Abstract
Mobilizing antitumour immunity through vaccination potentially constitutes a powerful anticancer strategy but has not yet provided robust clinical benefits in large patient populations. Although major hurdles still exist, we believe that currently available strategies for vaccines that target dendritic cells or use them to present antitumour antigens could be integrated into existing clinical practice using prime–boost approaches. In the priming phase, these approaches capitalize on either standard treatment modalities to trigger in situ vaccination and release tumour antigens or vaccination with dendritic cells loaded with tumour lysates or patient-specific neoantigens. In a second boost phase, personalized synthetic vaccines specifically boost T cells that were triggered during the priming phase. This immunotherapy approach has been enabled by the substantial recent improvements in dendritic cell vaccines. In this Perspective, we discuss these improvements, highlight how the prime–boost approach can be translated into clinical practice and provide solutions for various anticipated hurdles.
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References
Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).
Fu, Q. et al. Prognostic value of tumor-infiltrating lymphocytes in melanoma: a systematic review and meta-analysis. Oncoimmunology 8, 1593806 (2019).
Ingold Heppner, B., Loibl, S. & Denkert, C. Tumor-infiltrating lymphocytes: a promising biomarker in breast cancer. Breast Care 11, 96–100 (2016).
Beatty, G. L. & Gladney, W. L. Immune escape mechanisms as a guide for cancer immunotherapy. Clin. Cancer Res. 21, 687–692 (2015).
O’Keeffe, M., Mok, W. H. & Radford, K. J. Human dendritic cell subsets and function in health and disease. Cell Mol. Life Sci. 72, 4309–4325 (2015).
Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).
Disis, M. L. Mechanism of action of immunotherapy. Semin. Oncol. 41 (Suppl. 5), 3–13 (2014).
Martin Lluesma, S., Wolfer, A., Harari, A. & Kandalaft, L. E. Cancer vaccines in ovarian cancer: how can we improve? Biomedicines 4, 10 (2016).
Small, E. J. et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J. Clin. Oncol. 24, 3089–3094 (2006).
Garg, A. D., Coulie, P. G., Van den Eynde, B. J. & Agostinis, P. Integrating next-generation dendritic cell vaccines into the current cancer immunotherapy landscape. Trends Immunol. 38, 577–593 (2017).
Odunsi, K. et al. Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer. Proc. Natl Acad. Sci. USA 104, 12837–12842 (2007).
Zhao, L., Zhang, M. & Cong, H. Advances in the study of HLA-restricted epitope vaccines. Hum. Vaccin. Immunother. 9, 2566–2577 (2013).
Bezu, L. et al. Trial watch: peptide-based vaccines in anticancer therapy. Oncoimmunology 7, e1511506 (2018).
Chiang, C. L., Coukos, G. & Kandalaft, L. E. Whole tumor antigen vaccines: where are we? Vaccines 3, 344–372 (2015).
Alspach, E. et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 574, 696–701 (2019).
Melief, C. J. & van der Burg, S. H. Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat. Rev. Cancer 8, 351–360 (2008).
Dikov, M. M. et al. Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J. Immunol. 174, 215–222 (2005).
Rabinowich, H. et al. Lymphocyte apoptosis induced by Fas ligand-expressing ovarian carcinoma cells. Implications for altered expression of T cell receptor in tumor-associated lymphocytes. J. Clin. Invest. 101, 2579–2588 (1998).
Groh, V., Wu, J., Yee, C. & Spies, T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419, 734 (2002).
Loercher, A. E., Nash, M. A., Kavanagh, J. J., Platsoucas, C. D. & Freedman, R. S. Identification of an IL-10-producing HLA-DR-negative monocyte subset in the malignant ascites of patients with ovarian carcinoma that inhibits cytokine protein expression and proliferation of autologous T cells. J. Immunol. 163, 6251–6260 (1999).
Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A.-K. L. & Flavell, R. A. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 24, 99–146 (2006).
Vandenberk, L., Belmans, J., Van Woensel, M., Riva, M. & Van Gool, S. W. Exploiting the immunogenic potential of cancer cells for improved dendritic cell vaccines. Front. Immunol. 6, 663 (2015).
Mookerjee, A., Graciotti, M., Kandalaft, L. E. & Kandalaft, L. A cancer vaccine with dendritic cells differentiated with GM-CSF and IFNalpha and pulsed with a squaric acid treated cell lysate improves T cell priming and tumor growth control in a mouse model. Bioimpacts 8, 211–221 (2018).
Tanyi, J. L. et al. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer. Sci. Transl Med. 10, eaao5931 (2018).
Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).
Kawasaki, T. & Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 5, 461 (2014).
Chiang, C. L. & Kandalaft, L. E. In vivo cancer vaccination: which dendritic cells to target and how? Cancer Treat. Rev. 71, 88–101 (2018).
Su, Z. et al. Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res. 63, 2127–2133 (2003).
Kyte, J. A. et al. Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA. Cancer Gene Ther. 13, 905–918 (2006).
Vik-Mo, E. O. et al. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. Cancer Immunol. Immunother. 62, 1499–1509 (2013).
Markov, O., Oshchepkova, A. & Mironova, N. Immunotherapy based on dendritic cell-targeted/-derived extracellular vesicles — a novel strategy for enhancement of the anti-tumor immune response. Front. Pharmacol. 10, 1152 (2019).
Patel, G. K. et al. Comparative analysis of exosome isolation methods using culture supernatant for optimum yield, purity and downstream applications. Sci. Rep. 9, 5335 (2019).
Whiteside, T. L. Tumor-derived exosomes and their role in cancer progression. Adv. Clin. Chem. 74, 103–141 (2016).
Palucka, A. K. et al. Dendritic cells loaded with killed allogeneic melanoma cells can induce objective clinical responses and MART-1 specific CD8+ T-cell immunity. J. Immunother. 29, 545–557 (2006).
