/j.1365-2567.2009.03058.x.
    1. Spetz J, Presser AG, Sarosiek KA. T cells and regulated cell death: kill or be killed. Int Rev Cell Mol Biol. 2019;342:27–71.
    1. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–1570. doi:10.1126/science.1203486.
    1. Pages F, Mlecnik B, Marliot F, Bindea G, Ou F-S, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391(10135):539–545. doi:10.1016/S0140-6736(18)30789-X.
    1. Fridman WH, Zitvogel L, Sautes-Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017;14:717–734. doi:10.1038/nrclinonc.2017.101.
    1. Hensler M, Kasikova L, Fiser K, Rakova J, Skapa P, Laco J, Lanickova T, Pecen L, Truxova I, Vosahlikova S, et al. M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer. Journal for Immunotherapy of Cancer. 2020;8. doi:10.1136/jitc-2020-000979
    1. Frega G, Wu Q, Le Naour J, Vacchelli E, Galluzzi L, Kroemer G, Kepp O. Trial watch: experimental TLR7/TLR8 agonists for oncological indications. Oncoimmunology. 2020;9:1796002. doi:10.1080/2162402X.2020.1796002.
    1. Smith M, Garcia-Martinez E, Pitter MR, Fucikova J, Spisek R, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: toll-like receptor agonists in cancer immunotherapy. Oncoimmunology. 2018;7:e1526250. doi:10.1080/2162402X.2018.1526250.
    1. Barber GN. STING: infection, inflammation and cancer. Nat Rev Immunol. 2015;15:760–770. doi:10.1038/nri3921.
    1. McGrath K, Dotti G. Combining oncolytic viruses with chimeric antigen receptor T cell therapy. Hum Gene Ther. 2021;32(3–4):150–157. doi:10.1089/hum.2020.278.
    1. Le Naour J, Zitvogel L, Galluzzi L, Vacchelli E, Kroemer G. Trial watch: STING agonists in cancer therapy. Oncoimmunology. 2020;9:1777624. doi:10.1080/2162402X.2020.1777624.
    1. Pol JG, Levesque S, Workenhe ST, Gujar S, Le Boeuf F, Clements DR, Fahrner J-E, Fend L, Bell JC, Mossman KL, et al. Trial watch: oncolytic viro-immunotherapy of hematologic and solid tumors. Oncoimmunology. 2018;7:e1503032. doi:10.1080/2162402X.2018.1503032.
    1. Vanmeerbeek I, Sprooten J, De Ruysscher D, Tejpar S, Vandenberghe P, Fucikova J, Spisek R, Zitvogel L, Kroemer G, Galluzzi L, et al. Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology. Oncoimmunology. 2020;9(1):1703449. doi:10.1080/2162402X.2019.1703449.
    1. Pol JG, Workenhe ST, Konda P, Gujar S, Kroemer G. Cytokines in oncolytic virotherapy. Cytokine Growth Factor Rev. 2020;56:4–27.
    1. Buque A, Bloy N, Aranda F, Castoldi F, Eggermont A, Cremer I, Fridman WH, Fucikova J, Galon J, Marabelle A, et al. Trial watch: immunomodulatory monoclonal antibodies for oncological indications. Oncoimmunology. 2015;4:e1008814. doi:10.1080/2162402X.2015.1008814.
    1. Vanpouille-Box C, Lhuillier C, Bezu L, Aranda F, Yamazaki T, Kepp O, Fucikova J, Spisek R, Demaria S, Formenti SC, et al. Trial watch: immune checkpoint blockers for cancer therapy. Oncoimmunology. 2017;6:e1373237. doi:10.1080/2162402X.2017.1373237.
    1. Garg AD, Vara Perez M, Schaaf M, Agostinis P, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: dendritic cell-based anticancer immunotherapy. Oncoimmunology. 2017;6:e1328341. doi:10.1080/2162402X.2017.1328341.
    1. Aranda F, Buque A, Bloy N, Castoldi F, Eggermont A, Cremer I, Fridman WH, Fucikova J, Galon J, Spisek R, et al. Trial watch: adoptive cell transfer for oncological indications. Oncoimmunology. 2015;4:e1046673. doi:10.1080/2162402X.2015.1046673.
    1. Vacchelli E, Aranda F, Bloy N, Buque A, Cremer I, Eggermont A, Fridman WH, Fucikova J, Galon J, Spisek R, et al. Trial watch-immunostimulation with cytokines in cancer therapy. Oncoimmunology. 2016;5:e1115942. doi:10.1080/2162402X.2015.1115942.
    1. Pol JG, Caudana P, Paillet J, Piaggio E, Kroemer G. Effects of interleukin-2 in immunostimulation and immunosuppression. J Exp Med. 2020;217. doi:10.1084/jem.20191247.
    1. Nixon NA, Blais N, Ernst S, Kollmannsberger C, Bebb G, Butler M, Smylie M, Verma S. Current landscape of immunotherapy in the treatment of solid tumours, with future opportunities and challenges. Curr Oncol. 2018;25:e373–e84. doi:10.3747/co.25.3840.
    1. Aznar MA, Planelles L, Perez-Olivares M, Molina C, Garasa S, Etxeberria I, Perez G, Rodriguez I, Bolaños E, Lopez-Casas P, et al. Immunotherapeutic effects of intratumoral nanoplexed poly I:C. Journal for Immunotherapy of Cancer. 2019;7(1):116. doi:10.1186/s40425-019-0568-2.
    1. Jelinek I, Leonard JN, Price GE, Brown KN, Meyer-Manlapat A, Goldsmith PK, Wang Y, Venzon D, Epstein SL, Segal DM, et al. TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection. Journal of Immunology. 2011;186:2422–2429. doi:10.4049/jimmunol.1002845.
    1. Takeda Y, Kataoka K, Yamagishi J, Ogawa S, Seya T, Matsumoto M. A TLR3-specific adjuvant relieves innate resistance to PD-L1 blockade without cytokine toxicity in tumor vaccine immunotherapy. Cell Rep. 2017;19:1874–1887. doi:10.1016/j.celrep.2017.05.015.
    1. Gujar S, Pol JG, Kroemer G. Heating it up: oncolytic viruses make tumors ‘hot’ and suitable for checkpoint blockade immunotherapies. Oncoimmunology. 2018;7:e1442169. doi:10.1080/2162402X.2018.1442169.
    1. Melero I, Castanon E, Alvarez M, Champiat S, Marabelle A. Intratumoural administration and tumour tissue targeting of cancer immunotherapies. Nat Rev Clin Oncol. 2021;18:558–576. doi:10.1038/s41571-021-00507-y.
    1. De Lombaerde E, De Wever O, De Geest BG. Delivery routes matter: safety and efficacy of intratumoral immunotherapy. Biochim Biophys Acta Rev Cancer. 2021;1875:188526. doi:10.1016/j.bbcan.2021.188526.
    1. Harrington KJ, Puzanov I, Hecht JR, Hodi FS, Szabo Z, Murugappan S, Kaufman HL. Clinical development of talimogene laherparepvec (T-VEC): a modified herpes simplex virus type-1-derived oncolytic immunotherapy. Expert Rev Anticancer Ther. 2015;15:1389–1403. doi:10.1586/14737140.2015.1115725.
    1. Vacchelli E, Eggermont A, Sautes-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: oncolytic viruses for cancer therapy. Oncoimmunology. 2013;2:e24612. doi:10.4161/onci.24612.
    1. Renner A, Burotto M, Rojas C. Immune checkpoint inhibitor dosing: can we go lower without compromising clinical efficacy? J Glob Oncol. 2019;5:1–5.
    1. Abuodeh Y, Venkat P, Kim S. Systematic review of case reports on the abscopal effect. Curr Probl Cancer. 2016;40:25–37. doi:10.1016/j.currproblcancer.2015.10.001.
    1. Yamazaki T, Kirchmair A, Sato A, Buque A, Rybstein M, Petroni G, Bloy N, Finotello F, Stafford L, Navarro Manzano E, et al. Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy. Nat Immunol. 2020;21(10):1160–1171. doi:10.1038/s41590-020-0751-0.
