Skip to main content
SpringerLink
Log in

Combining ADCs with Immuno-Oncology Agents

  • Chapter
  • First Online:
Innovations for Next-Generation Antibody-Drug Conjugates

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Immuno-oncology (IO) has emerged as one of the most promising approaches to improve the therapeutic efficacy and durability of clinical responses in cancer patients. However, despite the clinical breakthroughs achieved with immuno-therapies, such as checkpoint blockade, the overall proportion of patients experiencing durable responses to single agent immuno-therapy remains relatively small. Therefore, the real promise for most cancer patients does not lie in monotherapeutic approaches but in synergistic combination therapies, which combine the best of IO with the immune-promoting/supporting properties of other therapeutic modalities. The latter help to breach physical barriers, to overcome immunosuppressive networks within the tumor microenvironment and improve immune cell infiltration into tumors.

Certain classes of cytotoxic compounds as well as radiation have been shown to induce immunogenic cell death (ICD), which leads to potent stimulation of effector T-cell activation as well as their recruitment into tumors. It has been recently demonstrated that some ADC payloads are also able to elicit ICD. Furthermore, several cytotoxic warheads used in ADCs can directly induce dendritic cell activation and maturation. These previously unknown immune-stimulatory activities of ADCs therefore have the potential to boost anti-tumor immunity and indeed the synergistic activity of various ADC/IO combinations has been observed in preclinical tumor models. These preclinical data have supported the clinical evaluation of ADC/IO combinatorial approaches.

This chapter summarizes the current scientific knowledge on the immunomodulatory properties of cytotoxic warheads used in ADCs, the underlying molecular mechanisms and immunological as well as therapeutic benefits of combination regimens with immuno-therapies. It further provides an overview of the current clinical landscape of more than 20 clinical trials evaluating the therapeutic benefit of ADC/IO combinations for cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480:480–489

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Lonberg N, Korman AJ (2017) Masterful antibodies: checkpoint blockade. Cancer Immunol Res 5:275–281

    Article  PubMed  Google Scholar 

  3. Hay CM, Sult E, Huang Q, Mulgrew K, Fuhrmann SR, McGlinchey KA, Hammond SA, Rothstein R, Rios-Doria J, Poon E, Holoweckyj N, Durham NM, Leow CC, Diedrich G, Damschroder M, Herbst R, Hollingsworth RE, Sachsenmeier KF (2016) Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology 5:e1208875

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Moran AE, Kovacsovics-Bankowski M, Weinberg AD (2013) The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol 25:230–237

    Article  PubMed  CAS  Google Scholar 

  5. Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348:69–74

    Article  CAS  PubMed  Google Scholar 

  6. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189–2199

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Wargo JA, Reddy SM, Reuben A, Sharma P (2016) Monitoring immune responses in the tumor microenvironment. Curr Opin Immunol 41:23–31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Cao A, Heiser R, Law CL, Gardai S (2016) Auristatin-based antibody drug conjugates activate multiple ER stress response pathways resulting in immunogenic cell death and amplified T-cell responses. Cancer Res 76:Abstract-4914

    Article  Google Scholar 

  9. Muller P, Martin K, Theurich S, Schreiner J, Savic S, Terszowski G, Lardinois D, Heinzelmann-Schwarz VA, Schlaak M, Kvasnicka HM, Spagnoli G, Dirnhofer S, Speiser DE, von Bergwelt-Baildon M, Zippelius A (2014) Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol Res 2:741–755

    Article  PubMed  CAS  Google Scholar 

  10. Muller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, Savic S, Harbeck N, Nitz U, Gluz O, von Bergwelt-Baildon M, Kreipe H, Reddy S, Christgen M, Zippelius A (2015) Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med 7:315ra188

    Article  PubMed  CAS  Google Scholar 

  11. Rios-Doria J, Harper J, Rothstein R, Wetzel L, Chesebrough J, Marrero AM, Chen C, Strout P, Mulgrew K, McGlinchey KA, Fleming R, Bezabeh B, Meekin J, Stewart D, Kennedy M, Martin P, Buchanan A, Dimasi N, Michelotti EF, Hollingsworth RE (2017) Antibody-drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads are immunomodulatory and synergize with multiple immunotherapies. Cancer Res 77:2686–2698