Di Nicola, M. et al. Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunologic responses in indolent B-cell lymphoma patients with relapsed and measurable disease: a pilot study. Blood 113, 18–27 (2009).
Ernstoff, M. S. et al. Developing a rational tumor vaccine therapy for renal cell carcinoma: immune yin and yang. Clin. Cancer Res. 13, 733s–740s (2007).
Neller, M. A., Lopez, J. A. & Schmidt, C. W. Antigens for cancer immunotherapy. Semin. Immunol. 20, 286–295 (2008).
Bol, K. F., Schreibelt, G., Gerritsen, W. R., de Vries, I. J. & Figdor, C. G. Dendritic cell-based immunotherapy: state of the art and beyond. Clin. Cancer Res. 22, 1897–1906 (2016).
Galluzzi, L., Senovilla, L., Zitvogel, L. & Kroemer, G. The secretally: immunostimulation by anticancer drugs. Nat. Rev. Drug Discov. 11, 215–233 (2012).
Mikyskova, R. et al. Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure induce strong immune responses and display therapeutic effects both in murine TC-1 and TRAMP-C2 tumors when combined with docetaxel chemotherapy. Int. J. Oncol. 48, 953–964 (2016).
Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).
Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).
Martin Lluesma, S., Graciotti, M., Chiang, C. L. & Kandalaft, L. E. Does the immunocompetent status of cancer patients have an impact on therapeutic DC vaccination strategies? Vaccines 6, 79 (2018).
Demaria, S., Coleman, C. N. & Formenti, S. C. Radiotherapy: changing the game in immunotherapy. Trends Cancer 2, 286–294 (2016).
Formenti, S. C. & Demaria, S. Radiation therapy to convert the tumor into an in situ vaccine. Int. J. Radiat. Oncol. Biol. Phys. 84, 879–880 (2012).
Golden, E. B., Demaria, S., Schiff, P. B., Chachoua, A. & Formenti, S. C. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol. Res. 1, 365–372 (2013).
Herrera, F. G., Fyles, A. & Milosevic, M. In regard to Ishikawa et al.: Cyclooxygenase-2 impairs treatment effect of radiotherapy for cervical cancer by inhibition of radiation-induced apoptosis (Int J Radiat Oncol Biol Phys 2006;66:1347–1355). Int. J. Radiat. Oncol. Biol. Phys. 68, 959–960; author reply 960 (2007).
Hiniker, S. M. et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol. 5, 404–407 (2012).
Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).
Tabi, Z. et al. Resistance of CD45RA- T cells to apoptosis and functional impairment, and activation of tumor-antigen specific T cells during radiation therapy of prostate cancer. J. Immunol. 185, 1330–1339 (2010).
Herrera, F. G. et al. 50-Gy stereotactic body radiation therapy to the dominant intraprostatic nodule: results from a phase 1a/b trial. Int. J. Radiat. Oncol. Biol. Phys. 103, 320–334 (2019).
Kato, T. et al. Characterization of the cryoablation-induced immune response in kidney cancer patients. Oncoimmunology 6, e1326441 (2017).
Yakkala, C., Chiang, C. L., Kandalaft, L., Denys, A. & Duran, R. Cryoablation and immunotherapy: an enthralling synergy to confront the tumors. Front. Immunol. 10, 2283 (2019).
Machlenkin, A. et al. Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity. Clin. Cancer Res. 11, 4955–4961 (2005).
Udagawa, M. et al. Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation. Clin. Cancer Res. 12, 7465–7475 (2006).
Collin, M. & Bigley, V. Human dendritic cell subsets: an update. Immunology 154, 3–20 (2018).
Wculek, S. K. et al. Dendritic cells in cancer immunology and immunotherapy. Nat. Rev. Immunol. 20, 7–24 (2020).
Osugi, Y., Vuckovic, S. & Hart, D. N. Myeloid blood CD11c+ dendritic cells and monocyte-derived dendritic cells differ in their ability to stimulate T lymphocytes. Blood 100, 2858–2866 (2002).
Prue, R. L. et al. A phase I clinical trial of CD1c (BDCA-1)+ dendritic cells pulsed with HLA-A*0201 peptides for immunotherapy of metastatic hormone refractory prostate cancer. J. Immunother. 38, 71–76 (2015).
Davis, I. D. et al. Blood dendritic cells generated with Flt3 ligand and CD40 ligand prime CD8+ T cells efficiently in cancer patients. J. Immunother. 29, 499–511 (2006).
Westdorp, H. et al. Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer. J. Immunother. Cancer 7, 302 (2019).
Hsu, J. L. et al. A blood dendritic cell vaccine for acute myeloid leukemia expands anti-tumor T cell responses at remission. Oncoimmunology 7, e1419114 (2018).
Koucky, V., Boucek, J. & Fialova, A. Immunology of plasmacytoid dendritic cells in solid tumors: a brief review. Cancers 11, 470 (2019).
Perez, C. R. & De Palma, M. Engineering dendritic cell vaccines to improve cancer immunotherapy. Nat. Commun. 10, 5408 (2019).
Bol, K. F. et al. The clinical application of cancer immunotherapy based on naturally circulating dendritic cells. J. Immunother. Cancer 7, 109 (2019).
Guo, C. et al. Therapeutic cancer vaccines: past, present, and future. Adv. Cancer Res. 119, 421–475 (2013).
Marciani, D. J. Vaccine adjuvants: role and mechanisms of action in vaccine immunogenicity. Drug Discov. Today 8, 934–943 (2003).
Obeid, J., Hu, Y. & Slingluff, C. L. Jr. Vaccines, adjuvants, and dendritic cell activators–current status and future challenges. Semin. Oncol. 42, 549–561 (2015).
Saxena, M. & Bhardwaj, N. Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines. Curr. Opin. Immunol. 47, 35–43 (2017).
Kong, B. Y. et al. On the other side: manipulating the immune checkpoint landscape of dendritic cells to enhance cancer immunotherapy. Front. Oncol. 9, 50–50 (2019).