    1. Rodriguez-Ruiz ME, Buque A, Hensler M, Chen J, Bloy N, Petroni G, et al. Apoptotic caspases inhibit abscopal responses to radiation and identify a new prognostic biomarker for breast cancer patients. Oncoimmunology. 2019;8:e1655964. doi:10.1080/2162402X.2019.1655964.
    1. Yamazaki T, Galluzzi L. Mitochondrial control of innate immune signaling by irradiated cancer cells. Oncoimmunology. 2020;9(1):1797292. doi:10.1080/2162402X.2020.1797292.
    1. Marabelle A, Andtbacka R, Harrington K, Melero I, Leidner R, De Baere T, Robert C, Ascierto PA, Baurain JF, Imperiale M, et al. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Annals of Oncology: Official Journal of the European Society for Medical Oncology. 2018;29:2163–2174. doi:10.1093/annonc/mdy423.
    1. Aznar MA, Tinari N, Rullan AJ, Sanchez-Paulete AR, Rodriguez-Ruiz ME, Melero I. Intratumoral delivery of immunotherapy-act locally, think globally. Journal of Immunology. 2017;198:31–39. doi:10.4049/jimmunol.1601145.
    1. Hong WX, Haebe S, Lee AS, Westphalen CB, Norton JA, Jiang W, Levy R. Intratumoral immunotherapy for early-stage solid tumors. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2020;26(13):3091–3099. doi:10.1158/1078-0432.CCR-19-3642.
    1. Champiat S, Tselikas L, Farhane S, Raoult T, Texier M, Lanoy E, et al. Intratumoral immunotherapy: from trial design to clinical practice. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2021;27:665–679. doi:10.1158/1078-0432.CCR-20-0473.
    1. Houot R, Schultz LM, Marabelle A, Kohrt H. T-cell–based immunotherapy: adoptive cell transfer and checkpoint inhibition. Cancer Immunol Res. 2015;3(10):1115–1122. doi:10.1158/2326-6066.CIR-15-0190.
    1. Hubert P, Amigorena S. Antibody-dependent cell cytotoxicity in monoclonal antibody-mediated tumor immunotherapy. Oncoimmunology. 2012;1:103–105. doi:10.4161/onci.1.1.17963.
    1. Mielke D, Bandawe G, Pollara J, Abrahams M-R, Nyanhete T, Moore PL, Thebus R, Yates NL, Kappes JC, Ochsenbauer C, et al. Antibody-Dependent Cellular Cytotoxicity (ADCC)-mediating antibodies constrain neutralizing antibody escape pathway. Front Immunol. 2019;10:2875. doi:10.3389/fimmu.2019.02875.
    1. Wang B, Yang C, Jin X, Du Q, Wu H, Dall’Acqua W, Mazor Y. Regulation of antibody-mediated complement-dependent cytotoxicity by modulating the intrinsic affinity and binding valency of IgG for target antigen. MAbs. 2020;12:1690959. doi:10.1080/19420862.2019.1690959.
    1. Weiner GJ. Rituximab: mechanism of action. Semin Hematol. 2010; 47:115–123. doi:10.1053/j.seminhematol.2010.01.011.
    1. Haase C, Michelsen BK, Jorgensen TN. CD40 is necessary for activation of naive T cells by a dendritic cell line in vivo but not in vitro. Scand J Immunol. 2004;59:237–245. doi:10.1111/j.0300-9475.2004.01390.x.
    1. Hernandez MG, Shen L, Rock KL. CD40-CD40 ligand interaction between dendritic cells and CD8+ T cells is needed to stimulate maximal T cell responses in the absence of CD4+ T cell help. Journal of Immunology. 2007;178:2844–2852. doi:10.4049/jimmunol.178.5.2844.
    1. Morrison AH, Diamond MS, Hay CA, Byrne KT, Vonderheide RH. Sufficiency of CD40 activation and immune checkpoint blockade for T cell priming and tumor immunity. Proc Natl Acad Sci U S A. 2020; 117:8022–8031. doi:10.1073/pnas.1918971117.
    1. Simon S, Labarriere N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology. 2017;7:e1364828. doi:10.1080/2162402X.2017.1364828.
    1. Laurent S, Queirolo P, Boero S, Salvi S, Piccioli P, Boccardo S, et al. The engagement of CTLA-4 on primary melanoma cell lines induces antibody-dependent cellular cytotoxicity and TNF-alpha production. J Transl Med. 2013;11:108. doi:10.1186/1479-5876-11-108.
    1. Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, Michielin O, Weide B, Romero P, Speiser DE, et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A. 2015;112:6140–6145. doi:10.1073/pnas.1417320112.
    1. Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, et al. Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. Journal of Immunology. 2015;194:950–959. doi:10.4049/jimmunol.1401686.
    1. Fransen MF, van der Sluis TC, Ossendorp F, Arens R, Melief CJ. Controlled local delivery of CTLA-4 blocking antibody induces CD8+ T-cell-dependent tumor eradication and decreases risk of toxic side effects. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2013;19:5381–5389. doi:10.1158/1078-0432.CCR-12-0781.
    1. Knorr DA, Dahan R, Ravetch JV. Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity. Proc Natl Acad Sci U S A. 2018; 115:11048–11053. doi:10.1073/pnas.1810566115.
    1. Narumi K, Miyakawa R, Shibasaki C, Henmi M, Mizoguchi Y, Ueda R, et al. Local administration of GITR agonistic antibody induces a stronger antitumor immunity than systemic delivery. Sci Rep. 2019;9:5562. doi:10.1038/s41598-019-41724-x.
    1. Houot R, Levy R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood. 2009;113:3546–3552. doi:10.1182/blood-2008-07-170274.
    1. Marabelle A, Tselikas L, De Baere T, Houot R. Intratumoral immunotherapy: using the tumor as the remedy. Annals of Oncology: Official Journal of the European Society for Medical Oncology. 2017;28:xii33–xii43. doi:10.1093/annonc/mdx683.
    1. Palazon A, Martinez-Forero I, Teijeira A, Morales-Kastresana A, Alfaro C, Sanmamed MF, Perez-Gracia JL, Peñuelas I, Hervás-Stubbs S, Rouzaut A, et al. The HIF-1α hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer Discov. 2012;2(7):608–623. doi:10.1158/-11-0314.
    1. Tselikas L, De Baere T, Isoardo T, Susini S, Ser-Le Roux K, Polrot M, Adam J, Rouanne M, Zitvogel L, Moine L, et al. Pickering emulsions with ethiodized oil and nanoparticles for slow release of intratumoral anti-CTLA4 immune checkpoint antibodies. Journal for Immunotherapy of Cancer. 2020;8:e000579. doi:10.1136/jitc-2020-000579.
    1. Perrot I, Michaud HA, Giraudon-Paoli M, Augier S, Docquier A, Gros L, Courtois R, Déjou C, Jecko D, Becquart O, et al. Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies. Cell Rep. 2019;27:2411–25 e9. doi:10.1016/j.celrep.2019.04.091.
    1. Rizzieri D. Zevalin((R)) (ibritumomab tiuxetan): after more than a decade of treatment experience, what have we learned? Crit Rev Oncol Hematol. 2016;105:5–17. doi:10.1016/j.critrevonc.2016.07.008.
    1. Mondello P, Cuzzocrea S, Navarra M, Mian M. 90 Y-ibritumomab tiuxetan: a nearly forgotten opportunityr. Oncotarget. 2016;7:7597–7609. doi:10.18632/oncotarget.6531.
    1. Dhillon S. Moxetumomab Pasudotox: first global approval. Drugs. 2018;78:1763–1767. doi:10.1007/s40265-018-1000-9.
    1. Peddi PF, Hurvitz SA. Trastuzumab emtansine: the first targeted chemotherapy for treatment of breast cancer. Future Oncol. 2013;9:319–326. doi:10.2217/fon.13.7.
