Skip to main content

Advertisement

SpringerLink
Log in

Emerging combination immunotherapy strategies for breast cancer: dual immune checkpoint modulation, antibody–drug conjugates and bispecific antibodies

  • Review
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Breast cancer has historically been considered a non-immunogenic tumor. Multiple studies over the last 10–15 years have demonstrated that a small subset of breast cancers is immune-activated, with PD-L1 expression and/or TILs in the tumor microenvironment. The PD-1 inhibitor pembrolizumab in combination with chemotherapy is now approved by the US FDA for the first-line treatment of metastatic PD-L1 + triple negative breast cancer, and the PD-L1 inhibitor atezolizumab has also demonstrated clinical activity. The median progression-free survival for pembrolizumab or atezolizumab combined with chemotherapy increased with the addition of immunotherapy by 4.1 months and 2.5 months, respectively. Despite this success, there is major room for improvement. Clinical benefit is modest. Only about 40% of triple negative breast cancers are PD-L1 + , not all PD-L1 + patients with advanced triple negative breast cancer respond, and immunotherapy is not yet approved for advanced PD-L1-negative triple negative breast cancer, HER2 + breast cancer, or ER + breast cancer. It is likely that redundant pathways of immune suppression are active in breast cancer, or that important pathways of immune activation are silent. In this review, we discuss emerging strategies for targeting multiple pathways of immunoregulation in advanced breast cancer with dual immune checkpoint inhibition, bispecific antibodies, and novel antibody drug conjugates. We also discuss the potential of nanotechnology to improve the delivery of immunotherapeutics to the breast tumor microenvironment to enhance their antitumor activity.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

Abbreviations

ADCC:

Antibody-dependent cytotoxicity

ADCs:

Antibody–drug conjugate

BiTE:

Bispecific T cell engager

CI:

Confidence interval

CTLA-4:

Cytotoxic T lymphocyte antigen-4

DART:

Dual affinity re-targeting molecule

ER:

Estrogen receptor

FDA:

Food and Drug Administration

HER2:

Human epidermal growth factor receptor 2

HER3:

Human epidermal growth factor receptor 3

HMGA2:

High mobility group AT-hook 2

HPV:

Human papillomavirus

ICI:

Immune checkpoint inhibitor

LAG-3:

Lymphocyte activation globulin-3

MDSC:

Myeloid-derived suppressor cell

MSS-CRC:

Microsatellite-stable colorectal cancer

NK:

Natural killer

NSCLC:

Non-small cell lung cancer

ORR:

Overall response rate

OS:

Overall survival

PD-1:

Programmed death-1

PD-L1:

Programmed death ligand-1

PFS:

Progression-free survival

STING:

Stimulator of interferon genes

TAM:

Tumor-associated macrophage

TCB:

T cell BiTE

TGFβ:

Transforming growth factor-beta

TIGIT:

T cell immunoreceptor with Ig and ITIM domains

TILs:

Tumor infiltrating lymphocytes

TLR:

Toll-like receptor

TMB:

Tumor mutational burden

TME:

Tumor microenvironment

TNBC:

Triple negative breast cancer

Treg:

Regulatory T cell

References

  1. Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1–10. https://doi.org/10.1016/j.immuni.2013.07.012

    Article  CAS  PubMed  Google Scholar 

  2. Topper MJ, Vaz M, Marrone KA, Brahmer JA, Baylin SB (2020) The emerging role of epigenetic therapeutics in immuno-oncology. Nat Rev Clin Oncol 17(2):75–90. https://doi.org/10.1038/s41571-019-0266-5

    Article  PubMed  Google Scholar 

  3. Jenkins RW, Barbie DA, Flaherty KT (2018) Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer 118(1):9–16. https://doi.org/10.1038/bjc.2017.434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Emens LA (2018) Breast cancer immunotherapy: facts and hopes. Clin Cancer Res 24(3):511–520. https://doi.org/10.1158/1078-0432.CCR-16-3001

    Article  CAS  PubMed  Google Scholar 

  5. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Hegg R, Im S-A, Wright GS, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA, IMpassion130 Trial Investigators (2018) Atezolizumab and nab-paclitaxel in advanced triple negative breast cancer. N Engl J Med 379(22):2108–2121. https://doi.org/10.1056/NEJM0a1809615

    Article  CAS  PubMed  Google Scholar 

  6. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im S-A, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P, KEYNOTE-355 Investigators (2020) Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomized, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 396(10265):1817–1828. https://doi.org/10.1016/S0140-6736(20)32531-9

    Article  PubMed  Google Scholar 

  7. Rugo H, Cortes J, Cescon DW, Im, S-A, Usof MM, Gallardo C, Lipatov O, Barrios CH, Perez-Garcia J, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhou X, Karantza V, Pan W, Schmid P (2021) KEYNOTE-355: Final results from a randomized, double-blind, phase 3 study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. ESMO Congress 2021, LBA16.