Brown, J. A. et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 170, 1257–1266 (2003).
Rosenblatt, J. et al. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J. Immunother. 34, 409–418 (2011).
Son, C. H. et al. CTLA-4 blockade enhances antitumor immunity of intratumoral injection of immature dendritic cells into irradiated tumor in a mouse colon cancer model. J. Immunother. 37, 1–7 (2014).
Ribas, A. et al. Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. Clin. Cancer Res. 15, 6267–6276 (2009).
Shimabukuro-Vornhagen, A. et al. The immunosuppressive factors IL-10, TGF-beta, and VEGF do not affect the antigen-presenting function of CD40-activated B cells. J. Exp. Clin. Cancer Res. 31, 47 (2012).
Kondo, E. et al. CD40-activated B cells can be generated in high number and purity in cancer patients: analysis of immunogenicity and homing potential. Clin. Exp. Immunol. 155, 249–256 (2009).
Wennhold, K., Shimabukuro-Vornhagen, A. & von Bergwelt-Baildon, M. B cell-based cancer immunotherapy. Transfus. Med. Hemother. 46, 36–46 (2019).
Andreesen, R., Hennemann, B. & Krause, S. W. Adoptive immunotherapy of cancer using monocyte-derived macrophages: rationale, current status, and perspectives. J. Leukoc. Biol. 64, 419–426 (1998).
Lee, S., Kivimae, S., Dolor, A. & Szoka, F. C. Macrophage-based cell therapies: the long and winding road. J. Control. Rel. 240, 527–540 (2016).
Dohnal, A. M. et al. Phase I study of tumor Ag-loaded IL-12 secreting semi-mature DC for the treatment of pediatric cancer. Cytotherapy 9, 755–770 (2007).
Fong, L., Brockstedt, D., Benike, C., Wu, L. & Engleman, E. G. Dendritic cells injected via different routes induce immunity in cancer patients. J. Immunol. 166, 4254–4259 (2001).
West, E. et al. Clinical grade OK432-activated dendritic cells: in vitro characterization and tracking during intralymphatic delivery. J. Immunother. 32, 66–78 (2009).
Salgaller, M. L. et al. Report of immune monitoring of prostate cancer patients undergoing T-cell therapy using dendritic cells pulsed with HLA-A2-specific peptides from prostate-specific membrane antigen (PSMA). Prostate 35, 144–151 (1998).
Morse, M. A. et al. A phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen. Clin. Cancer Res. 5, 1331–1338 (1999).
Barratt-Boyes, S. M., Watkins, S. C. & Finn, O. J. Migration of cultured chimpanzee dendritic cells following intravenous and subcutaneous injection. Adv. Exp. Med. Biol. 417, 71–75 (1997).
Nestle, F. O. et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat. Med. 4, 328–332 (1998).
Koski, G. K., Cohen, P. A., Roses, R. E., Xu, S. & Czerniecki, B. J. Reengineering dendritic cell-based anti-cancer vaccines. Immunol. Rev. 222, 256–276 (2008).
Lambert, L. A. et al. Intranodal immunization with tumor lysate-pulsed dendritic cells enhances protective antitumor immunity. Cancer Res. 61, 641–646 (2001).
Seyfizadeh, N., Muthuswamy, R., Mitchell, D. A., Nierkens, S. & Seyfizadeh, N. Migration of dendritic cells to the lymph nodes and its enhancement to drive anti-tumor responses. Crit. Rev. Oncol. Hematol. 107, 100–110 (2016).
Aarntzen, E. H. et al. Targeting of 111In-labeled dendritic cell human vaccines improved by reducing number of cells. Clin. Cancer Res. 19, 1525–1533 (2013).
Aarntzen, E. H. et al. Reducing cell number improves the homing of dendritic cells to lymph nodes upon intradermal vaccination. Oncoimmunology 2, e24661 (2013).
Weiden, J., Tel, J. & Figdor, C. G. Synthetic immune niches for cancer immunotherapy. Nat. Rev. Immunol. 18, 212–219 (2018).
Hori, Y., Winans, A. M., Huang, C. C., Horrigan, E. M. & Irvine, D. J. Injectable dendritic cell-carrying alginate gels for immunization and immunotherapy. Biomaterials 29, 3671–3682 (2008).
Verma, V. et al. Activated dendritic cells delivered in tissue compatible biomatrices induce in-situ anti-tumor CTL responses leading to tumor regression. Oncotarget 7, 39894–39906 (2016).
Aurisicchio, L. & Ciliberto, G. Genetic cancer vaccines: current status and perspectives. Expert. Opin. Biol. Ther. 12, 1043–1058 (2012).
Graciotti, M., Berti, C., Klok, H. A. & Kandalaft, L. The era of bioengineering: how will this affect the next generation of cancer immunotherapy? J. Transl Med. 15, 142 (2017).
Calmeiro, J. et al. Biomaterial-based platforms for in situ dendritic cell programming and their use in antitumor immunotherapy. J. Immunother. Cancer 7, 238 (2019).
Manolova, V. et al. Nanoparticles target distinct dendritic cell populations according to their size. Eur. J. Immunol. 38, 1404–1413 (2008).
Cruz, L. J. et al. Targeting nanoparticles to CD40, DEC-205 or CD11c molecules on dendritic cells for efficient CD8+ T cell response: a comparative study. J. Control. Rel. 192, 209–218 (2014).
Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016).
Ali, O. A., Emerich, D., Dranoff, G. & Mooney, D. J. In situ regulation of DC subsets and T cells mediates tumor regression in mice. Sci. Transl Med. 1, 8ra19 (2009).
Ali, O. A., Huebsch, N., Cao, L., Dranoff, G. & Mooney, D. J. Infection-mimicking materials to program dendritic cells in situ. Nat. Mater. 8, 151–158 (2009).