    1. Goldenberg DM, Sharkey RM. Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: a case study of anti-TROP-2 sacituzumab govitecan. MAbs. 2019;11:987–995. doi:10.1080/19420862.2019.1632115.
    1. Okamoto H, Oitate M, Hagihara K, Shiozawa H, Furuta Y, Ogitani Y, et al. Pharmacokinetics of trastuzumab deruxtecan (T-DXd), a novel anti-HER2 antibody-drug conjugate, in HER2-positive tumour-bearing mice. Xenobiotica. 2020;50:1242–1250. doi:10.1080/00498254.2020.1755909.
    1. Thomas A, Pommier Y. Targeting Topoisomerase I in the era of precision medicine. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2019;25:6581–6589. doi:10.1158/1078-0432.CCR-19-1089.
    1. Bruins WSC, Zweegman S, Mutis T, van de Donk N. Targeted therapy with immunoconjugates for multiple myeloma. Front Immunol. 2020;11:1155. doi:10.3389/fimmu.2020.01155.
    1. Ponziani S, Di Vittorio G, Pitari G, Cimini AM, Ardini M, Gentile R, Iacobelli S, Sala G, Capone E, Flavell DJ, et al. Antibody-drug conjugates: the new frontier of chemotherapy. Int J Mol Sci. 2020;21. doi:10.3390/ijms21155510
    1. Hamilton GS. Antibody-drug conjugates for cancer therapy: the technological and regulatory challenges of developing drug-biologic hybrids. Biologicals. 2015;43:318–332. doi:10.1016/j.biologicals.2015.05.006.
    1. Hassan R, Alewine C, Mian I, Spreafico A, Siu LL, Gomez-Roca C, Delord J-P, Italiano A, Lassen U, Soria J-C, et al. Phase 1 study of the immunotoxin LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin. Cancer. 2020;126:4936–4947. doi:10.1002/cncr.33145.
    1. Yang Y, Yang Z, Yang Y. Potential role of CD47-directed bispecific antibodies in cancer immunotherapy. Front Immunol. 2021;12:686031. doi:10.3389/fimmu.2021.686031.
    1. Salvaris R, Ong J, Gregory GP. Bispecific antibodies: a review of development, clinical efficacy and toxicity in B-cell lymphomas. J Pers Med. 2021;11:355. doi:10.3390/jpm11050355.
    1. Teng MW, Bowman EP, McElwee JJ, Smyth MJ, Casanova JL, Cooper AM, Cua DJ. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med. 2015;21:719–729. doi:10.1038/nm.3895.
    1. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6:836–848. doi:10.1038/nri1961.
    1. von Locquenghien M, Rozalen C, Celia-Terrassa T. Interferons in cancer immunoediting: sculpting metastasis and immunotherapy response. J Clin Invest. 2021;131(1). doi:10.1172/JCI143296.
    1. Medrano RFV, Hunger A, Mendonca SA, Barbuto JAM, Strauss BE. Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy. Oncotarget. 2017;8:71249–71284. doi:10.18632/oncotarget.19531.
    1. Castro F, Cardoso AP, Goncalves RM, Serre K, Oliveira MJ. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol. 2018;9:847.
    1. Aldesleukin . LiverTox: clinical and research information on drug-induced liver injury. Bethesda (MD); 2012.
    1. Yan WL, Shen KY, Tien CY, Chen YA, Liu SJ. Recent progress in GM-CSF-based cancer immunotherapy. Immunotherapy. 2017;9:347–360. doi:10.2217/imt-2016-0141.
    1. Cavalheiro S, Di Rocco C, Valenzuela S, Dastoli PA, Tamburrini G, Massimi L, Nicacio JM, Faquini IV, Ierardi DF, Silva NS, et al. Craniopharyngiomas: intratumoral chemotherapy with interferon-alpha: a multicenter preliminary study with 60 cases. Neurosurg Focus. 2010;28:E12. doi:10.3171/2010.1.FOCUS09310.
    1. Baldo BA. Side effects of cytokines approved for therapy. Drug Saf. 2014;37:921–943.
    1. Vial T, Descotes J. Immune-mediated side-effects of cytokines in humans. Toxicology. 1995;105:31–57. doi:10.1016/0300-483X(95)03124-X.
    1. Momin N, Mehta NK, Bennett NR, Ma L, Palmeri JR, Chinn MM, Lutz EA, Kang B, Irvine DJ, Spranger S, et al. Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy. Sci Transl Med. 2019;11:eaaw2614. doi:10.1126/scitranslmed.aaw2614.
    1. Chiocca EA, Yu JS, Lukas RV, Solomon IH, Ligon KL, Nakashima H, Triggs DA, Reardon DA, Wen P, Stopa BM, et al. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: results of a phase 1 trial. Sci Transl Med. 2019;11:eaaw5680. doi:10.1126/scitranslmed.aaw5680.
    1. van Herpen CM, Looman M, Zonneveld M, Scharenborg N, De Wilde PC, van de Locht L, Merkx MAW, Adema GJ, De Mulder PH. Intratumoral administration of recombinant human interleukin 12 in head and neck squamous cell carcinoma patients elicits a T-helper 1 profile in the locoregional lymph nodes. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2004;10:2626–2635. doi:10.1158/1078-0432.CCR-03-0304.
    1. Li Y, Su Z, Zhao W, Zhang X, Momin N, Zhang C, Wittrup KD, Dong Y, Irvine DJ, Weiss R. Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity. Nature Cancer. 2020;1:882–893. doi:10.1038/s43018-020-0095-6.
    1. Yao W, Li Y, Zeng L, Zhang X, Zhou Z, Zheng M, et al. Intratumoral injection of dendritic cells overexpressing interleukin12 inhibits melanoma growth. Oncol Rep. 2019;42:370–376.
    1. Akiyama Y, Watanabe M, Maruyama K, Ruscetti FW, Wiltrout RH, Yamaguchi K. Enhancement of antitumor immunity against B16 melanoma tumor using genetically modified dendritic cells to produce cytokines. Gene Ther. 2000;7:2113–2121. doi:10.1038/sj.gt.3301353.
    1. Wei X, Orchardson M, Gracie JA, Leung BP, Gao B, Guan H, et al. The Sushi domain of soluble IL-15 receptor alpha is essential for binding IL-15 and inhibiting inflammatory and allogenic responses in vitro and in vivo. Journal of Immunology. 2001;167:277–282. doi:10.4049/jimmunol.167.1.277.
    1. Bechter O, Utikal J, Baurain J-F, Massard C, Sahin U, Derhovanessian E, Ozoux M-L, Marpadga R, Imedio E-R, Acquavella N, et al. A first-in-human study of intratumoral SAR441000, an mRNA mixture encoding IL-12sc, interferon alpha2b, GM-CSF and IL-15sushi as monotherapy and in combination with cemiplimab in advanced solid tumors. Journal for ImmunoTherapy of Cancer. 2020;8:A416–A416. doi:10.1136/jitc-2020-SITC2020.0391.
    1. Yamane BH, Hank JA, Albertini MR, Sondel PM. The development of antibody-IL-2 based immunotherapy with hu14.18-IL2 (EMD-273063) in melanoma and neuroblastoma. Expert Opin Investig Drugs. 2009;18:991–1000. doi:10.1517/13543780903048911.
    1. Albertini MR, Ranheim E, Hank JA, Zuleger C, McFarland T, Collins J, Clements E, Weber SM, Weigel T, Neuman HB, et al. A pilot trial of hu14.18-IL2 in patients with completely resectable recurrent stage III or stage IV melanoma. Journal of Clinical Oncology. 2014;32:9044. doi:10.1200/jco.2014.32.15_suppl.9044.
    1. Danielli R, Patuzzo R, Di Giacomo AM, Gallino G, Maurichi A, Di Florio A, Cutaia O, Lazzeri A, Fazio C, Miracco C, et al. Intralesional administration of L19-IL2/L19-TNF in stage III or stage IVM1a melanoma patients: results of a phase II study. Cancer Immunology, Immunotherapy: CII. 2015;64:999–1009. doi:10.1007/s00262-015-1704-6.