  8. Emens LA, Ascierto PA, Darcy PK, Demaria S, Eggermont AMM, Redmond WL, Seliger B, Marincola FM (2017) Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer 81:116–129. https://doi.org/10.1016/j.ejca.2017.01.035

    Article  CAS  PubMed  Google Scholar 

  9. Vonderheide RH, Domchek SM, Clark AS (2017) Immunotherapy for breast cancer: what are we missing? Clin Cancer Res 23(11):2640–2646. https://doi.org/10.11158/1078-0432.CCR-16-2569

    Article  PubMed  PubMed Central  Google Scholar 

  10. Goldberg J, Pastorello RG, Vallius T, Davis J, Cui YX, Agudo J, Waks AG, Keenan T, McAllister SS, Tolaney SM, Mittendorf EA (2021) Guerriero JL (2021) The immunology of hormone receptor positive breast cancer. Front Immunol 12:674192. https://doi.org/10.33389/fimmu.2021.674192.eCollection

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang H, Li S, Wang Q, Jin Z, Shao W, Gao Y, Li L, Lin K, Zhu L, Wang H, Liao X, Wang D (2021) Tumor immunological phenotype signature-based high-throughput screening for the discovery of combination immunotherapy compounds. Sci Adv. https://doi.org/10.1126/sciadv.abd7851

    Article  PubMed  PubMed Central  Google Scholar 

  12. Umansky V, Blattner C, Gebbardt C, Utikal J (2016) The role of myeloid-derived suppressor cells (MDSC) in cancer progression. Vaccines 4(4):36. https://doi.org/10.3390/vaccines4040036

    Article  CAS  PubMed Central  Google Scholar 

  13. Markowitz J, Wesolowski R, Papenfuss T, Brooks TR, Carson WE (2013) Myeloid-derived suppressor cells in breast cancer. Breast Cancer Res Treat 140(1):13–21. https://doi.org/10.1007/s10549-013-2618-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Watanabe MAE, Oda JMM, Amarante MK, Voltarelli JC (2010) Regulatory T cells and breast cancer: implications for immunopathogenesis. Cancer Metastasis Rev 29(4):569–579. https://doi.org/10.1007/s1055-010-9247-y

    Article  CAS  PubMed  Google Scholar 

  15. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nature Rev Immunol 12(4):253–268. https://doi.org/10.1038/nri3175

    Article  CAS  Google Scholar 

  16. Gatti-Mays ME, Balko J, Gameiro SR, Bear HD, Pabhakaran S, Fukui J, Disis ML, Nanda R, Gulley JL, Kalinsky K, Sater HA, Sparano JA, Cescon D, Page DB, McArthur H, Adams S, Mittendorf EA (2019) If we build it they will come: targeting the immune response to breast cancer. NPJ Breast Cancer. https://doi.org/10.1038/s41523/019/0133-7

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lao L, Fan S, Song E (2017) Tumor-associated macrophages as therapeutic targets for breast cancer. Advances in Experimental Medicine and Biology, vol 1026. Springer, New York LLC, pp 331–370

    Google Scholar 

  18. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossman K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34. https://doi.org/10.1056/NEJMoa1504030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Santa-Maria CA, Kato T, Park JH, Kiyotani K, Rademaker A, Shah AN, Gross L, Blanco LZ, Jain S, Flaum L, Tellez C, Stein R, Uthe R, Gradishar WJ, Cristofanilli M, Nakamura Y, Giles FJ (2018) A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer. Oncotarget 9(27):18985–18996. https://doi.org/10.18632/oncotarget.24867