Tran Janco, J. M., Lamichhane, P., Karyampudi, L. & Knutson, K. L. Tumor-infiltrating dendritic cells in cancer pathogenesis. J. Immunol. 194, 2985–2991 (2015).
Karthaus, N., Torensma, R. & Tel, J. Deciphering the message broadcast by tumor-infiltrating dendritic cells. Am. J. Pathol. 181, 733–742 (2012).
Herr, H. W. et al. Intravesical bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J. Clin. Oncol. 13, 1404–1408 (1995).
Carpentier, A. et al. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro Oncol. 8, 60–66 (2006).
Fricke, I. & Gabrilovich, D. I. Dendritic cells and tumor microenvironment: a dangerous liaison. Immunol. Invest. 35, 459–483 (2006).
Laoui, D. et al. The tumour microenvironment harbours ontogenically distinct dendritic cell populations with opposing effects on tumour immunity. Nat. Commun. 7, 13720 (2016).
Vigneron, N., Stroobant, V., Van den Eynde, B. J. & van der Bruggen, P. Database of T cell-defined human tumor antigens: the 2013 update. Cancer Immun. 13, 15 (2013).
Cobbold, M. et al. MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia. Sci. Transl Med. 5, 203ra125 (2013).
Lin, M. H. et al. Immunological evaluation of a novel HLA-A2 restricted phosphopeptide of tumor associated antigen, TRAP1, on cancer therapy. Vaccine X 1, 100017 (2019).
Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
McGranahan, N. & Swanton, C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168, 613–628 (2017).
Wolf, Y. et al. UVB-induced tumor heterogeneity diminishes immune response in melanoma. Cell 179, 219–235 (2019).
Gejman, R. S. et al. Rejection of immunogenic tumor clones is limited by clonal fraction. eLife 7, e41090 (2018).
Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017).
Robbins, P. F. et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21, 1019–1027 (2015).
Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl Med. 7, 303ra139 (2015).
Yamamoto, T. N., Kishton, R. J. & Restifo, N. P. Developing neoantigen-targeted T cell–based treatments for solid tumors. Nat. Med. 25, 1488–1499 (2019).
McGranahan, N. et al. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci. Transl Med. 7, 283ra254 (2015).
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Laumont, C. M. et al. Global proteogenomic analysis of human MHC class I-associated peptides derived from non-canonical reading frames. Nat. Commun. 7, 10238 (2016).
Sebestyen, E. et al. Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks. Genome Res. 26, 732–744 (2016).
Uenaka, A. et al. Identification of a unique antigen peptide pRL1 on BALB/c RL male 1 leukemia recognized by cytotoxic T lymphocytes and its relation to the Akt oncogene. J. Exp. Med. 180, 1599–1607 (1994).
Coulie, P. G. et al. A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc. Natl Acad. Sci. USA 92, 7976–7980 (1995).
Robbins, P. F. et al. The intronic region of an incompletely spliced gp100 gene transcript encodes an epitope recognized by melanoma-reactive tumor-infiltrating lymphocytes. J. Immunol. 159, 303–308 (1997).
Lupetti, R. et al. Translation of a retained intron in tyrosinase-related protein (TRP) 2 mRNA generates a new cytotoxic T lymphocyte (CTL)-defined and shared human melanoma antigen not expressed in normal cells of the melanocytic lineage. J. Exp. Med. 188, 1005–1016 (1998).
Wang, R. F., Parkhurst, M. R., Kawakami, Y., Robbins, P. F. & Rosenberg, S. A. Utilization of an alternative open reading frame of a normal gene in generating a novel human cancer antigen. J. Exp. Med. 183, 1131–1140 (1996).
Wang, R. F. et al. A breast and melanoma-shared tumor antigen: T cell responses to antigenic peptides translated from different open reading frames. J. Immunol. 161, 3598–3606 (1998).
Rosenberg, S. A. et al. Identification of BING-4 cancer antigen translated from an alternative open reading frame of a gene in the extended MHC class II region using lymphocytes from a patient with a durable complete regression following immunotherapy. J. Immunol. 168, 2402–2407 (2002).
Ronsin, C. et al. A non-AUG-defined alternative open reading frame of the intestinal carboxyl esterase mRNA generates an epitope recognized by renal cell carcinoma-reactive tumor-infiltrating lymphocytes in situ. J. Immunol. 163, 483–490 (1999).
Mayrand, S. M., Schwarz, D. A. & Green, W. R. An alternative translational reading frame encodes an immunodominant retroviral CTL determinant expressed by an immunodeficiency-causing retrovirus. J. Immunol. 160, 39–50 (1998).
Van Den Eynde, B. J. et al. A new antigen recognized by cytolytic T lymphocytes on a human kidney tumor results from reverse strand transcription. J. Exp. Med. 190, 1793–1800 (1999).
Attig, J. et al. LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly. Genome Res. 29, 1578–1590 (2019).
Chong, C. et al. Integrated proteogenomic deep sequencing and analytics accurately identify non-canonical peptides in tumor immunopeptidomes. Nat. Commun. 11, 1293 (2020).
Laumont, C. M. et al. Noncoding regions are the main source of targetable tumor-specific antigens. Sci. Transl Med. 10, eaau5516 (2018).
Smart, A. C. et al. Intron retention is a source of neoepitopes in cancer. Nat. Biotechnol. 36, 1056–1058 (2018).
Zhao, Q. et al. Proteogenomics uncovers a vast repertoire of shared tumor-specific antigens in ovarian cancer. Cancer Immunol. Res. https://doi.org/10.1158/2326-6066.CIR-19-0541 (2020).
Abelin, J. G. et al. Defining HLA-II ligand processing and binding rules with mass spectrometry enhances cancer epitope prediction. Immunity 51, 766–779 (2019).
Abelin, J. G. et al. Mass spectrometry profiling of HLA-associated peptidomes in mono-allelic cells enables more accurate epitope prediction. Immunity 46, 315–326 (2017).