    1. Corbellari R, Nadal L, Villa A, Neri D, De Luca R. The immunocytokine L19-TNF eradicates sarcomas in combination with chemotherapy agents or with immune check-point inhibitors. Anticancer Drugs. 2020;31:799–805. doi:10.1097/CAD.0000000000000938.
    1. Dias Junior AG, Sampaio NG, Rehwinkel J, Balancing Act: A. MDA5 in antiviral immunity and autoinflammation. Trends Microbiol. 2019;27:75–85. doi:10.1016/j.tim.2018.08.007.
    1. Rehwinkel J, Gack MU. RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol. 2020;20:537–551. doi:10.1038/s41577-020-0288-3.
    1. Cerboni S, Gentili M, Manel N. Diversity of pathogen sensors in dendritic cells. Adv Immunol. 2013;120:211–237.
    1. Cui J, Chen Y, Wang HY, Wang RF. Mechanisms and pathways of innate immune activation and regulation in health and cancer. Hum Vaccin Immunother. 2014;10:3270–3285. doi:10.4161/21645515.2014.979640.
    1. Reis e Sousa C. Dendritic cells as sensors of infection. Immunity. 2001;14:495–498. doi:10.1016/S1074-7613(01)00136-4.
    1. Szabo A, Rajnavolgyi E. Collaboration of toll-like and RIG-I-like receptors in human dendritic cells: tRIGgering antiviral innate immune responses. Am J Clin Exp Immunol. 2013;2:195–207.
    1. Kepp O, Tesniere A, Schlemmer F, Michaud M, Senovilla L, Zitvogel L, Kroemer G. Immunogenic cell death modalities and their impact on cancer treatment. Apoptosis. 2009;14:364–375. doi:10.1007/s10495-008-0303-9.
    1. Tesniere A, Apetoh L, Ghiringhelli F, Joza N, Panaretakis T, Kepp O, Schlemmer F, Zitvogel L, Kroemer G. Immunogenic cancer cell death: a key-lock paradigm. Curr Opin Immunol. 2008;20:504–511. doi:10.1016/j.coi.2008.05.007.
    1. Vanpouille-Box C, Galluzzi L. Nucleic acid sensing at the interface between innate and adaptive immunity. Int Rev Cell Mol Biol. 2019;344:xi–xv.
    1. Bianchi F, Pretto S, Tagliabue E, Balsari A, Sfondrini L. Exploiting poly(I:C) to induce cancer cell apoptosis. Cancer Biol Ther. 2017;18:747–756. doi:10.1080/15384047.2017.1373220.
    1. Sultan H, Salazar AM, Celis E. Poly-ICLC, a multi-functional immune modulator for treating cancer. Semin Immunol. 2020;49:101414. doi:10.1016/j.smim.2020.101414.
    1. Kyi C, Roudko V, Sabado R, Saenger Y, Loging W, Mandeli J, Thin TH, Lehrer D, Donovan M, Posner M, et al. Therapeutic immune modulation against solid cancers with intratumoral poly-ICLC: a pilot trial. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2018;24:4937–4948. doi:10.1158/1078-0432.CCR-17-1866.
    1. Rodriguez-Ruiz ME, Perez-Gracia JL, Rodriguez I, Alfaro C, Onate C, Perez G, Gil-Bazo I, Benito A, Inogés S, López-Diaz de Cerio A, et al. Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients. Annals of Oncology: Official Journal of the European Society for Medical Oncology. 2018;29:1312–1319. doi:10.1093/annonc/mdy089.
    1. Alderson MR, McGowan P, Baldridge JR, Probst P. TLR4 agonists as immunomodulatory agents. J Endotoxin Res. 2006;12:313–319. doi:10.1177/09680519060120050701.
    1. Shetab Boushehri MA, Lamprecht A. TLR4-based immunotherapeutics in cancer: a review of the achievements and shortcomings. Mol Pharm. 2018;15(11):4777–4800. doi:10.1021/acs.molpharmaceut.8b00691.
    1. Petes C, Odoardi N, Gee K. The toll for trafficking: toll-like receptor 7 delivery to the endosome. Front Immunol. 2017;8:1075. doi:10.3389/fimmu.2017.01075.
    1. Chi H, Li C, Zhao FS, Zhang L, Ng TB, Jin G, Sha O. Anti-tumor activity of toll-like receptor 7 agonists. Front Pharmacol. 2017;8:304. doi:10.3389/fphar.2017.00304.
    1. Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, Kluger HM, Gettinger SN, Sznol M, Tykodi SS, et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov. 2020;10:1158–1173. doi:10.1158/-19-1510.
    1. Veatch JR, Singhi N, Jesernig B, Paulson KG, Zalevsky J, Iaccucci E, Tykodi SS, Riddell SR. Mobilization of pre-existing polyclonal T cells specific to neoantigens but not self-antigens during treatment of a patient with melanoma with bempegaldesleukin and nivolumab. Journal for Immunotherapy of Cancer. 2020;8:e001591. doi:10.1136/jitc-2020-001591.
    1. Cervantes JL, Weinerman B, Basole C, Salazar JC. TLR8: the forgotten relative revindicated. Cell Mol Immunol. 2012;9:434–438. doi:10.1038/cmi.2012.38.
    1. Chuang YC, Tseng JC, Huang LR, Huang CM, Huang CF, Chuang TH. Adjuvant effect of toll-like receptor 9 activation on cancer immunotherapy using checkpoint blockade. Front Immunol. 2020;11:1075. doi:10.3389/fimmu.2020.01075.
    1. Karapetyan L, Luke JJ, Davar D. Toll-like receptor 9 agonists in cancer. Onco Targets Ther. 2020;13:10039–10060. doi:10.2147/OTT.S247050.
    1. Krieg AM. Development of TLR9 agonists for cancer therapy. J Clin Invest. 2007;117:1184–1194. doi:10.1172/JCI31414.
    1. Krieg AM. Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene. 2008;27:161–167. doi:10.1038/sj.onc.1210911.
    1. Melisi D, Frizziero M, Tamburrino A, Zanotto M, Carbone C, Piro G, Tortora G. Toll-like receptor 9 agonists for cancer therapy. Biomedicines. 2014;2:211–228. doi:10.3390/biomedicines2030211.
    1. Haymaker C, Johnson DH, Murthy R, Bentebibel SE, Uemura MI, Hudgens CW, Safa H, James M, Andtbacka RHI, Johnson DB, et al. Tilsotolimod with ipilimumab drives tumor responses in anti-PD-1 refractory melanoma. Cancer Discov. 2021. doi:10.1158/-20-1546.
    1. Timmer FEF, Geboers B, Ruarus AH, Schouten EAC, Nieuwenhuizen S, Puijk RS, De Vries JJJ, Meijerink MR, Scheffer HJ. Irreversible electroporation for locally advanced pancreatic cancer. Tech Vasc Interv Radiol. 2020;23:100675. doi:10.1016/j.tvir.2020.100675.
    1. Crunkhorn S. Strengthening the sting of immunotherapy. Nat Rev Immunol. 2020;20:589. doi:10.1038/s41577-020-00447-1.
    1. Su T, Zhang Y, Valerie K, Wang X-Y, Lin S, Zhu G. STING activation in cancer immunotherapy. Theranostics. 2019;9(25):7759–7771. doi:10.7150/thno.37574.
    1. Harrington K, Parkes E, Weiss J, Ingham M, Cervantes A, Calvo E, Riese M, Klinkhardt U, Sikken P, Schmohl M, et al. Phase I, first-in-human trial evaluating BI 1387446 (stimulator of interferon genes [STING] agonist) alone and combined with BI 754091 (anti-programmed cell death [PD]-1) in solid tumors. J Immuno Therapy Cancer. 2020;8:A433–A433. doi:10.1136/jitc-2020-SITC2020.0408.
    1. Kasumba DM, Grandvaux N. Therapeutic targeting of RIG-I and MDA5 might not lead to the same rome. Trends Pharmacol Sci. 2019;40:116–127. doi:10.1016/j.tips.2018.12.003.