    Article  PubMed  PubMed Central  Google Scholar 

  20. Christmas BJ, Rafie CI, Hopkins AC, Scott BA, Ma HS, Cruz KA, Woolman S, Armstrong TD, Connolly RM, Azad NA, Jaffee EM, Roussos Torres ET (2018) Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. Cancer Immunol Res 6(12):1561–1577. https://doi.org/10.1158/2326-6066.CIR-18-0070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. McCaw TR, Li M, Starenki D, Liu M, Cooper SJ, Arend RC, Forero A, Buchsbaum DJ, Randall TD (2019) Histone deacetylase inhibition promotes intratumoral CD8+ T cell responses, sensitizing murine breast tumors to anti-PD1. Cancer Immunol Immunother 68(12):2081–2094. https://doi.org/10.1007/s00262-019-02430-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wolchok J, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbe C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377(14):1345–1356. https://doi.org/10.1056/NEJMoa1709684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Desnoyers LR, Vasiljeva O, Richardson JH, Yang A, Menendez EE, Liang TW, Wong C, Bessette PH, Kamath K, Moore SJ, Sagert JG, Hostetter DR, Han F, Gee J, Flandez J, Markham K, Nguyen M, Krimm M, Wong KR, Liu S, Daugherty PS, West JW, Lowman HB (2013) Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci Transl Med 5(207):207ra144. https://doi.org/10.1126/scitranslmed.3006682

    Article  CAS  PubMed  Google Scholar 

  24. Polu KR, Lowman HB (2014) Probody therapeutics for targeting antibodies to diseased tissue. Expert Opin Biol Ther 14(8):1049–1053. https://doi.org/10.1517/14712598.2014.920814

    Article  CAS  PubMed  Google Scholar 

  25. Autio KA, Boni V, Humphrey RW, Naing A (2020) Probody therapeutics: an emerging class of therapies designed to enhance on-target effects with reduced off-tumor toxicity for us in immuno-oncology. Clin Cancer Res 26(5):984–989. https://doi.org/10.1158/1078-0432.CCR-19-1457

    Article  CAS  PubMed  Google Scholar 

  26. Rowland GF, O’Neill GJ, Davies DA (1975) Suppression of tumour growth in mice by a drug-antibody conjugate using a novel approach to linkage. Nature 255(5508):487–488

    Article  CAS  Google Scholar 

  27. Moolten FL, Cooperband SR (1970) Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells. Science 169(3940):68–70. https://doi.org/10.1126/science.169.3940.68

    Article  CAS  PubMed  Google Scholar 

  28. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Dieras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K, EMILIA Study Group (2013) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367(19):1783–1791. https://doi.org/10.1056/NEJMoa1209124

    Article  CAS  Google Scholar 

  29. Saini KS, Punie K, Twelves C, Bortini S, deAzambuja E, Anderson S, Criscitiello C, Awada A, Loi S (2021) Antibody-drug conjugates, immune checkpoint inhibitors, and their combination in breast cancer therapeutics. Expert Opin Biol Ther 21(7):945–962. https://doi.org/10.1080/1472598.2021.1936494

    Article  CAS  PubMed  Google Scholar 

  30. Barroso-Sousa R, Tolaney SM (2021) Clinical development of new antibody-drug conjugates in breast cancer: to infinity and beyond. BioDrugs 35(2):159–174. https://doi.org/10.1007/s40259-021-00472-z

    Article  CAS  PubMed  Google Scholar 

  31. Sau S, Petrovici A, Alsaab HO, Bhise K, Iyer AK (2019) PDL-1 antibody drug conjugate for selective chemo-guided immune modulation of cancer. Cancers (Basel) 11(2):232. https://doi.org/10.3390/cancers11020232

    Article  CAS  Google Scholar 

  32. Scribner JA, Brown JB, Son T, Chiechi M, Li P, Sharma S, Li H, De Costa A, Li Y, Chen Y, Easton A, Yee-Toy NC, Chen FZ, Goriatov S, Barat B, Huang L, Wolff CR, Hooley J, Hotaling TE, Gaynutdinov T, Ciccarone V, Tamura J, Koenig S, Moore PA, Bonvini E, Loo D (2020) Preclinical development of MGC018, a duocarmycin-based antibody-drug conjugate targeting B7–H3 for solid cancer. Mol Cancer Ther. https://doi.org/10.1158/1535-7163.MCT-20-0116