    Article  PubMed  CAS  Google Scholar 

  12. Kroemer G, Galluzzi L, Kepp O, Zitvogel L (2013) Immunogenic cell death in cancer therapy. Annu Rev Immunol 31:51–72

    Article  CAS  PubMed  Google Scholar 

  13. Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P, Apetoh L, Aranda F, Barnaba V, Bloy N, Bracci L, Breckpot K, Brough D, Buque A, Castro MG, Cirone M, Colombo MI, Cremer I, Demaria S, Dini L, Eliopoulos AG, Faggioni A, Formenti SC, Fucikova J, Gabriele L, Gaipl US, Galon J, Garg A, Ghiringhelli F, Giese NA, Guo ZS, Hemminki A, Herrmann M, Hodge JW, Holdenrieder S, Honeychurch J, Hu HM, Huang X, Illidge TM, Kono K, Korbelik M, Krysko DV, Loi S, Lowenstein PR, Lugli E, Ma Y, Madeo F, Manfredi AA, Martins I, Mavilio D, Menger L, Merendino N, Michaud M, Mignot G, Mossman KL, Multhoff G, Oehler R, Palombo F, Panaretakis T, Pol J, Proietti E, Ricci JE, Riganti C, Rovere-Querini P, Rubartelli A, Sistigu A, Smyth MJ, Sonnemann J, Spisek R, Stagg J, Sukkurwala AQ, Tartour E, Thorburn A, Thorne SH, Vandenabeele P, Velotti F, Workenhe ST, Yang H, Zong WX, Zitvogel L, Kroemer G, Galluzzi L (2014) Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 3:e955691

    Article  PubMed  PubMed Central  Google Scholar 

  14. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13:54–61

    Article  CAS  PubMed  Google Scholar 

  15. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G (2017) Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol 17:97–111

    Article  PubMed  CAS  Google Scholar 

  16. Inoue H, Tani K (2014) Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments. Cell Death Differ 21:39–49

    Article  PubMed  CAS  Google Scholar 

  17. Garg AD, De Ruysscher D, Agostinis P (2016) Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: a large-scale meta-analysis. Oncoimmunology 5:e1069938

    Article  PubMed  CAS  Google Scholar 

  18. Ladoire S, Enot D, Andre F, Zitvogel L, Kroemer G (2016) Immunogenic cell death-related biomarkers: impact on the survival of breast cancer patients after adjuvant chemotherapy. Oncoimmunology 5:e1082706

    Article  PubMed  CAS  Google Scholar 

  19. Ladoire S, Senovilla L, Enot D, Ghiringhelli F, Poirier-Colame V, Chaba K, Erdag G, Schaefer JT, Deacon DH, Zitvogel L, Slingluff CL Jr, Kroemer G (2016) Biomarkers of immunogenic stress in metastases from melanoma patients: correlations with the immune infiltrate. Oncoimmunology 5:e1160193

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Obeid M, Panaretakis T, Joza N, Tufi R, Tesniere A, van Endert P, Zitvogel L, Kroemer G (2007) Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ 14:1848–1850

    Article  PubMed  CAS  Google Scholar 

  21. Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, Bratton DL, Oldenborg PA, Michalak M, Henson PM (2005) Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321–334

    Article  CAS  PubMed  Google Scholar 

  22. Zitvogel L, Kepp O, Senovilla L, Menger L, Chaput N, Kroemer G (2010) Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway. Clin Cancer Res 16:3100–3104

    Article  PubMed  CAS  Google Scholar 

  23. Panaretakis T, Joza N, Modjtahedi N, Tesniere A, Vitale I, Durchschlag M, Fimia GM, Kepp O, Piacentini M, Froehlich KU, van Endert P, Zitvogel L, Madeo F, Kroemer G (2008) The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ 15:1499–1509

    Article  PubMed  CAS  Google Scholar 

  24. Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ, Volkmer J, Weiskopf K, Willingham SB, Raveh T, Park CY, Majeti R, Weissman IL (2010) Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med 2:63ra94

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Liu X, Pu Y, Cron K, Deng L, Kline J, Frazier WA, Xu H, Peng H, Fu YX, Xu MM (2015) CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat Med 21:1209–1215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Fucikova J, Becht E, Iribarren K, Goc J, Remark R, Damotte D, Alifano M, Devi P, Biton J, Germain C, Lupo A, Fridman WH, Dieu-Nosjean MC, Kroemer G, Sautes-Fridman C, Cremer I (2016) Calreticulin expression in human non-small cell lung cancers correlates with increased accumulation of antitumor immune cells and favorable prognosis. Cancer Res 76:1746–1756