    1. Elion DL, Cook RS. Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment. Oncotarget. 2018;9(48):29007–29017. doi:10.18632/oncotarget.25626.
    1. Iurescia S, Fioretti D, Rinaldi M. The innate immune signalling pathways: turning RIG-I sensor activation against cancer. Cancers. 2020;12:3158. doi:10.3390/cancers12113158.
    1. Al-Ramadi BK, Fernandez-Cabezudo MJ, El-Hasasna H, Al-Salam S, Attoub S, Xu D, Chouaib S. Attenuated bacteria as effectors in cancer immunotherapy. Ann N Y Acad Sci. 2008;1138:351–357. doi:10.1196/annals.1414.036.
    1. Kaimala S, Al-Sbiei A, Cabral-Marques O, Fernandez-Cabezudo MJ, Al-Ramadi BK. Attenuated bacteria as immunotherapeutic tools for cancer treatment. Front Oncol. 2018;8:136. doi:10.3389/fonc.2018.00136.
    1. Kumar S, Sunagar R, Gosselin E. Bacterial protein toll-like-receptor agonists: a novel perspective on vaccine adjuvants. Front Immunol. 2019;10:1144. doi:10.3389/fimmu.2019.01144.
    1. Staedtke V, Roberts NJ, Bai RY, Zhou S. Clostridium novyi-NT in cancer therapy. Genes Dis. 2016;3:144–152. doi:10.1016/j.gendis.2016.01.003.
    1. Roberts NJ, Zhang L, Janku F, Collins A, Bai RY, Staedtke V, et al. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci Transl Med. 2014;6:249ra111. doi:10.1126/scitranslmed.3008982.
    1. Wang L, Wang Q, Tian X, Shi X. Learning from Clostridium novyi-NT: how to defeat cancer. J Cancer Res Ther. 2018;14:S1–S6. doi:10.4103/0973-1482.204841.
    1. Janku F, Fu S, Murthy R, Karp D, Hong D, Tsimberidou A, Gillison M, Adat A, Raina A, Call G, et al. First-in-man clinical trial of intratumoral injection of clostridium Novyi-NT spores in combination with pembrolizumab in patients with treatment-refractory advanced solid tumors. Journal for Immunotherapy of Cancer. 2020;8:A408–A408. doi:10.1136/jitc-2020-SITC2020.0383.
    1. Gebremeskel S, Johnston B. Concepts and mechanisms underlying chemotherapy induced immunogenic cell death: impact on clinical studies and considerations for combined therapies. Oncotarget. 2015;6:41600–41619. doi:10.18632/oncotarget.6113.
    1. Fucikova J, Kralikova P, Fialova A, Brtnicky T, Rob L, Bartunkova J, Špíšek R. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res. 2011;71:4821–4833. doi:10.1158/0008-5472.CAN-11-0950.
    1. Kepp O, Bezu L, Yamazaki T, Di Virgilio F, Smyth MJ, Kroemer G, et al. ATP and cancer immunosurveillance. EMBO J. 2021;40:e108130.
    1. Galluzzi L, Vitale I, Warren S, Adjemian S, Agostinis P, Martinez AB, Chan TA, Coukos G, Demaria S, Deutsch E, et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. Journal for Immunotherapy of Cancer. 2020;8:e000337. doi:10.1136/jitc-2019-000337.
    1. Zhou H, Forveille S, Sauvat A, Yamazaki T, Senovilla L, Ma Y, Liu P, Yang H, Bezu L, Müller K, et al. The oncolytic peptide LTX-315 triggers immunogenic cell death. Cell Death Dis. 2016;7:e2134. doi:10.1038/cddis.2016.47.
    1. Humeau J, Sauvat A, Cerrato G, Xie W, Loos F, Iannantuoni F, Bezu L, Lévesque S, Paillet J, Pol J, et al. Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress. EMBO Mol Med. 2020;12:e11622. doi:10.15252/emmm.201911622.
    1. Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV. Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood. 2007;109:4839–4845. doi:10.1182/blood-2006-10-054221.
    1. Garg AD, More S, Rufo N, Mece O, Sassano ML, Agostinis P, et al. Trial watch: immunogenic cell death induction by anticancer chemotherapeutics. Oncoimmunology. 2017;6:e1386829. doi:10.1080/2162402X.2017.1386829.
    1. Christensen SB. Natural products that changed society. Biomedicines. 2021;9:472. doi:10.3390/biomedicines9050472.
    1. Twarog C, Fattah S, Heade J, Maher S, Fattal E, Brayden DJ. Intestinal permeation enhancers for oral delivery of macromolecules: a comparison between salcaprozate sodium (SNAC) and sodium caprate (C10). Pharmaceutics. 2019;11:78. doi:10.3390/pharmaceutics11020078.
    1. Zhou H, Mondragon L, Xie W, Mauseth B, Leduc M, Sauvat A, Gomes-da-Silva LC, Forveille S, Iribarren K, Souquere S, et al. Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals. Cell Death Dis. 2018;9:1086. doi:10.1038/s41419-018-1127-3.
    1. Szczepanski C, Tenstad O, Baumann A, Martinez A, Myklebust R, Bjerkvig R, Prestegarden L. Identification of a novel lytic peptide for the treatment of solid tumours. Genes Cancer. 2014;5:186–200. doi:10.18632/genesandcancer.18.
    1. Sveinbjornsson B, Camilio KA, Haug BE, Rekdal O. LTX-315: a first-in-class oncolytic peptide that reprograms the tumor microenvironment. Future Med Chem. 2017;9:1339–1344. doi:10.4155/fmc-2017-0088.
    1. Li L, Liu S, Han D, Tang B, Ma J. Delivery and biosafety of oncolytic virotherapy. Front Oncol. 2020;10:475. doi:10.3389/fonc.2020.00475.
    1. Kepp O, Marabelle A, Zitvogel L, Kroemer G. Oncolysis without viruses - inducing systemic anticancer immune responses with local therapies. Nat Rev Clin Oncol. 2020;17:49–64. doi:10.1038/s41571-019-0272-7.
    1. Huang H, Liu Y, Liao W, Cao Y, Liu Q, Guo Y, Lu Y, Xie Z. Oncolytic adenovirus programmed by synthetic gene circuit for cancer immunotherapy. Nat Commun. 2019;10:4801. doi:10.1038/s41467-019-12794-2.
    1. Pol J, Buque A, Aranda F, Bloy N, Cremer I, Eggermont A, Erbs P, Fucikova J, Galon J, Limacher J-M, et al. Trial watch-oncolytic viruses and cancer therapy. Oncoimmunology. 2016;5:e1117740. doi:10.1080/2162402X.2015.1117740.
    1. Pol J, Bloy N, Obrist F, Eggermont A, Galon J, Cremer I, Erbs P, Limacher J-M, Preville X, Zitvogel L, et al. Trial watch: oncolytic viruses for cancer therapy. Oncoimmunology. 2014;3:e28694. doi:10.4161/onci.28694.
    1. Shi Y, Liu CH, Roberts AI, Das J, Xu G, Ren G, Zhang Y, Zhang L, Yuan ZR, Tan HSW, et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don’t know. Cell Res. 2006;16:126–133. doi:10.1038/sj.cr.7310017.
    1. Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: a new era of cancer treatment at Dawn. Cancer Sci. 2016;107:1373–1379. doi:10.1111/cas.13027.
    1. Ma W, He H, Wang H. Oncolytic herpes simplex virus and immunotherapy. BMC Immunol. 2018;19:40. doi:10.1186/s12865-018-0281-9.
    1. Rehman H, Silk AW, Kane MP, Kaufman HL. Into the clinic: talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy. Journal for Immunotherapy of Cancer. 2016;4:53. doi:10.1186/s40425-016-0158-5.
    1. Pol J, Kroemer G, Galluzzi L. First oncolytic virus approved for melanoma immunotherapy. Oncoimmunology. 2016;5:e1115641. doi:10.1080/2162402X.2015.1115641.