    Article  PubMed  Google Scholar 

  33. Scribner JA, Chiechi M, Li P, Son T, Hooley J, Li Y, De Costa A, Lung P, Yee-Toy N, Chen F, Barat B, Wolff C, Ciccarone V, Tamura J, Koenig S, Bohac C, Wigginton J, Moore PA, Bonvini E, Loo D (2020) Abstract 5203: MGC018, a duocarmycin-based antibody-drug conjugate targeting B7–H3, exhibits immunomodulatory activity and enhanced antitumor activity in combination with checkpoint inhibitors. Cancer Res 80(16S):5203. https://doi.org/10.1158/1538-7445.am2020-5203

    Article  Google Scholar 

  34. Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, O’Shaughnessy J, Moroose RL, Santin AD, Abramson VG, Shah NC, Rugo HS, Goldenberg DM, Sweidan AM, Iannone R, Washkowitz S, Sharkey RM, Wegener WA, Kalinsky K (2019) Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 380(8):741–751. https://doi.org/10.1056/NEJMoa1814213

    Article  CAS  PubMed  Google Scholar 

  35. Savas P, Salgado R, Denkert C, Sotiriou C, Darcy PK, Smyth MJ, Loi S (2016) Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol 13(4):228–241. https://doi.org/10.1038/nrclinonc.2015.215

    Article  CAS  PubMed  Google Scholar 

  36. Stagg J, Loi S, Divisekera U, Ngiow SF, Duret H, Yagita H, Teng MW, Smyth MJ (2011) Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci USA 108(17):7142–7247. https://doi.org/10.1073/pnas.1016569108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Akiyama K, Ebihara S, Yada A, Matsumura K, Aiba S, Nukiwa T, Takai T (2003) Targeting apoptotic tumor cells to Fc gamma R provides efficient and versatile vaccination against tumors by dendritic cells. J Immunol 170(4):1641–1648. https://doi.org/10.4049/jimmunol.170.4.1641

    Article  CAS  PubMed  Google Scholar 

  38. Varchetta S, Gibelli N, Olivero B, Nardini E, Gennari R, Gatti G, Silva LS, Villani L, Tagliabue E, Menard S, Costa A, Fagnoni FF (2007) Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer. Cancer Res 67(24):11991–11999. https://doi.org/10.1158/008-5472.CAN-07-2068

    Article  CAS  PubMed  Google Scholar 

  39. Su S, Zhao J, Xing Y, Zhang X, Liu J, Ouyang Q, Chen J, Su F, Liu Q, Song E (2018) Immune checkpoint inhibition overcomes ADCP-induced immunosuppression by macrophages. Cell 175(2):442-457.e23. https://doi.org/10.1016/j.cell.2018.09.007

    Article  CAS  PubMed  Google Scholar 

  40. 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(315):315ra188. https://doi.org/10.1126/scitranslmed.aac4925

    Article  CAS  PubMed  Google Scholar 

  41. Emens LA, Esteva FJ, Beresford M, Saura C, De Laurentiis M, Kim SB, Im S-A, Wang Y, Salgado R, Mani A, Shah J, Lambertini C, Liu H, de Haas SL, Patre M, Loi S (2020) Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomized, double-blind trial. Lancet Oncol 21(10):128301295. https://doi.org/10.1016/S1470-2045(20)304650-4

    Article  Google Scholar 

  42. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Corest J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I, DESTINY-Breast01 Investigators (2020) Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382(7):610–621. https://doi.org/10.1056/NEJMoa1914510

    Article  CAS  PubMed  Google Scholar 

  43. Kohrt HE, Houot R, Weiskopf K, Goldstein MJ, Scheeren F, Czerwinski D, Colevas AD, Weng WK, Clarke MF, Carlson RW, Stockdale FE, Mollick JA, Chen L, Levy RJ (2012) Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest 122(3):1066–1075. https://doi.org/10.1172/JCI61226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kohrt HE, Houot R, Weiskopf K, Goldstein MJ, Scheeren F, Czerwinski D, Colevas AD, Weng WK, Clarke MF, Carlson RW, Stockdale FE, Mollick JA, Chen L, Levy RJ (2019) Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest 129(6):2595. https://doi.org/10.1172/JCI29688