    Article  PubMed  CAS  Google Scholar 

  27. Stebbing J, Bower M, Gazzard B, Wildfire A, Pandha H, Dalgleish A, Spicer J (2004) The common heat shock protein receptor CD91 is up-regulated on monocytes of advanced melanoma slow progressors. Clin Exp Immunol 138:312–316

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Liu R, Gong J, Chen J, Li Q, Song C, Zhang J, Li Y, Liu Z, Dong Y, Chen L, Jin B (2012) Calreticulin as a potential diagnostic biomarker for lung cancer. Cancer Immunol Immunother 61:855–864

    Article  PubMed  CAS  Google Scholar 

  29. Peng RQ, Chen YB, Ding Y, Zhang R, Zhang X, Yu XJ, Zhou ZW, Zeng YX, Zhang XS (2010) Expression of calreticulin is associated with infiltration of T-cells in stage IIIB colon cancer. World J Gastroenterol 16:2428–2434

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P (2012) Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 12:860–875

    Article  PubMed  CAS  Google Scholar 

  31. El-Mashed S, O’Donovan TR, Kay EW, Abdallah AR, Cathcart MC, O'Sullivan J, O’Grady A, Reynolds J, O’Reilly S, O’Sullivan GC, McKenna SL (2015) LC3B globular structures correlate with survival in esophageal adenocarcinoma. BMC Cancer 15:582

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Koukourakis MI, Kalamida D, Giatromanolaki A, Zois CE, Sivridis E, Pouliliou S, Mitrakas A, Gatter KC, Harris AL (2015) Autophagosome proteins LC3A, LC3B and LC3C have distinct subcellular distribution kinetics and expression in cancer cell lines. PLoS One 10:e0137675

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ladoire S, Enot D, Senovilla L, Chaix M, Zitvogel L, Kroemer G (2016) Positive impact of autophagy in human breast cancer cells on local immunosurveillance. Oncoimmunology 5:e1174801

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Ladoire S, Penault-Llorca F, Senovilla L, Dalban C, Enot D, Locher C, Prada N, Poirier-Colame V, Chaba K, Arnould L, Ghiringhelli F, Fumoleau P, Spielmann M, Delaloge S, Poillot ML, Arveux P, Goubar A, Andre F, Zitvogel L, Kroemer G (2015) Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer. Autophagy 11:1878–1890

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, Park D, Woodson RI, Ostankovich M, Sharma P, Lysiak JJ, Harden TK, Leitinger N, Ravichandran KS (2009) Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461:282–286

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Allard B, Longhi MS, Robson SC, Stagg J (2017) The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev 276:121–144

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Mantegazza AR, Zajac AL, Twelvetrees A, Holzbaur EL, Amigorena S, Marks MS (2014) TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation. Proc Natl Acad Sci U S A 111:15508–15513

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Nair-Gupta P, Baccarini A, Tung N, Seyffer F, Florey O, Huang Y, Banerjee M, Overholtzer M, Roche PA, Tampe R, Brown BD, Amsen D, Whiteheart SW, Blander JM (2014) TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation. Cell 158:506–521

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Shiratsuchi A, Watanabe I, Takeuchi O, Akira S, Nakanishi Y (2004) Inhibitory effect of Toll-like receptor 4 on fusion between phagosomes and endosomes/lysosomes in macrophages. J Immunol 172:2039–2047

    Article  PubMed  CAS  Google Scholar 

  40. Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot DP, Adam J, Vitale I, Goubar A, Baracco EE, Remedios C, Fend L, Hannani D, Aymeric L, Ma Y, Niso-Santano M, Kepp O, Schultze JL, Tuting T, Belardelli F, Bracci L, La Sorsa V, Ziccheddu G, Sestili P, Urbani F, Delorenzi M, Lacroix-Triki M, Quidville V, Conforti R, Spano JP, Pusztai L, Poirier-Colame V, Delaloge S, Penault-Llorca F, Ladoire S, Arnould L, Cyrta J, Dessoliers MC, Eggermont A, Bianchi ME, Pittet M, Engblom C, Pfirschke C, Preville X, Uze G, Schreiber RD, Chow MT, Smyth MJ, Proietti E, Andre F, Kroemer G, Zitvogel L (2014) Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med 20:1301–1309