    1. Koch MS, Lawler SE, Chiocca EA. HSV-1 oncolytic viruses from bench to bedside: an overview of current clinical trials. Cancers. 2020;12:3514. doi:10.3390/cancers12123514.
    1. Wang X, Cui C, Si L, Li C, Dai J, Mao L, Bai X, Chi Z, Sheng X, Kong Y, et al. A phase Ib clinical trial of neoadjuvant OrienX010, an oncolytic virus, in combination with toripalimab in patients with resectable stage IIIb to stage IVM1a acral melanoma. Journal of Clinical Oncology. 2021;39:9570. doi:10.1200/JCO.2021.39.15_suppl.9570.
    1. Zhang B, Huang J, Tang J, Hu S, Luo S, Luo Z, Zhou F, Tan S, Ying J, Chang Q, et al. Intratumoral OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: a multicenter, phase I/II clinical trial. Journal for Immunotherapy of Cancer. 2021;9:e002224. doi:10.1136/jitc-2020-002224.
    1. Friedman GK, Johnston JM, Bag AK, Bernstock JD, Li R, Aban I, Kachurak K, Nan L, Kang K-D, Totsch S, et al. Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade Gliomas. N Engl J Med. 2021;384:1613–1622. doi:10.1056/NEJMoa2024947.
    1. Markert JM, Razdan SN, Kuo HC, Cantor A, Knoll A, Karrasch M, Nabors LB, Markiewicz M, Agee BS, Coleman JM, et al. A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol Ther. 2014;22:1048–1055. doi:10.1038/mt.2014.22.
    1. Peters C, Grandi P, Nigim F. Updates on oncolytic virus immunotherapy for cancers. Mol Ther Oncolytics. 2019;12:259–262. doi:10.1016/j.omto.2019.01.008.
    1. Haines BB, Denslow A, Grzesik P, Lee JS, Farkaly T, Hewett J, et al. ONCR-177, an oncolytic HSV-1 designed to potently activate systemic antitumor immunity. Cancer Immunol Res. 2021;9(3):291–308. doi:10.1158/2326-6066.CIR-20-0609.
    1. Macedo N, Miller DM, Haq R, Kaufman HL. Clinical landscape of oncolytic virus research in 2020. Journal for Immunotherapy of Cancer. 2020;8:e001486. doi:10.1136/jitc-2020-001486.
    1. Peter M, Kuhnel F. Oncolytic adenovirus in cancer immunotherapy. Cancers. 2020;12:3354. doi:10.3390/cancers12113354.
    1. Rosewell Shaw A, Suzuki M. Recent advances in oncolytic adenovirus therapies for cancer. Curr Opin Virol. 2016;21:9–15. doi:10.1016/j.coviro.2016.06.009.
    1. Dong W, Van Ginkel JW, Au KY, Alemany R, Meulenberg JJ, Van Beusechem VW. ORCA-010, a novel potency-enhanced oncolytic adenovirus, exerts strong antitumor activity in preclinical models. Hum Gene Ther. 2014;25:897–904. doi:10.1089/hum.2013.229.
    1. Goradel NH, Mohajel N, Malekshahi ZV, Jahangiri S, Najafi M, Farhood B, Mortezaee K, Negahdari B, Arashkia A. Oncolytic adenovirus: a tool for cancer therapy in combination with other therapeutic approaches. J Cell Physiol. 2019;234:8636–8646. doi:10.1002/jcp.27850.
    1. Springgay LK, Strauwald AM, Ewald B, Robbins JM, Chan WM. Abstract 6713: oncolytic adenoviruses expressing immune modulators enhance tumor cell killing in human cancer 3D microtumor models. Cancer Res. 2020;80:6713.
    1. Eriksson E, Milenova I, Wenthe J, Stahle M, Leja-Jarblad J, Ullenhag G, Dimberg A, Moreno R, Alemany R, Loskog A, et al. Shaping the tumor stroma and sparking immune activation by CD40 and 4-1BB signaling induced by an armed oncolytic virus. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2017;23:5846–5857. doi:10.1158/1078-0432.CCR-17-0285.
    1. Kumar V, Giacomantonio MA, Gujar S. Role of myeloid cells in oncolytic reovirus-based cancer therapy. Viruses. 2021;13:654. doi:10.3390/v13040654.
    1. Ku GY, Winter KA, Williams TM, Adusumilli PS, Nishimura M, Yock A, Ilson DH, Hong TS. NRG Oncology NRG-GI007 trial-in-progress: phase I study of OBP-301 (Telomelysin) and definitive chemoradiation (CRT) for patients with locally advanced esophageal and gastroesophageal adenocarcinoma who are not candidates for surgery. Journal of Clinical Oncology. 2021;39:TPS262. doi:10.1200/JCO.2021.39.3_suppl.TPS262.
    1. Jacobs BL, Langland JO, Kibler KV, Denzler KL, White SD, Holechek SA, Wong S, Huynh T, Baskin CR. Vaccinia virus vaccines: past, present and future. Antiviral Res. 2009;84:1–13. doi:10.1016/j.antiviral.2009.06.006.
    1. Belongia EA, Naleway AL. Smallpox vaccine: the good, the bad, and the ugly. Clin Med Res. 2003;1(2):87–92. doi:10.3121/cmr.1.2.87.
    1. Umer BA, Noyce RS, Franczak BC, Shenouda MM, Kelly RG, Favis NA, Desaulniers M, Baldwin TA, Hitt MM, Evans DH, et al. Deciphering the immunomodulatory capacity of oncolytic vaccinia virus to enhance the immune response to breast cancer. Cancer Immunol Res. 2020;8:618–631. doi:10.1158/2326-6066.CIR-19-0703.
    1. Marchand J-B, Semmrich M, Fend L, Rehn M, Silvestre N, Teige I, et al. Abstract 5602: BT-001, an oncolytic vaccinia virus armed with a Treg-depletion-optimized recombinant human anti-CTLA4 antibody and GM-CSF to target the tumor microenvironment. Cancer Res. 2020;80:5602.
    1. Kim JH, Oh JY, Park BH, Lee DE, Kim JS, Park HE, Roh MS, Je JE, Yoon JH, Thorne SH, et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol Ther. 2006;14:361–370. doi:10.1016/j.ymthe.2006.05.008.
    1. Rha SY, Merchan J, Oh SY, Kim C, Bae WK, Lee HW, Dillon M, Deering R, Kroog G, Ha KS. A phase Ib study of recombinant vaccinia virus in combination with immune checkpoint inhibition (ICI) in advanced renal cell carcinoma (RCC). Cancer Res. 2020;80(16_suppl).
    1. Iankov ID, Haralambieva IH, Galanis E. Immunogenicity of attenuated measles virus engineered to express Helicobacter pylori neutrophil-activating protein. Vaccine. 2011;29:1710–1720. doi:10.1016/j.vaccine.2010.12.020.
    1. Holbrook MC, Goad DW, Grdzelishvili VZ. Expanding the spectrum of pancreatic cancers responsive to vesicular stomatitis virus-based oncolytic virotherapy: challenges and solutions. Cancers. 2021;13:1171. doi:10.3390/cancers13051171.
    1. Jenner AL, Cassidy T, Belaid K, Bourgeois-Daigneault M-C, Craig M. In silico trials predict that combination strategies for enhancing vesicular stomatitis oncolytic virus are determined by tumor aggressivity. Journal for Immunotherapy of Cancer. 2021;9:e001387. doi:10.1136/jitc-2020-001387.
    1. Galibert M-D, Gilot D, Migault M, Bachelot L, Journé F, Rogiers A, et al. Abstract 3048: a noncoding function of TYRP1 mRNA promotes melanoma growth. Cancer Res. 2017;77:3048.
    1. Ghanem G, Fabrice J. Tyrosinase related protein 1 (TYRP1/gp75) in human cutaneous melanoma. Mol Oncol. 2011;5(2):150–155. doi:10.1016/j.molonc.2011.01.006.