Bassani-Sternberg, M. et al. Deciphering HLA-I motifs across HLA peptidomes improves neo-antigen predictions and identifies allostery regulating HLA specificity. PLoS Comput. Biol. 13, e1005725 (2017).
Bassani-Sternberg, M. & Gfeller, D. Unsupervised HLA peptidome deconvolution improves ligand prediction accuracy and predicts cooperative effects in peptide-HLA interactions. J. Immunol. 197, 2492–2499 (2016).
Guillaume, P. et al. The C-terminal extension landscape of naturally presented HLA-I ligands. Proc. Natl Acad. Sci. USA 115, 5083–5088 (2018).
Jurtz, V. et al. NetMHCpan-4.0: improved peptide-MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data. J. Immunol. https://doi.org/10.4049/jimmunol.1700893 (2017).
Mei, S. et al. A comprehensive review and performance evaluation of bioinformatics tools for HLA class I peptide-binding prediction. Brief Bioinform. https://doi.org/10.1093/bib/bbz051 (2019).
Muller, M., Gfeller, D., Coukos, G. & Bassani-Sternberg, M. ‘Hotspots’ of antigen presentation revealed by human leukocyte antigen ligandomics for neoantigen prioritization. Front. Immunol. 8, 1367 (2017).
Bassani-Sternberg, M. et al. Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry. Nat. Commun. 7, 13404 (2016).
Ebrahimi-Nik, H. et al. Mass spectrometry driven exploration reveals nuances of neoepitope-driven tumor rejection. JCI Insight 5, e129152 (2019).
Schmidt, J. et al. In silico and cell-based analyses reveal strong divergence between prediction and observation of T-cell–recognized tumor antigen T-cell epitopes. J. Biol. Chem. 292, 11840–11849 (2017).
Calis, J. J. et al. Properties of MHC class I presented peptides that enhance immunogenicity. PLoS Comput. Biol. 9, e1003266 (2013).
Bjerregaard, A. M. et al. An analysis of natural T cell responses to predicted tumor neoepitopes. Front. Immunol. 8, 1566 (2017).
Duan, F. et al. Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity. J. Exp. Med. 211, 2231–2248 (2014).
Jorgensen, K. W., Rasmussen, M., Buus, S. & Nielsen, M. NetMHCstab - predicting stability of peptide-MHC-I complexes; impacts for cytotoxic T lymphocyte epitope discovery. Immunology 141, 18–26 (2014).
Garcia-Garijo, A., Fajardo, C. A. & Gros, A. Determinants for neoantigen identification. Front. Immunol. 10, 1392 (2019).
Finn, O. J. Human tumor antigens yesterday, today, and tomorrow. Cancer Immunol. Res. 5, 347–354 (2017).
Hundal, J. et al. pVACtools: a computational toolkit to identify and visualize cancer neoantigens. Cancer Immunol. Res. 8, 409–420 (2020).
Hundal, J. et al. pVAC-Seq: a genome-guided in silico approach to identifying tumor neoantigens. Genome Med. 8, 11 (2016).
Bjerregaard, A. M., Nielsen, M., Hadrup, S. R., Szallasi, Z. & Eklund, A. C. MuPeXI: prediction of neo-epitopes from tumor sequencing data. Cancer Immunol. Immunother. 66, 1123–1130 (2017).
Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).
Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).
Carreno, B. M. et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803–808 (2015).
Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019).
Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).
DeVault, V. L. et al. Vaccine neoantigens empirically identified through the ex vivo ATLAS platform promote potent therapeutic responses to cancer in mice. SITC https://sitc.planion.com/Web.User/AbstractDet?ACCOUNT=SITC&ABSID=12169&CONF=SITC19&ssoOverride=OFF&CKEY=) (2019).
Gfeller, D. & Bassani-Sternberg, M. Predicting antigen presentation-what could we learn from a million peptides? Front. Immunol. 9, 1716 (2018).
Chen, B. et al. Predicting HLA class II antigen presentation through integrated deep learning. Nat. Biotechnol. 37, 1332–1343 (2019).
Racle, J. et al. Robust prediction of HLA class II epitopes by deep motif deconvolution of immunopeptidomes. Nat. Biotechnol. 37, 1283–1286 (2019).
Sarivalasis, A. et al. A phase I/II trial comparing autologous dendritic cell vaccine pulsed either with personalized peptides (PEP-DC) or with tumor lysate (OC-DC) in patients with advanced high-grade ovarian serous carcinoma. J. Transl Med. 17, 391 (2019).
Anguille, S., Smits, E. L., Lion, E., van Tendeloo, V. F. & Berneman, Z. N. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 15, e257–e267 (2014).
Figdor, C. G., de Vries, I. J. M., Lesterhuis, W. J. & Melief, C. J. M. Dendritic cell immunotherapy: mapping the way. Nat. Med. 10, 475–480 (2004).
Bol, K. F. et al. Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination. Oncoimmunology 5, e1057673 (2016).
Nakai, N., Hartmann, G., Kishimoto, S. & Katoh, N. Dendritic cell vaccination in human melanoma: relationships between clinical effects and vaccine parameters. Pigment. Cell Melanoma Res. 23, 607–619 (2010).
Failli, A., Legitimo, A., Orsini, G., Romanini, A. & Consolini, R. Numerical defect of circulating dendritic cell subsets and defective dendritic cell generation from monocytes of patients with advanced melanoma. Cancer Lett. 337, 184–192 (2013).
Legitimo, A., Consolini, R., Failli, A., Orsini, G. & Spisni, R. Dendritic cell defects in the colorectal cancer. Hum. Vaccin. Immunother. 10, 3224–3235 (2014).
Ormandy, L. A. et al. Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma. World J. Gastroenterol. 12, 3275–3282 (2006).
Della Bella, S. et al. Altered maturation of peripheral blood dendritic cells in patients with breast cancer. Br. J. Cancer 89, 1463–1472 (2003).