    Article  PubMed  CAS  Google Scholar 

  41. Han L, Diao L, Yu S, Xu X, Li J, Zhang R, Yang Y, Werner HMJ, Eterovic AK, Yuan Y, Li J, Nair N, Minelli R, Tsang YH, Cheung LWT, Jeong KJ, Roszik J, Ju Z, Woodman SE, Lu Y, Scott KL, Li JB, Mills GB, Liang H (2015) The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell 28:515–528

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Hartner JC, Walkley CR, Lu J, Orkin SH (2009) ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol 10:109–115

    Article  PubMed  CAS  Google Scholar 

  43. Paz-Yaacov N, Bazak L, Buchumenski I, Porath HT, Danan-Gotthold M, Knisbacher BA, Eisenberg E, Levanon EY (2015) Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors. Cell Rep 13:267–276

    Article  PubMed  CAS  Google Scholar 

  44. Menger L, Vacchelli E, Adjemian S, Martins I, Ma Y, Shen S, Yamazaki T, Sukkurwala AQ, Michaud M, Mignot G, Schlemmer F, Sulpice E, Locher C, Gidrol X, Ghiringhelli F, Modjtahedi N, Galluzzi L, Andre F, Zitvogel L, Kepp O, Kroemer G (2012) Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci Transl Med 4:143ra99

    Article  PubMed  CAS  Google Scholar 

  45. Yamazaki T, Hannani D, Poirier-Colame V, Ladoire S, Locher C, Sistigu A, Prada N, Adjemian S, Catani JP, Freudenberg M, Galanos C, Andre F, Kroemer G, Zitvogel L (2014) Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists. Cell Death Differ 21:69–78

    Article  PubMed  CAS  Google Scholar 

  46. Chen DS, Mellman I (2017) Elements of cancer immunity and the cancer-immune set point. Nature 541:321–330

    Article  CAS  PubMed  Google Scholar 

  47. Golden EB, Apetoh L (2015) Radiotherapy and immunogenic cell death. Semin Radiat Oncol 25:11–17

    Article  PubMed  Google Scholar 

  48. Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, Yamazaki T, Poirier-Colame V, Newton A, Redouane Y, Lin YJ, Wojtkiewicz G, Iwamoto Y, Mino-Kenudson M, Huynh TG, Hynes RO, Freeman GJ, Kroemer G, Zitvogel L, Weissleder R, Pittet MJ (2016) Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 44:343–354

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Rios-Doria J, Durham N, Wetzel L, Rothstein R, Chesebrough J, Holoweckyj N, Zhao W, Leow CC, Hollingsworth R (2015) Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models. Neoplasia 17:661–670

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Beck A, Goetsch L, Dumontet C, Corvaia N (2017) Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov 16:315–337

    Article  PubMed  CAS  Google Scholar 

  51. Martin K, Muller P, Schreiner J, Prince SS, Lardinois D, Heinzelmann-Schwarz VA, Thommen DS, Zippelius A (2014) The microtubule-depolymerizing agent ansamitocin P3 programs dendritic cells toward enhanced anti-tumor immunity. Cancer Immunol Immunother 63:925–938

    Article  PubMed  CAS  Google Scholar 

  52. Garg AD, Agostinis P (2014) ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses. Photochem Photobiol Sci 13:474–487

    Article  PubMed  CAS  Google Scholar 

  53. Kepp O, Menger L, Vacchelli E, Locher C, Adjemian S, Yamazaki T, Martins I, Sukkurwala AQ, Michaud M, Senovilla L, Galluzzi L, Kroemer G, Zitvogel L (2013) Crosstalk between ER stress and immunogenic cell death. Cytokine Growth Factor Rev 24:311–318

    Article  PubMed  CAS  Google Scholar 

  54. Oslowski CM, Urano F (2011) Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol 490:71–92

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Gardai SJ, Epp A, Law C-L (2015) Brentuximab vedotin-mediated immunogenic cell death. Cancer Res 75(15 Suppl):Abstract nr 2469

    Article  Google Scholar 

  56. Mizumoto N, Gao J, Matsushima H, Ogawa Y, Tanaka H, Takashima A (2005) Discovery of novel immunostimulants by dendritic-cell-based functional screening. Blood 106(9):3082

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Tanaka H, Matsushima H, Mizumoto N, Takashima A (2009) Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res 69:6978–6986