    Article  PubMed  PubMed Central  Google Scholar 

  45. Yonezawa A, Dutt S, Chester C, Kim J, Kohrt HE (2015) Boosting cancer immunotherapy with anti-CD137 antibody therapy. Clin Cancer Res 21(14):3113–3120. https://doi.org/10.1158/1078-0432.CCR-15-0263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Corrales L, Matson V, Flood B, Spranger S, Gajewski TF (2017) Innate immune signaling and regulation in cancer immunotherapy. Cell Res 27(1):96–108. https://doi.org/10.1038/cr.2016.149

    Article  CAS  PubMed  Google Scholar 

  47. Vanpouille-Box C, Hoffmann JA, Galluzzi L (2019) Pharmacologic modulation of nucleic acid sensors—therapeutic potential and persisting obstacles. Nat Rev Drug Discov 18(11):845–867. https://doi.org/10.1038/s41573-019-0043-2

    Article  CAS  PubMed  Google Scholar 

  48. Comeau MR, Brender T, Childs M, Brevik J, Winship D, Metz H, Chang J, Adamo J, Setter B, Xu H, Fan L-Q, Stevens B, Smith SW, Tan P, DuBose R, Latchman Y, Baum P, Odegard V (2020) Abstract 4537: SBT6050, a HER2-directed TLR8 ImmunoTACTM therapeutic is a potent human myeloid cell agonist that provides opportunity for single agent clinical activity. Cancer Res, abstract nr. https://doi.org/10.1158/1538-7445.AM2020-4537

    Article  Google Scholar 

  49. Ackerman SE, Pearson CI, Gregorio JD, Gonzalez JC, Kenkel JA, Hartmann FJ, Luo A, Ho PY, LeBlanc H, Blum LK, Kimmey SC, Luo A, Nguyen ML, Paik JC, Sheu LY, Ackerman B, Lee A, Li H, Melrose J, Laura RP, Ramani VC, Henning KA, Jackson DY, Safina BS, Yonehiro G, Devens BH, Carmi Y, Chapin SJ, Bendall SC, Kowanetz M, Dornan D, Engleman EG, Alonso MN (2021) Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nat Cancer 2:18–33. https://doi.org/10.1038/s43018-020-00136-x

    Article  Google Scholar 

  50. Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI (2019) Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov 18(8):585–608. https://doi.org/10.1038/s41573-019-0028-1

    Article  CAS  PubMed  Google Scholar 

  51. Przepiorka D, Ko CW, Deisseroth A, Yancey CL, Candau-Chacon R, Chiu HJ, Gehrke BJ, Gomez-Broughton C, Kane RC, Kirshner S, Mehrotra N, Ricks TK, Schmiel D, Song P, Zhao P, Zhou Q, Farrell AT, Pazdur R (2015) FDA approval: blinatumomab. Clin Cancer Res 21(18):4035–4039. https://doi.org/10.1158/1078-0432.CCR-15-0612

    Article  CAS  PubMed  Google Scholar 

  52. Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foa R, Bassan R, Arslan O, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Bukrggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS (2017) Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 376(9):836–847. https://doi.org/10.1056/NEJMoa1609783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mittal D, Vijayan D, Neijssen J, Kreijtz J, Habraken MMJM, Van Eenennaam H, Van Elsas A, Smyth MJ (2019) Blockade of ErbB2 and PD-L1 using a bispecific antibody to improve targeted anti-ErbB2 therapy. Oncoimmunol 8(11):e1648171. https://doi.org/10.1080/2162402X.2019.1648171

    Article  Google Scholar 

  54. Ruiz IR, Vicario R, Morancho B, Morales CB, Arenas EJ, Herter S, Freimoser-Grundschober A, Somandin J, Sam J, Ast O, Barriocanal AM, Luque A, Escorihuela M, Varela I, Cuartas I, Nuciforo P, Fasani R, Peg V, Rubio I, Cortes J, Serra V, Escriva-de-Romani S, Sperinde J, Chenna A, Huang W, Winslow J, Albanell J, Seoane J, Scaltriti M, Baselga J, Tabernero J, Umana P, Bacac M, Saura C, Klein C, Arribas J (2018) p95HER2-T cell bispecific antibody for breast cancer treatment. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aat1445

    Article  PubMed  PubMed Central  Google Scholar 

  55. Chang CH, Wang Y, Li R, Rossi DL, Liu D, Rossi EA, Cardillo TM, Goldenberg DM (2017) Combination therapy with bispecific antibodies and PD-1 blockade enhances the antitumor potency of T cells. Cancer Res 77(19):5384–5394. https://doi.org/10.1158/0008-5472.CAN-16-3431

    Article  CAS  PubMed  Google Scholar 

  56. Kamada H, Taki S, Nagano K, Inoue M, Ando D, Mukai Y, Higashisaka K, Yoshioka Y, Tsutsumi Y, Tshunoda S (2015) Generation and characterization of a bispecific diabody targeting both EPH receptor A10 and CD3. Biochem Biophys Res Commun 456(4):908–912. https://doi.org/10.1016/j.bbrc.2014.12.030

    Article  CAS  PubMed  Google Scholar 

  57. Fisher TS, Hooper AT, Lucas J, Clark TH, Rohner AK, Peano B, Elliott MW, Tsaparikos K, Wang H, Golas J, Gavriil M, Haddish-Berhane N, Tchistiakova L, Gerber H-P, Root AR, May C (2018) A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established tumors in mice. Cancer Immunol Immunother 67(2):247–259. https://doi.org/10.1007/s00262-017-2081-0

    Article  CAS  PubMed  Google Scholar 

  58. Kubo M, Umebayashi M, Kurata K, Mori H, Kai M, Onishi H, Katao M, Nakamura M, Morisaki T (2018) Catumaxomab with activated T-cells efficiently lyses chemoresistant EpCAM-positive triple-negative breast cancer cell lines. Anticancer Res 38(7):4273–4279. https://doi.org/10.21873/anticanres.12724

    Article  CAS  PubMed  Google Scholar 

  59. Del Bano J, Flores-Flores R, Josselin E, Goubard A, Ganier L, Castellano R, Chames P, Baty D, Kerfelec B (2019) A bispecific antibody-based approach for targeting mesothelin in triple negative breast cancer. Front Immunol 10:1593. https://doi.org/10.3389/fimmu.2019.01593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Berezhnoy A, Sumrow BJ, Stahl K, Shah K, Liu D, Li J, Hao S-S, De Costa A, Kaul S, Bendell J, Cote GM, Luke JJ, Sanborn RE, Sharma MR, Chen F, Li H, Diedrich G, Bonvini E, Moore PA (2020) Development and preliminary clinical activity of PD-1-guided CTLA-4 blocking bispecific DART molecule. Cell Rep Med 1(9):100163. https://doi.org/10.1016/j.xcrm.2020.100163

    Article  PubMed  PubMed Central  Google Scholar 

  61. La Motte-Mohs R, Shah K, Brown JG, Smith D, Gorlatov S, Ciccarone V, Tamura JK, Li H, Rillema JR, Licea M, Shoemaker C, He L, Vasanwala F, Hill J, Whiddon A, Pascuccio M, Saini S, Chen FZ, De Costa A, Easton A, Lung P, Li J, Stahl K, Nordstrom J, Koenig S, Bonvini E, Johnshon S, Moore PA. (2017) Abstract Preclinical characterization of MGD013, a PD-1 x LAG-3 Bispecific DART molecule. Presented at the Society for Immunotherapy of Cancer 32nd Annual Meeting, November 8–12, 2017, National Harbor, MD.

  62. Patel M, Luke J, Hamilton E, Chmielowski B, Blumenschein G, Kindler H, Bahadur S, Santa-Maria C, Koucheki J, Sun J, Kaul S, Chen F, Zhang X, Muth J, Kaminker P, Moore P, Sumrow B, Ulahannan S (2020) Abstract 313: A phase 1 evaluation of tebotelimab, a bispecific PD-1 x LAG-3 DART molecule, in combination with margetuximab in patients with advanced HER2+ neoplasms. J Immunother Cancer. https://doi.org/10.1136/jitc-2020-SITC2020.0313

    Article  PubMed  PubMed Central  Google Scholar 

  63. Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, Lamping E, Marte JL, Donahue RN, Grenga I, Cordes L, Christensen O, Mahnke L, Helwig C, Gulley JL (2018) Phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFbeta in advanced solid tumors. Clin Cancer Res 24(6):1287–1295. https://doi.org/10.1158/1078-0432.CCR-17-2653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Strauss J, Gatti-Mays ME, Cho BC, Hill A, Salas S, McClay E, Redman JM, Sater HA, Donahue RN, Jochems C, Lamping E, Burmeister A, Marte JL, Cordes LM, Bilusic M, Karzai F, Ojalvo LS, Jehl G, Rolfe PA, Hinrichs CS, Madan RA, Schlom J, Gulley JL (2020) Abstract 1395: Bintrafusp alpha, a bifunctional fusion protein targeting TGF-beta and PD-L1, in patients with human papillomavirus malignancies. J Immunother Cancer 8:e001395. https://doi.org/10.1136/jitc-2020-001395

    Article  PubMed  PubMed Central  Google Scholar 

  65. Bahreyni A, Mohamud Y, Luo H (2020) Emerging nanomedicines for effective breast cancer immunotherapy. J Nanobiotechnol 18(1):180. https://doi.org/10.1186/s12951-020-00741-z

    Article  Google Scholar 

  66. Shao K, Singha S, Clemente-Casares X, Tsai S, Yang Y, Santamaria P (2015) Nanoparticle-based immunotherapy of cancer. ACS Nano 9(1):16–30. https://doi.org/10.1021/nn5062029

    Article  CAS  PubMed  Google Scholar 

  67. Ramesh A, Brouillard A, Kumar S, Nandi D, Kulkarni A (2020) Dual inhibition of CSF1R and MAPK pathways using supramoleculuar nanoparticles enhances macrophage immunotherapy. Biomaterials 227:119559. https://doi.org/10.1016/j.biomaterials.2019.119559

    Article  CAS  PubMed  Google Scholar 

  68. Buss CG, Bhatia SN (2020) Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics. Proc Natl Acad Sci USA 177(24):13428–13436. https://doi.org/10.1073/pnas.2001569117

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The cartoon in Fig. 1 was created using Biorender.com.

Funding

This work is supported by funding to ERT from P30CA014089, Tower Research Foundation-Career Development Award, Concern Foundation-Conquer Cancer Now Award, and to LAE from the Breast Cancer Research Foundation, Stand Up to Cancer, the Department of Defense, and the National Institutes of Health.

Author information

Authors and Affiliations

  1. Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA

    Evanthia T. Roussos Torres

  2. Department of Medicine–Oncology, Norris Comprehensive Cancer Center, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA

    Evanthia T. Roussos Torres

  3. UPMC Hillman Cancer Center, 5117 Centre Avenue, Room 1.46e, Pittsburgh, PA, 15213, USA

    Leisha A. Emens

  4. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Leisha A. Emens

Authors
  1. Evanthia T. Roussos Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leisha A. Emens
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ERT, LAE: Writing original draft, editing, revision, final approval.

Corresponding authors

Correspondence to Evanthia T. Roussos Torres or Leisha A. Emens.

Ethics declarations

Conflict of interest

ERT declares no conflicts of interest. LAE discloses the following: Employment: University of Pittsburgh, UPMC UPP; Royalties: Elsevier; Intellectual Property Rights: Aduro Biotech; Consulting fees; Genentech, F Hoffman La Roche, Syndax, Lilly, Abbvie, Astrazeneca, Medimmune, Bayer, GCPR, Gilead, Gritstone, Macrogenics, Novartis, Peregrine, Replimune, Shionogi, Silverback, Vaccinex, Celgene, Chugai; Travel support: Genentech, F Hoffman La Roche, Amgen, Macrogenics, Replimune, Vaccinex, Bristol Myers Squibb; Contracted research: Abbvie, Aduro Biotech, Astrazeneca, Bolt Therapeutics, Bristol Myers Squibb, Corvus, EMD Serono, Genentech, F Hoffman La Roche, Maxcyte, Merck, Silverback, Tempest, Takeda, CytomX, Compugen; Third party publication support: Genentech/F Hoffman La Roche; In kind support (provision of drug for preclinical studies). The author is the current Vice President for the Society for the Immunotherapy of Cancer (2021–2022) and a former at-large member of the Board of Directors from 2016 to 2019.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Torres, E.T.R., Emens, L.A. Emerging combination immunotherapy strategies for breast cancer: dual immune checkpoint modulation, antibody–drug conjugates and bispecific antibodies. Breast Cancer Res Treat 191, 291–302 (2022). https://doi.org/10.1007/s10549-021-06423-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-021-06423-0

Keywords

Search

Navigation