Yanagimoto, H. et al. Impaired function of circulating dendritic cells in patients with pancreatic cancer. Clin. Immunol. 114, 52–60 (2005).
Tucci, M. et al. The immune escape in melanoma: role of the impaired dendritic cell function. Expert. Rev. Clin. Immunol. 10, 1395–1404 (2014).
Orsini, G. et al. Defective generation and maturation of dendritic cells from monocytes in colorectal cancer patients during the course of disease. Int. J. Mol. Sci. 14, 22022–22041 (2013).
van Willigen, W. W. et al. Dendritic cell cancer therapy: vaccinating the right patient at the right time. Front. Immunol. 9, 2265 (2018).
Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30, 44–56 (2019).
Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).
Rizvi, H. et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J. Clin. Oncol. 36, 633–641 (2018).
Goodman, A. M. et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol. Cancer Ther. 16, 2598–2608 (2017).
Zarogoulidis, P. et al. Nivolumab as first-line treatment in non-small cell lung cancer patients-key factors: tumor mutation burden and PD-L1 >/=50. Transl Lung Cancer Res. 7, S28–S30 (2018).
Park, S. E. et al. Clinical implication of tumor mutational burden in patients with HER2-positive refractory metastatic breast cancer. Oncoimmunology 7, e1466768 (2018).
Lauss, M. et al. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat. Commun. 8, 1738 (2017).
Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).
Truxova, I. et al. Rationale for the combination of dendritic cell-based vaccination approaches with chemotherapy agents. Int. Rev. Cell Mol. Biol. 330, 115–156 (2017).
Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).
Bassani-Sternberg, M. et al. A phase Ib study of the combination of personalized autologous dendritic cell vaccine, aspirin, and standard of care adjuvant chemotherapy followed by nivolumab for resected pancreatic adenocarcinoma-a proof of antigen discovery feasibility in three patients. Front. Immunol. 10, 1832 (2019).
Garg, A. D. et al. Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma. Sci. Transl Med. 8, 328ra327 (2016).
Chen, F. et al. Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors. J. Clin. Invest. 129, 2056–2070 (2019).
Yang, W. et al. Immunogenic neoantigens derived from gene fusions stimulate T cell responses. Nat. Med. 25, 767–775 (2019).
Sharma, G., Rive, C. M. & Holt, R. A. Rapid selection and identification of functional CD8(+) T cell epitopes from large peptide-coding libraries. Nat. Commun. 10, 4553 (2019).
Beard, R. E. et al. Multiple chimeric antigen receptors successfully target chondroitin sulfate proteoglycan 4 in several different cancer histologies and cancer stem cells. J. Immunother. Cancer 2, 25 (2014).
Zacharakis, N. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24, 724–730 (2018).
Bentzen, A. K. et al. Large-scale detection of antigen-specific T cells using peptide-MHC-I multimers labeled with DNA barcodes. Nat. Biotechnol. 34, 1037–1045 (2016).
Newell, E. W. et al. Combinatorial tetramer staining and mass cytometry analysis facilitate T-cell epitope mapping and characterization. Nat. Biotechnol. 31, 623–629 (2013).
Peng, S. et al. Sensitive detection and analysis of neoantigen-specific T cell populations from tumors and blood. Cell Rep. 28, 2728–2738 e2727 (2019).
Zhang, S. Q. et al. High-throughput determination of the antigen specificities of T cell receptors in single cells. Nat. Biotechnol. https://doi.org/10.1038/nbt.4282 (2018).
Bobisse, S. et al. Sensitive and frequent identification of high avidity neo-epitope specific CD8+ T cells in immunotherapy-naive ovarian cancer. Nat. Commun. 9, 1092 (2018).
Yossef, R. et al. Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy. JCI Insight 3, e122467 (2018).
Seliktar-Ofir, S. et al. Selection of shared and neoantigen-reactive T cells for adoptive cell therapy based on CD137 separation. Front. Immunol. 8, 1211 (2017).
Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 2724 (2018).
Pasetto, A. et al. Tumor- and neoantigen-reactive T-cell receptors can be identified based on their frequency in fresh tumor. Cancer Immunol. Res. 4, 734–743 (2016).
Scheper, W. et al. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat. Med. 25, 89–94 (2019).
Segaliny, A. I. et al. Functional TCR T cell screening using single-cell droplet microfluidics. Lab Chip 18, 3733–3749 (2018).
Arnaud, M. et al. Biotechnologies to tackle the challenge of neoantigen identification. Curr. Opin. Biotechnol. 65, 52–59 (2020).
Glass, D. G., McAlinden, N., Millington, O. R. & Wright, A. J. A minimally invasive optical trapping system to understand cellular interactions at onset of an immune response. PLoS ONE 12, e0188581 (2017).
Puech, P. H. et al. Force measurements of TCR/pMHC recognition at T cell surface. PLoS ONE 6, e22344 (2011).
Huang, J., Edwards, L. J., Evavold, B. D. & Zhu, C. Kinetics of MHC-CD8 interaction at the T cell membrane. J. Immunol. 179, 7653–7662 (2007).
Dura, B. et al. Profiling lymphocyte interactions at the single-cell level by microfluidic cell pairing. Nat. Commun. 6, 5940 (2015).
Hoover, H. C. Jr., Surdyke, M., Dangel, R. B., Peters, L. C. & Hanna, M. G. Jr. Delayed cutaneous hypersensitivity to autologous tumor cells in colorectal cancer patients immunized with an autologous tumor cell: bacillus Calmette-Guerin vaccine. Cancer Res. 44, 1671–1676 (1984).
Wallack, M. K. et al. Positive relationship of clinical and serologic responses to vaccinia melanoma oncolysate. Arch. Surg. 122, 1460–1463 (1987).
Mitchell, M. S. et al. Effectiveness and tolerability of low-dose cyclophosphamide and low-dose intravenous interleukin-2 in disseminated melanoma [corrected]. J. Clin. Oncol. 6, 409–424 (1988).