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Tanaka H, Matsushima H, Nishibu A, Clausen BE, Takashima A (2009) Dual therapeutic efficacy of vinblastine as a unique chemotherapeutic agent capable of inducing dendritic cell maturation. Cancer Res 69:6987–6994

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Huang Y, Fang Y, Wu J, Dziadyk JM, Zhu X, Sui M, Fan W (2004) Regulation of Vinca alkaloid-induced apoptosis by NF-kappaB/IkappaB pathway in human tumor cells. Mol Cancer Ther 3:271–277

    PubMed  CAS  Google Scholar 

  60. Kolomeichuk SN, Terrano DT, Lyle CS, Sabapathy K, Chambers TC (2008) Distinct signaling pathways of microtubule inhibitors – vinblastine and Taxol induce JNK-dependent cell death but through AP-1-dependent and AP-1-independent mechanisms, respectively. FEBS J 275:1889–1899

    Article  PubMed  CAS  Google Scholar 

  61. Parola C, Salogni L, Vaira X, Scutera S, Somma P, Salvi V, Musso T, Tabbia G, Bardessono M, Pasquali C, Mantovani A, Sozzani S, Bosisio D (2013) Selective activation of human dendritic cells by OM-85 through a NF-kB and MAPK dependent pathway. PLoS One 8:e82867

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Patil S, Pincas H, Seto J, Nudelman G, Nudelman I, Sealfon SC (2010) Signaling network of dendritic cells in response to pathogens: a community-input supported knowledgebase. BMC Syst Biol 4:137

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Rescigno M, Martino M, Sutherland CL, Gold MR, Ricciardi-Castagnoli P (1998) Dendritic cell survival and maturation are regulated by different signaling pathways. J Exp Med 188:2175–2180

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Theurich S, Malcher J, Wennhold K, Shimabukuro-Vornhagen A, Chemnitz J, Holtick U, Krause A, Kobe C, Kahraman D, Engert A, Scheid C, Chakupurakal G, Hallek M, von Bergwelt-Baildon M (2013) Brentuximab vedotin combined with donor lymphocyte infusions for early relapse of Hodgkin lymphoma after allogeneic stem-cell transplantation induces tumor-specific immunity and sustained clinical remission. J Clin Oncol 31:e59–e63

    Article  PubMed  Google Scholar 

  65. Theurich S, Wennhold K, Wedemeyer I, Rothe A, Hubel K, Shimabukuro-Vornhagen A, Holtick U, Hallek M, Scheid C, von Bergwelt-Baildon M (2013) CD30-targeted therapy with brentuximab vedotin and DLI in a patient with T-cell posttransplantation lymphoma: induction of clinical remission and cellular immunity. Transplantation 96:e16–e18

    Article  PubMed  Google Scholar 

  66. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 68:9280–9290

    Article  CAS  PubMed  Google Scholar 

  67. Belvin M, Mellman I (2015) Is all cancer therapy immunotherapy? Sci Transl Med 7:315fs48

    Article  PubMed  CAS  Google Scholar 

  68. Speiser DE, Ho PC, Verdeil G (2016) Regulatory circuits of T cell function in cancer. Nat Rev Immunol 16:599–611

    Article  PubMed  CAS  Google Scholar 

  69. Facciabene A, Motz GT, Coukos G (2012) T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res 72:2162–2171

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Gerber HP, Sapra P, Loganzo F, May C (2016) Combining antibody-drug conjugates and immune-mediated cancer therapy: what to expect? Biochem Pharmacol 102:1–6

    Article  CAS  PubMed  Google Scholar 

  71. Stefan N, Gebleux R, Waldmeier L, Hell T, Escher M, Wolter FI, Grawunder U, Beerli RR (2017) Highly potent, anthracycline-based antibody-drug conjugates generated by enzymatic, site-specific conjugation. Mol Cancer Ther 16:879–892

    Article  PubMed  CAS  Google Scholar 

  72. Beerli RR (2017) Anthracycline-based antibody drug conjugates with potent immune-stimulatory functions. Cancer Res 77(13 Suppl):Abstract nr 66

    Article  Google Scholar 

  73. Hartley JA (2011) The development of pyrrolobenzodiazepines as antitumour agents. Expert Opin Investig Drugs 20:733–744