    1. Journe F, Id Boufker H, Van Kempen L, Galibert MD, Wiedig M, Sales F, Theunis A, Nonclercq D, Frau A, Laurent G, et al. TYRP1 mRNA expression in melanoma metastases correlates with clinical outcome. Br J Cancer. 2011;105:1726–1732. doi:10.1038/bjc.2011.451.
    1. Sznol M, Lutzky J, Adjei AA, Powell SF, He AR, Patel M, O’Day S, Pandya NB, Kaesshaefer S, Reckner M, et al. Phase II trial of Voyager-V1 (vesicular stomatitis virus expressing human IFNβ and NIS, VV1), in combination with cemiplimab (C) in patients with NSCLC, melanoma, HCC or endometrial carcinoma. Journal of Clinical Oncology. 2020;38:TPS3161. doi:10.1200/JCO.2020.38.15_suppl.TPS3161.
    1. Atherton MJ, Stephenson KB, Nikota JK, Hu QN, Nguyen A, Wan Y, Lichty BD. Preclinical development of peptide vaccination combined with oncolytic MG1-E6E7 for HPV-associated cancer. Vaccine. 2018;36:2181–2192. doi:10.1016/j.vaccine.2018.02.070.
    1. Pol JG, Acuna SA, Yadollahi B, Tang N, Stephenson KB, Atherton MJ, et al. Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials. Oncoimmunology. 2019;8:e1512329. doi:10.1080/2162402X.2018.1512329.
    1. Holl EK, Brown MC, Boczkowski D, McNamara MA, George DJ, Bigner DD, Gromeier M, Nair SK. Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models. Oncotarget. 2016;7(48):79828–79841. doi:10.18632/oncotarget.12975.
    1. Walton RW, Brown MC, Sacco MT, Gromeier M, Pfeiffer JK. Engineered oncolytic poliovirus PVSRIPO subverts MDA5-dependent innate immune responses in cancer cells. J Virol. 2018;92. doi:10.1128/JVI.00879-18.
    1. Beasley GM, Nair SK, Farrow NE, Landa K, Selim MA, Wiggs CA, Jung S-H, Bigner DD, True Kelly A, Gromeier M, et al. Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma. Journal for Immunotherapy of Cancer. 2021;9:e002203. doi:10.1136/jitc-2020-002203.
    1. Sloan AE, Buerki RA, Murphy C, Kelly AT, Ambady P, Brown M, Butowski NA, Cavaliere R, Curry WT, Desjardins A, et al. LUMINOS-101: phase 2 study of PVSRIPO with pembrolizumab in recurrent glioblastoma. 2021;39(15_suppl).
    1. Burman B, Niu J, Leidner RS, Wang D, Richardson DL, Iacobucci C, Hwang A, Qing X, Matushansky I, Zamarin D, et al. A phase I/II study of HB-201, an arenavirus-based cancer immunotherapy, alone, or in combination with anti-PD-1 in patients with HPV16+ cancers. Journal of Clinical Oncology. 2020;38(15).
    1. Shaw AR, Suzuki M. Immunology of adenoviral vectors in cancer therapy. Mol Ther Methods Clin Dev. 2019;15:418–429. doi:10.1016/j.omtm.2019.11.001.
    1. Suzawa K, Shien K, Peng H, Sakaguchi M, Watanabe M, Hashida S, MAKI Y, YAMAMOTO H, TOMIDA S, SOH J, et al. Distant bystander effect of REIC/DKK3 gene therapy through immune system stimulation in thoracic malignancies. Anticancer Res. 2017;37:301–307. doi:10.21873/anticanres.11321.
    1. Sobol RE, Chada S, Wiederhold DB, Yun C-O, Ahn H, Oh E, Murthy R, Subbiah V, Menander KB. Effect of adenoviral p53 (Ad-p53) tumor suppressor immune gene therapy on checkpoint inhibitor resistance and abscopal therapeutic efficacy. Journal of Clinical Oncology. 2017;35:e14610–e. doi:10.1200/JCO.2017.35.15_suppl.e14610.
    1. Sobol RE, Menander KB, Chada S, Wiederhold D, Sellman B, Talbott M, Nemunaitis JJ. Analysis of adenoviral p53 gene therapy clinical trials in recurrent head and neck squamous cell carcinoma. Front Oncol. 2021;11:645745. doi:10.3389/fonc.2021.645745.
    1. Madan RA, Arlen PM, Mohebtash M, Hodge JW, Gulley JL. Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs. 2009;18:1001–1011. doi:10.1517/13543780902997928.
    1. Maughan BL, Sanchez A, O’Neil BB, Lowrance WT, Dechet CB, Albertson DJ, Sirohi D, Gupta S, Swami U, Agarwal N. A phase Ib/II trial of perioperative intratumoral MVA-BN-brachyury (MVA) plus systemic PROSTVAC and atezolizumab (Atezo) for intermediate-risk and high-risk localized prostate cancer (AtezoVax). Journal of Clinical Oncology. 2020;36(6_suppl).
    1. Li C-X, Qi Y-D, Feng J, Zhang X-Z. Cell-based bio-hybrid delivery system for disease treatments. Advanced Nanobiomed Research. 2021;2000052. doi:10.1002/anbr.202000052.
    1. Kabiljo J, Laengle J, Bergmann M. From threat to cure: understanding of virus-induced cell death leads to highly immunogenic oncolytic influenza viruses. Cell Death Discov. 2020;6:48. doi:10.1038/s41420-020-0284-1.
    1. Jou J, Harrington KJ, Zocca MB, Ehrnrooth E, Cohen EEW. The changing landscape of therapeutic cancer vaccines-novel platforms and neoantigen identification. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2021;27:689–703. doi:10.1158/1078-0432.CCR-20-0245.
    1. Saxena M, Van Der Burg SH, Melief CJM, Bhardwaj N. Therapeutic cancer vaccines. Nat Rev Cancer. 2021;21:360–378.
    1. Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang XY. Therapeutic cancer vaccines: past, present, and future. Adv Cancer Res. 2013;119:421–475.
    1. Liu W, Tang H, Li L, Wang X, Yu Z, Li J. Peptide-based therapeutic cancer vaccine: current trends in clinical application. Cell Prolif. 2021;54:e13025. doi:10.1111/cpr.13025.
    1. Peng M, Mo Y, Wang Y, Wu P, Zhang Y, Xiong F, Guo C, Wu X, Li Y, Li X, et al. Neoantigen vaccine: an emerging tumor immunotherapy. Mol Cancer. 2019;18:128. doi:10.1186/s12943-019-1055-6.
    1. Laumont CM, Vincent K, Hesnard L, Audemard E, Bonneil E, Laverdure JP, Gendron P, Courcelles M, Hardy M-P, Côté C, et al. Noncoding regions are the main source of targetable tumor-specific antigens. Sci Transl Med. 2018;10:eaau5516. doi:10.1126/scitranslmed.aau5516.
    1. Ehx G, Larouche JD, Durette C, Laverdure JP, Hesnard L, Vincent K, et al. Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes. Immunity. 2021;54:737–52 e10. doi:10.1016/j.immuni.2021.03.001.
    1. Pol J, Bloy N, Buque A, Eggermont A, Cremer I, Sautes-Fridman C, Galon J, Tartour E, Zitvogel L, Kroemer G, et al. Trial watch: peptide-based anticancer vaccines. Oncoimmunology. 2015;4:e974411. doi:10.4161/2162402X.2014.974411.
    1. Bezu L, Kepp O, Cerrato G, Pol J, Fucikova J, Spisek R, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: peptide-based vaccines in anticancer therapy. Oncoimmunology. 2018;7:e1511506. doi:10.1080/2162402X.2018.1511506.
    1. Markowitz J, Brohl A, Sarnaik AA, Eroglu Z, De Aquino DB, Khushalani N, et al. Abstract CT241: trial in progress: iFx-Hu2.0 (plasmid DNA coding for Emm55 streptococcal antigen in a cationic polymer) phase I first in human study for unresectable stage III or stage IV cutaneous melanoma. Cancer Res. 2020;80:CT241–CT.
    1. Markowitz J, Kodumudi KN, Aquino DBD, Sondak VK, Pilon-Thomas S. Abstract CT119: trial in progress: first in human Phase I study using a plasmid DNA coding for Emm55 streptococcal antigen (IFx-Hu2.0) in patients with unresectable stage III or stage IV cutaneous melanoma. Cancer Res. 2019;79:CT119–CT.
    1. Madan RA, Antonarakis ES, Drake CG, Fong L, Yu EY, McNeel DG, Lin DW, Chang NN, Sheikh NA, Gulley JL, et al. Putting the pieces together: completing the mechanism of action Jigsaw for Sipuleucel-T. J Natl Cancer Inst. 2020;112:562–573. doi:10.1093/jnci/djaa021.
    1. Anassi E, Ndefo UA. Sipuleucel-T (provenge) injection: the first immunotherapy agent (vaccine) for hormone-refractory prostate cancer. P T. 2011;36:197–202.
    1. Handy CE, Antonarakis ES. Sipuleucel-T for the treatment of prostate cancer: novel insights and future directions. Future Oncol. 2018;14:907–917. doi:10.2217/fon-2017-0531.
    1. Magill ST, Choy W, Nguyen MP, McDermott MW. Ommaya reservoir insertion: a technical note. Cureus. 2020;12:e7731.
    1. Kar UK, Srivastava MK, Andersson A, Baratelli F, Huang M, Kickhoefer VA, Dubinett SM, Rome LH, Sharma S, et al. Novel CCL21-vault nanocapsule intratumoral delivery inhibits lung cancer growth. PloS One. 2011;6:e18758. doi:10.1371/journal.pone.0018758.
    1. Stefanski HE, Jonart L, Goren E, Mule JJ, Blazar BR, Labrecque N. A novel approach to improve immune effector responses post transplant by restoration of CCL21 expression. PloS One. 2018;13:e0193461. doi:10.1371/journal.pone.0193461.
    1. Lee JM, Garon EB, Baratelli F, Schaue D, Pak PS, Wallace WD, Suh R, Abtin F, Zeng G, Dubinett SM. Phase I trial of CCL21 gene modified dendritic cells in non-small cell lung cancer. Journal of Clinical Oncology. 2010;28(15_suppl).
    1. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8:299–308. doi:10.1038/nrc2355.
    1. Xie G, Dong H, Liang Y, Ham JD, Rizwan R, Chen J. CAR-NK cells: a promising cellular immunotherapy for cancer. EBioMedicine. 2020;59:102975. doi:10.1016/j.ebiom.2020.102975.
    1. Kundu S, Gurney M, O’Dwyer M. Generating natural killer cells for adoptive transfer: expanding horizons. Cytotherapy. 2021;23:559–566. doi:10.1016/j.jcyt.2020.12.002.
    1. Beyar-Katz O, Gill S. Advances in chimeric antigen receptor T cells. Curr Opin Hematol. 2020;27:368–377. doi:10.1097/MOH.0000000000000614.
    1. Han D, Xu Z, Zhuang Y, Ye Z, Qian Q. Current progress in CAR-T cell therapy for hematological malignancies. J Cancer. 2021;12:326–334. doi:10.7150/jca.48976.
    1. Approvals expand multiple myeloma treatment options. Cancer Discov. 2021; 11: OF5. doi:10.1158/-NB2021-0338.
    1. Powell K, Russler-Germain D, Prasad V. Idecabtagene vicleucel: questions regarding the appropriate role and cost. Br J Haematol. 2021. doi:10.1111/bjh.17784.
    1. Rodriguez-Lobato LG, Ganzetti M, Fernandez de Larrea C, Hudecek M, Einsele H, Danhof S. CAR T-cells in multiple myeloma: state of the art and future directions. Front Oncol. 2020;10:1243.
    1. Sadeqi Nezhad M, Yazdanifar M, Abdollahpour-Alitappeh M, Sattari A, Seifalian A, Bagheri N. Strengthening the CAR-T cell therapeutic application using CRISPR/Cas9 technology. Biotechnol Bioeng. 2021;118:3691–3705. doi:10.1002/bit.27882.
    1. De Jaeghere EA, Denys HG, De Wever O. Fibroblasts fuel immune escape in the tumor microenvironment. Trends Cancer. 2019;5:704–723. doi:10.1016/j.trecan.2019.09.009.
    1. Petroni G, Buque A, Yamazaki T, Bloy N, Liberto MD, Chen-Kiang S, Formenti SC, Galluzzi L. Radiotherapy delivered before CDK4/6 inhibitors mediates superior therapeutic effects in ER breast cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2021;27:1855–1863. doi:10.1158/1078-0432.CCR-20-3871.
    1. Pilones KA, Hensler M, Daviaud C, Kraynak J, Fucikova J, Galluzzi L, et al. Converging focal radiation and immunotherapy in a preclinical model of triple negative breast cancer: contribution of Vista blockade. Oncoimmunology. 2020;9:1830524. doi:10.1080/2162402X.2020.1830524.
    1. Yamazaki T, Buque A, Ames TD, Galluzzi L. PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models. Oncoimmunology. 2020;9(1):1721810. doi:10.1080/2162402X.2020.1721810.
    1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. doi:10.1016/j.immuni.2013.07.012.
    1. Schwarze JK, Awada G, Cras L, Tijtgat J, Forsyth R, Dufait I, et al. Intratumoral combinatorial administration of CD1c (BDCA-1)(+) myeloid dendritic cells plus ipilimumab and avelumab in combination with intravenous low-dose nivolumab in patients with advanced solid tumors: a phase IB clinical trial. Vaccines (Basel). 2020 Nov 10;8(4):670.
    1. Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, Chen CJJ, Dunbar PR, Wadley RB, Jeet V, et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. 2010;207:1247–1260. doi:10.1084/jem.20092140.
    1. Patel MR, Bauer TM, Jimeno A, Wang D, LoRusso P, Do KT, Stemmer SM, Maurice-Dror C, Geva R, Zacharek S, et al. A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab. Journal of Clinical Oncology. 2020;38:3092.
    1. Beck JD, Reidenbach D, Salomon N, Sahin U, Tureci O, Vormehr M, Kranz LM. mRNA therapeutics in cancer immunotherapy. Mol Cancer. 2021;20:69. doi:10.1186/s12943-021-01348-0.
    1. Lardone RD, Chan AA, Lee AF, Foshag LJ, Faries MB, Sieling PA, Lee DJ. Mycobacterium bovis bacillus calmette-guerin alters melanoma microenvironment favoring antitumor T cell responses and improving M2 macrophage function. Front Immunol. 2017;8:965. doi:10.3389/fimmu.2017.00965.
    1. Klinghoffer RA, Bahrami SB, Hatton BA, Frazier JP, Moreno-Gonzalez A, Strand AD, Kerwin WS, Casalini JR, Thirstrup DJ, You S, et al. A technology platform to assess multiple cancer agents simultaneously within a patient’s tumor. Sci Transl Med. 2015;7:284ra58. doi:10.1126/scitranslmed.aaa7489.
    1. Klinghoffer R, Thompson MJ, Davidson DJ, Bertout JA, Sottero KHW, Grenley MO, et al. Multidrug analyses in cancer patients via intratumoral microdosing with CIVO: a microinjection technology for phase 0 drug investigation. Journal of Clinical Oncology. 2018;36:e23569–e. doi:10.1200/JCO.2018.36.15_suppl.e23569.
    1. Nakamura A, Song K, Grossman S, Xega K, Zhang Y, Berger A, et al. 552 SUMOylation inhibitor TAK-981 activates NK cells and macrophages via type I interferon signaling and shows synergistic activity in combination with rituximab and daratumumab in preclinical models. Journal for Immunotherapy of Cancer. 2020;8(Suppl 3):A334–A5. doi:10.1136/jitc-2020-SITC2020.0552.
    1. Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, Yamazaki T, Poirier-Colame V, Newton A, Redouane Y, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44:343–354. doi:10.1016/j.immuni.2015.11.024.
    1. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–377. doi:10.1038/nature14292.

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