Elliott, G. T., McLeod, R. A., Perez, J. & Von Eschen, K. B. Interim results of a phase II multicenter clinical trial evaluating the activity of a therapeutic allogeneic melanoma vaccine (theraccine) in the treatment of disseminated malignant melanoma. Semin. Surg. Oncol. 9, 264–272 (1993).
Wallack, M. K. et al. Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. J. Am. Coll. Surg. 187, 69–79 (1998).
Chang, A. E. et al. A phase I trial of tumor lysate-pulsed dendritic cells in the treatment of advanced cancer. Clin. Cancer Res. 8, 1021–1032 (2002).
Marten, A. et al. Therapeutic vaccination against metastatic renal cell carcinoma by autologous dendritic cells: preclinical results and outcome of a first clinical phase I/II trial. Cancer Immunol. Immunother. 51, 637–644 (2002).
Nagayama, H. et al. Results of a phase I clinical study using autologous tumour lysate-pulsed monocyte-derived mature dendritic cell vaccinations for stage IV malignant melanoma patients combined with low dose interleukin-2. Melanoma Res. 13, 521–530 (2003).
Jocham, D. et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 363, 594–599 (2004).
Sondak, V. K. et al. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. J. Clin. Oncol. 20, 2058–2066 (2002).
Yamanaka, R. et al. Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial. Br. J. Cancer 89, 1172–1179 (2003).
Powell, A., Creaney, J., Broomfield, S., Van Bruggen, I. & Robinson, B. Recombinant GM-CSF plus autologous tumor cells as a vaccine for patients with mesothelioma. Lung Cancer 52, 189–197 (2006).
Kim, J. H. et al. Phase I/II study of immunotherapy using autologous tumor lysate-pulsed dendritic cells in patients with metastatic renal cell carcinoma. Clin. Immunol. 125, 257–267 (2007).
Kuwabara, K. et al. Results of a phase I clinical study using dendritic cell vaccinations for thyroid cancer. Thyroid 17, 53–58 (2007).
Ovali, E. et al. Active immunotherapy for cancer patients using tumor lysate pulsed dendritic cell vaccine: a safety study. J. Exp. Clin. Cancer Res. 26, 209–214 (2007).
Dudek, A. Z. et al. Autologous large multivalent immunogen vaccine in patients with metastatic melanoma and renal cell carcinoma. Am. J. Clin. Oncol. 31, 173–181 (2008).
Redman, B. G. et al. Phase Ib trial assessing autologous, tumor-pulsed dendritic cells as a vaccine administered with or without IL-2 in patients with metastatic melanoma. J. Immunother. 31, 591–598 (2008).
Berntsen, A. et al. Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial. J. Immunother. 31, 771–780 (2008).
Burgdorf, S. K. et al. Clinical responses in patients with advanced colorectal cancer to a dendritic cell based vaccine. Oncol. Rep. 20, 1305–1311 (2008).
Schwaab, T. et al. Clinical and immunologic effects of intranodal autologous tumor lysate-dendritic cell vaccine with Aldesleukin (Interleukin 2) and IFN-{alpha}2a therapy in metastatic renal cell carcinoma patients. Clin. Cancer Res. 15, 4986–4992 (2009).
Ardon, H. et al. Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: a pilot study. J. Neurooncol. 99, 261–272 (2010).
Um, S. J. et al. Phase I study of autologous dendritic cell tumor vaccine in patients with non-small cell lung cancer. Lung Cancer 70, 188–194 (2010).
Trepiakas, R. et al. Vaccination with autologous dendritic cells pulsed with multiple tumor antigens for treatment of patients with malignant melanoma: results from a phase I/II trial. Cytotherapy 12, 721–734 (2010).
Baek, S. et al. Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial. J. Transl Med. 9, 178 (2011).
Cho, D. Y. et al. Adjuvant immunotherapy with whole-cell lysate dendritic cells vaccine for glioblastoma multiforme: a phase II clinical trial. World Neurosurg. 77, 736–744 (2012).
Ellebaek, E. et al. Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial. Cancer Immunol. Immunother. 61, 1791–1804 (2012).
Himoudi, N. et al. Lack of T-cell responses following autologous tumour lysate pulsed dendritic cell vaccination, in patients with relapsed osteosarcoma. Clin. Transl Oncol. 14, 271–279 (2012).
Prins, R. M. et al. Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J. Immunother. 36, 152–157 (2013).
Kamigaki, T. et al. Immunotherapy of autologous tumor lysate-loaded dendritic cell vaccines by a closed-flow electroporation system for solid tumors. Anticancer Res. 33, 2971–2976 (2013).
Bapsy, P. P. et al. Open-label, multi-center, non-randomized, single-arm study to evaluate the safety and efficacy of dendritic cell immunotherapy in patients with refractory solid malignancies, on supportive care. Cytotherapy 16, 234–244 (2014).
Baek, S. et al. Therapeutic DC vaccination with IL-2 as a consolidation therapy for ovarian cancer patients: a phase I/II trial. Cell Mol. Immunol. 12, 87–95 (2015).
Caballero-Banos, M. et al. Phase II randomised trial of autologous tumour lysate dendritic cell plus best supportive care compared with best supportive care in pre-treated advanced colorectal cancer patients. Eur. J. Cancer 64, 167–174 (2016).
Miwa, S. et al. Phase 1/2 study of immunotherapy with dendritic cells pulsed with autologous tumor lysate in patients with refractory bone and soft tissue sarcoma. Cancer 123, 1576–1584 (2017).
Inoges, S. et al. A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fluorescence-guided surgery in newly diagnosed glioblastoma patients. J. Transl Med. 15, 104 (2017).
Liau, L. M. et al. First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J. Transl Med. 16, 142 (2018).