    Article  PubMed  CAS  Google Scholar 

  74. Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, Rebelatto MC, Hinrichs MJ, Bezabeh BZ, Fleming RL, Dimasi N, Feng H, Toader D, Yuan AQ, Xu L, Lin J, Gao C, Wu H, Dixit R, Osbourn JK, Coats SR (2016) A biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell 29:117–129

    Article  PubMed  CAS  Google Scholar 

  75. Jackson D, Gooya J, Mao S, Kinneer K, Xu L, Camara M, Fazenbaker C, Fleming R, Swamynathan S, Meyer D, Senter PD, Gao C, Wu H, Kinch M, Coats S, Kiener PA, Tice DA (2008) A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo. Cancer Res 68:9367–9374

    Article  PubMed  CAS  Google Scholar 

  76. Melero I, Hirschhorn-Cymerman D, Morales-Kastresana A, Sanmamed MF, Wolchok JD (2013) Agonist antibodies to TNFR molecules that costimulate T and NK cells. Clin Cancer Res 19:1044–1053

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Teng MW, Swann JB, von Scheidt B, Sharkey J, Zerafa N, McLaughlin N, Yamaguchi T, Sakaguchi S, Darcy PK, Smyth MJ (2010) Multiple antitumor mechanisms downstream of prophylactic regulatory T-cell depletion. Cancer Res 70:2665–2674

    Article  PubMed  CAS  Google Scholar 

  78. Leyland R, Watkins A, Mulgrew K, Holoweckyj N, Bamber L, Tigue NJ, Offer E, Andrews J, Yan L, Mullins S, Oberst MD, Coates Ulrichsen J, Leinster DA, McGlinchey KA, Young L, Morrow M, Hammond SA, Mallinder PR, Herath A, Leow CC, Wilkinson RW, Stewart R (2017) A novel murine GITR ligand fusion protein induces antitumor activity as a monotherapy, which is further enhanced in combination with an OX40 agonist. Clin Cancer Res 23:3416–3427

    Article  PubMed  CAS  Google Scholar 

  79. Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD (2017) Combination immunotherapy: a road map. J Immunother Cancer 5:16

    Article  PubMed  PubMed Central  Google Scholar 

  80. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168:707–723

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312–322

    Article  PubMed  CAS  Google Scholar 

  82. Donaghy H (2016) Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs 8:659–671

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Hinrichs MJ, Dixit R (2015) Antibody drug conjugates: nonclinical safety considerations. AAPS J 17:1055–1064

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Larkin J, Lao CD, Urba WJ, McDermott DF, Horak C, Jiang J, Wolchok JD (2015) Efficacy and safety of nivolumab in patients with BRAF V600 mutant and BRAF wild-type advanced melanoma: a pooled analysis of 4 clinical trials. JAMA Oncol 1:433–440

    Article  PubMed  Google Scholar 

  85. Balar AV, Weber JS (2017) PD-1 and PD-L1 antibodies in cancer: current status and future directions. Cancer Immunol Immunother 66:551–564

    Article  PubMed  CAS  Google Scholar 

  86. Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, Keegan P, Pazdur R (2016) FDA approval summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist 21:634–642

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Hazarika M, Chuk MK, Theoret MR, Mushti S, He K, Weis SL, Putman AH, Helms WS, Cao X, Li H, Zhao H, Zhao L, Welch J, Graham L, Libeg M, Sridhara R, Keegan P, Pazdur R (2017) U.S. FDA approval summary: nivolumab for treatment of unresectable or metastatic melanoma following progression on ipilimumab. Clin Cancer Res 23:3484–3488

    Article  PubMed  CAS  Google Scholar 

  88. Xu JX, Maher VE, Zhang L, Tang S, Sridhara R, Ibrahim A, Kim G, Pazdur R (2017) FDA Approval summary: nivolumab in advanced renal cell carcinoma after anti-angiogenic therapy and exploratory predictive biomarker analysis. Oncologist 22:311–317

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375:1856–1867

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Ansell SM (2017) Nivolumab in the treatment of Hodgkin lymphoma. Clin Cancer Res 23:1623–1626

    Article  PubMed  CAS  Google Scholar 

  91. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm M-O, Bracarda S, Arranz JA, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. The Lancet Oncology 18(3):312–322

    Article  PubMed  CAS  Google Scholar 

  92. Poh A (2017) Nivolumab gets FDA nod for bladder cancer. Cancer Discov 7:OF7

    Google Scholar 

  93. Sul J, Blumenthal GM, Jiang X, He K, Keegan P, Pazdur R (2016) FDA approval summary: pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist 21:643–650