Herbert, G. S. et al. Initial phase I/IIa trial results of an autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine in patients with solid tumors. Vaccine 36, 3247–3253 (2018).
Buchroithner, J. et al. Audencel immunotherapy based on dendritic cells has no effect on overall and progression-free survival in newly diagnosed glioblastoma: a phase II randomized trial. Cancers 10, 372 (2018).
Benitez-Ribas, D. et al. Immune response generated with the administration of autologous dendritic cells pulsed with an allogenic tumoral cell-lines lysate in patients with newly diagnosed diffuse intrinsic pontine glioma. Front. Oncol. 8, 127 (2018).
Rodriguez-Ruiz, M. E. et al. Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients. Ann. Oncol. 29, 1312–1319 (2018).
Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).
Chu, K. F. & Dupuy, D. E. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat. Rev. Cancer 14, 199–208 (2014).
Saxena, M., Balan, S., Roudko, V. & Bhardwaj, N. Towards superior dendritic-cell vaccines for cancer therapy. Nat. Biomed. Eng. 2, 341–346 (2018).
Patente, T. A. et al. Human dendritic cells: their heterogeneity and clinical application potential in cancer immunotherapy. Front. Immunol. 9, 3176 (2018).
Sheen, M. R. & Fiering, S. In situ vaccination: harvesting low hanging fruit on the cancer immunotherapy tree. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1524 (2019).
Wang, Y.-J., Fletcher, R., Yu, J. & Zhang, L. Immunogenic effects of chemotherapy-induced tumor cell death. Genes. Dis. 5, 194–203 (2018).
Pol, J. et al. Trial watch: immunogenic cell death inducers for anticancer chemotherapy. Oncoimmunology 4, e1008866 (2015).
Wu, J. & Waxman, D. J. Immunogenic chemotherapy: dose and schedule dependence and combination with immunotherapy. Cancer Lett. 419, 210–221 (2018).
Ghiringhelli, F. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 56, 641–648 (2007).
Liu, Y., Cao, C. S., Yu, Y. & Si, Y. M. Thermal ablation in cancer. Oncol. Lett. 12, 2293–2295 (2016).
Takaki, H. et al. Thermal ablation and immunomodulation: from preclinical experiments to clinical trials. Diagn. Interv. Imaging 98, 651–659 (2017).
Nakagawa, H. et al. In vivo immunological antitumor effect of OK-432-stimulated dendritic cell transfer after radiofrequency ablation. Cancer Immunol. Immunother. 63, 347–356 (2014).
Xu, H. et al. Synergism between cryoablation and GM-CSF: enhanced immune function of splenic dendritic cells in mice with glioma. Neuroreport 26, 346–353 (2015).
den Brok, M. H. et al. Synergy between in situ cryoablation and TLR9 stimulation results in a highly effective in vivo dendritic cell vaccine. Cancer Res. 66, 7285–7292 (2006).
Levy, M. Y. et al. Cyclophosphamide unmasks an antimetastatic effect of local tumor cryoablation. J. Pharmacol. Exp. Ther. 330, 596–601 (2009).
den Brok, M. H. et al. In situ tumor ablation creates an antigen source for the generation of antitumor immunity. Cancer Res. 64, 4024–4029 (2004).
Shi, L. et al. PD-1 blockade boosts radiofrequency ablation–elicited adaptive immune responses against tumor. Clin. Cancer Res. 22, 1173–1184 (2016).
Thakur, A. et al. Induction of specific cellular and humoral responses against renal cell carcinoma after combination therapy with cryoablation and granulocyte-macrophage colony stimulating factor: a pilot study. J. Immunother. 34, 457–467 (2011).
Niu, L. et al. Combination treatment with comprehensive cryoablation and immunotherapy in metastatic pancreatic cancer. Pancreas 42, 1143–1149 (2013).
McArthur, H. L. et al. A pilot study of preoperative single-dose ipilimumab and/or cryoablation in women with early-stage breast cancer with comprehensive immune profiling. Clin. Cancer Res. 22, 5729–5737 (2016).
Hlavata, Z. et al. The abscopal effect in the era of cancer immunotherapy: a spontaneous synergism boosting anti-tumor immunity? Target. Oncol. 13, 113–123 (2018).
Golden, E. B. & Apetoh, L. Radiotherapy and immunogenic cell death. Semin. Radiat. Oncol. 25, 11–17 (2015).
Matsumura, S. & Demaria, S. Up-regulation of the pro-inflammatory chemokine CXCL16 is a common response of tumor cells to ionizing radiation. Radiat. Res. 173, 418–425 (2010).
Reits, E. A. et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271 (2006).
Bockel, S., Durand, B. & Deutsch, E. Combining radiation therapy and cancer immune therapies: from preclinical findings to clinical applications. Cancer Radiother. 22, 567–580 (2018).
Janeway, C. A. Jr. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).
Vacchelli, E. et al. Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy. Oncoimmunology 1, 894–907 (2012).
Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).
Vacchelli, E. et al. Trial watch: toll-like receptor agonists for cancer therapy. Oncoimmunology 2, e25238 (2013).
Kaczanowska, S., Joseph, A. M. & Davila, E. TLR agonists: our best frenemy in cancer immunotherapy. J. Leukoc. Biol. 93, 847–863 (2013).
Tomasicchio, M. et al. An autologous dendritic cell vaccine polarizes a Th-1 response which is tumoricidal to patient-derived breast cancer cells. Cancer Immunol. Immunother. 68, 71–83 (2019).
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The authors thank K. Balint for assisting in collecting information in Table 1, P. Romero for critically reading the manuscript and G. Coukos for useful discussion.
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Harari, A., Graciotti, M., Bassani-Sternberg, M. et al. Antitumour dendritic cell vaccination in a priming and boosting approach. Nat Rev Drug Discov 19, 635–652 (2020). https://doi.org/10.1038/s41573-020-0074-8
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DOI: https://doi.org/10.1038/s41573-020-0074-8
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