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Barone A, Hazarika M, Theoret MR, Mishra-Kalyani P, Chen H, He K, Sridhara R, Subramaniam S, Pfuma E, Wang Y, Li H, Zhao H, Fourie Zirkelbach J, Keegan P, Pazdur R (2017) FDA approval summary: pembrolizumab for the treatment of patients with unresectable or metastatic melanoma. Clin Cancer Res 23:5661–5665

    Article  PubMed  CAS  Google Scholar 

  95. Chuk MK, Chang JT, Theoret MR, Sampene E, He K, Weis SL, Helms WS, Jin R, Li H, Yu J, Zhao H, Zhao L, Paciga M, Schmiel D, Rawat R, Keegan P, Pazdur R (2017) FDA approval summary: accelerated approval of pembrolizumab for second-line treatment of metastatic melanoma. Clin Cancer Res 23:5666–5670

    Article  PubMed  CAS  Google Scholar 

  96. Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, Saba NF, Weiss J, Wirth L, Sukari A, Kang H, Gibson MK, Massarelli E, Powell S, Meister A, Shu X, Cheng JD, Haddad R (2017) Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase ii study. J Clin Oncol 35(14):1542–1549. https://doi.org/10.1200/JCO.2016.70.1524

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Colwell J (2017) Pembrolizumab approved for Hodgkin lymphoma. Cancer Discov 7:OF1

    Google Scholar 

  98. Inman BA, Longo TA, Ramalingam S, Harrison MR (2017) Atezolizumab: a PD-L1-blocking antibody for bladder cancer. Clin Cancer Res 23:1886–1890

    Article  PubMed  CAS  Google Scholar 

  99. Camacho LH (2015) CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Cancer Med 4:661–672

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Cameron F, Whiteside G, Perry C (2011) Ipilimumab first global approval. Drugs 71:12

    Article  Google Scholar 

  101. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Ramakrishna V, Sundarapandiyan K, Zhao B, Bylesjo M, Marsh HC, Keler T (2015) Characterization of the human T cell response to in vitro CD27 costimulation with varlilumab. J Immunother Cancer 3:37

    Article  PubMed  PubMed Central  Google Scholar 

  103. Purcell J, Hickson J, Tanlimco S, Fox M, Chao D, Hsi E, Sho M, Powers R, Foster-Duke K, McGonigal T, Uziel S, Kumar T, Samayoa J, Longenecker K, Lai D, Hollenbaugh D, Afar D, Iyer S, Morgan-Lappe S, Gish K (2016) ABBV-085 is a novel antibody–drug conjugate (ADC) that targets LRRC15 in the tumor microenvironment. EJC 69(Supplement 1):S10. (Abstract)

    Article  Google Scholar 

  104. Diefenbach CS, Hong F, Cohen JB, Robertson MJ, Ambinder RF, Fenske TS, Advani RH, Kahl BS, Ansell S (2015) Preliminary safety and efficacy of the combination of brentuximab vedotin and ipilimumab in relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN Cancer Research Group (E4412). Blood 126:4

    Article  Google Scholar 

  105. Herrera AF, Bartlett NL, Ramchandren R, et al (2016) Preliminary results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. In: 58th American Society of Hematology annual meeting, Abstract 1105

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cancer Immunology & Immune Modulation, Biberach an der Riss, Germany

    Philipp Müller

  2. MedImmune, Gaithersburg, MD, USA

    Jonathan Rios-Doria & Jay Harper

  3. Incyte, Wilmington, DE, USA

    Jonathan Rios-Doria

  4. Seattle Genetics, Inc, Bothell, WA, USA

    Anthony Cao

Authors
  1. Philipp Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan Rios-Doria
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jay Harper
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anthony Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philipp Müller .

Editor information

Editors and Affiliations

  1. Mersana Therapeutics, Inc., Cambridge, Massachusetts, USA

    Marc Damelin

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Müller, P., Rios-Doria, J., Harper, J., Cao, A. (2018). Combining ADCs with Immuno-Oncology Agents. In: Damelin, M. (eds) Innovations for Next-Generation Antibody-Drug Conjugates. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-78154-9_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-78154-9_2

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-78153-2

  • Online ISBN: 978-3-319-78154-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation