Skip to main content

Advertisement

SpringerLink
Log in

Current advances in immune checkpoint inhibitor combinations with radiation therapy or cryotherapy for breast cancer

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

Abstract

Purpose

Immune checkpoint inhibition (ICI) has demonstrated clinically significant efficacy when combined with chemotherapy in triple negative breast cancer (TNBC). Although many patients derived benefit, others do not respond to immunotherapy, therefore relying upon innovative combinations to enhance response. Local therapies such as radiation therapy (RT) and cryotherapy are immunogenic and potentially optimize responses to immunotherapy. Strategies combining these therapies and ICI are actively under investigation. This review will describe the rationale for combining ICI with targeted local therapies in breast cancer.

Methods

A literature search was performed to identify pre-clinical and clinical studies assessing ICI combined with RT or cryotherapy published as of August 2021 using PubMed and ClinicalTrials.gov.

Results

Published studies of ICI with RT and IPI have demonstrated safety and signals of early efficacy.

Conclusion

RT and cryotherapy are local therapies that can be integrated safely with ICI and has shown promise in early trials. Randomized phase II studies testing both of these approaches, such as P-RAD (NCT04443348) and ipilimumab/nivolumab/cryoablation for TNBC (NCT03546686) are current enrolling. The results of these studies are paramount as they will provide long term data on the safety and efficacy of these regimens.

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

Similar content being viewed by others

References

  1. Siegel RL et al (2021) Cancer statistics. CA Cancer J Clin 71:7–33. https://doi.org/10.3322/caac.21654

    Article  PubMed  Google Scholar 

  2. Perou CM et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. https://doi.org/10.1038/35021093

    Article  CAS  PubMed  Google Scholar 

  3. Dent R et al (2009) Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 115(2):423–428. https://doi.org/10.1007/s10549-008-0086-2

    Article  PubMed  Google Scholar 

  4. Prat A et al (2015) Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Med 13:303. https://doi.org/10.1186/s12916-015-0540-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wilson TR et al (2016) The molecular landscape of high-risk early breast cancer: comprehensive biomarker analysis of a phase III adjuvant population. NPJ Breast Cancer 2:16022. https://doi.org/10.1038/npjbcancer.2016.22

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cortes J et al (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. Schmid P et al (2020) Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21(1):44–59. https://doi.org/10.1016/S1470-2045(19)30689-8

    Article  CAS  PubMed  Google Scholar 

  8. Demaria S et al (2001) Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res 7(10):3025–3030

    CAS  PubMed  Google Scholar 

  9. Schmid P et al (2021) VP7-2021: KEYNOTE-522: Phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC. Ann Oncol 32(9):1198–1200

    Article  Google Scholar 

  10. Kachikwu EL et al (2011) Radiation enhances regulatory T cell representation. Int J Radiat Oncol Biol Phys 81(4):1128–1135. https://doi.org/10.1016/j.ijrobp.2010.09.034

    Article  PubMed  Google Scholar 

  11. Postow MA et al (2012) Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366(10):925–931. https://doi.org/10.1056/NEJMoa1112824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Deng L et al (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124(2):687–695. https://doi.org/10.1172/JCI67313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Burnette BC et al (2011) The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res 71(7):2488–2496. https://doi.org/10.1158/0008-5472.CAN-10-2820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Demaria S et al (2005) Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 11(2 Pt 1):728–734

    CAS  PubMed  Google Scholar 

  15. Dewan MZ et al (2009) Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15(17):5379–5388. https://doi.org/10.1158/1078-0432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sabel MS et al (2005) Immmunologic response to cryoablation of breast cancer. Breast Cancer Res Treat 90(1):97–104. https://doi.org/10.1007/s10549-004-3289-1

    Article  CAS  PubMed  Google Scholar 

  17. Page DB et al (2016) Deep sequencing of T-cell receptor DNA as a biomarker of clonnally expanded TILS in breast cancer after immunotherapy. Cancer Immunol Res 4(10):835–844. https://doi.org/10.1158/2326-6066.CIR-16-0013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. McArthur HL et al (2016) 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. https://doi.org/10.1158/1078-0432.CCR-16-0190

    Article  PubMed  PubMed Central  Google Scholar 

  19. Comen E et al (2019) Preoperative checkpoint inhibition (ICI) and cryoablation (Cryo) in women with early-stage breast cancer (ESBC). JCO 37(Suppl 15):592–592. https://doi.org/10.1200/JCO.2019.37.15_suppl.592

    Article  Google Scholar 

  20. Ono M et al (2012) Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer. Breast Cancer Res Treat 132:793–805. https://doi.org/10.1007/s10549-011-1554-7

    Article  CAS  PubMed  Google Scholar 

  21. Salgado R et al (2015) Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free Survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab. JAMA Oncol 1:448. https://doi.org/10.1001/jamaoncol.2015.0830

    Article  PubMed  PubMed Central  Google Scholar 

  22. Denkert C et al (2018) Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 19:40–50. https://doi.org/10.1016/s1470-2045(17)30904

    Article  PubMed  Google Scholar 

  23. Loi S et al (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase iii randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02–98. J Clin Oncol 31:860–867. https://doi.org/10.1200/jco.2011.41.0902

    Article  CAS  PubMed  Google Scholar 

  24. Adams S et al (2014) Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32:2959–2966. https://doi.org/10.1200/jco.2013.55.0491

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gibney GT, Weiner LM, Atkins MB (2016) Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 17(12):e542–e551. https://doi.org/10.1016/S1470-2045(16)30406-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tumeh PC et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571. https://doi.org/10.1038/nature13954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen P-L et al (2016) Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov 6(8):827–837. https://doi.org/10.1158/2159-8290.CD-15-1545 (Epub 2016 Jun 14)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nanda R et al (2016) Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 34:2460–2467. https://doi.org/10.1200/jco.2015.64.8931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rugo HS et al (2018) Safety and antitumor activity of pembrolizumab in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Clin Cancer Res 24:2804–2811. https://doi.org/10.1158/1078-0432.ccr-17-3452

    Article  CAS  PubMed  Google Scholar 

  30. Dirix LY et al (2018) Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN solid tumor study. Breast Cancer Res Treat 167:671–686. https://doi.org/10.1007/s10549-017-4537-5

    Article  CAS  PubMed  Google Scholar 

  31. Rieber M, Strasberg Rieber M (2008) Sensitization to radiation-induced DNA damage accelerates loss of bcl-2 and increases apoptosis and autophagy. Cancer Biol Ther 7:1561–1566. https://doi.org/10.4161/cbt.7.10.6540

    Article  CAS  PubMed  Google Scholar 

  32. Rodriguez-Rocha H, Garcia-Garcia A, Panayiotidis MI, Franco R (2011) DNA damage and autophagy. Mutat Res Mol Mech Mutagen 711:158–166. https://doi.org/10.1016/j.mrfmmm.2011.03.007

    Article  CAS  Google Scholar 

  33. Apetoh L et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059. https://doi.org/10.1038/nm1622

    Article  CAS  PubMed  Google Scholar 

  34. Obeid M et al (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13:54–61. https://doi.org/10.1038/nm1523

    Article  CAS  PubMed  Google Scholar 

  35. Surace L, Scheifinger NA, Gupta A, van den Broek M (2016) Radiotherapy supports tumor-specific immunity by acute inflammation. Oncoimmunology 5:e1060391. https://doi.org/10.1080/2162402x.2015.1060391

    Article  PubMed  Google Scholar 

  36. Lim JYH, Gerber SA, Murphy SP, Lord EM (2014) Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8+ T cells. Cancer Immunol Immunother 63:259–271. https://doi.org/10.1007/s00262-013-1506-7

    Article  CAS  PubMed  Google Scholar 

  37. Burnette BC et al (2011) The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res 71:2488–2496. https://doi.org/10.1158/0008-5472.can-10-2820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gupta A et al (2012) Radiotherapy supports protective tumor-specific immunity. Oncoimmunology 1:1610–1611. https://doi.org/10.4161/onci.21478

    Article  PubMed  PubMed Central  Google Scholar 

  39. Deng L et al (2014) STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41:843–852. https://doi.org/10.1016/j.immuni.2014.10.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Woo S-R et al (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830–842. https://doi.org/10.1016/j.immuni.2014.10.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hou Y et al (2021) Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity. Sci Transl Med. 13(582):eabb0130. https://doi.org/10.1126/scitranslmed.abb0130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vanpouille-Box C et al (2017) DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun 8:15618. https://doi.org/10.1038/ncomms15618

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ganss R, Ryschich E, Klar E, Arnold B, Hämmerling GJ (2002) Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res 62:1462–1470

    CAS  PubMed  Google Scholar 

  44. Lugade AA et al (2005) Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol 174:7516–7523. https://doi.org/10.4049/jimmunol.174.12.7516

    Article  CAS  PubMed  Google Scholar 

  45. Lugade AA et al (2008) Radiation-induced IFN-production within the tumor microenvironment influences antitumor immunity. J Immunol 180:3132–3139. https://doi.org/10.4049/jimmunol.180.5.3132

    Article  CAS  PubMed  Google Scholar 

  46. Klug F et al (2013) Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24:589–602. https://doi.org/10.1016/j.ccr.2013.09.014

    Article  CAS  PubMed  Google Scholar 

  47. Tsai C-S et al (2007) Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. Int J Radiat Oncol Biol Phys 68:499–507. https://doi.org/10.1016/j.ijrobp.2007.01.041

    Article  CAS  PubMed  Google Scholar 

  48. Matsumura S, Demaria S (2010) Up-regulation of the pro-inflammatory chemokine CXCL16 is a common response of tumor cells to ionizing radiation. Radiat Res 173:418–425. https://doi.org/10.1667/rr1860.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Matsumura S et al (2008) Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol 181:3099–3107. https://doi.org/10.4049/jimmunol.181.5.3099

    Article  CAS  PubMed  Google Scholar 

  50. Chen IX et al (2019) Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc Natl Acad Sci U S A 116:4558–4566. https://doi.org/10.1073/pnas.1815515116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xu J et al (2013) CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res 73:2782–2794. https://doi.org/10.1158/0008-5472.can-12-3981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Komatsu N, Hori S (2007) Full restoration of peripheral Foxp3+ regulatory T cell pool by radioresistant host cells in scurfy bone marrow chimeras. Proc Natl Acad Sci U S A 104:8959–8964. https://doi.org/10.1073/pnas.0702004104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schaue D et al (2012) Regulatory T-cells in radiotherapeutic responses. Front Oncol 2:90. https://doi.org/10.3389/fonc.2012.00090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shiao SL et al (2015) TH2-polarized CD4+ T-cells and macrophages limit efficacy of radiotherapy. Cancer Immunol Res 3:518–525. https://doi.org/10.1158/2326-6066.cir-14-0232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Vanpouille-Box C et al (2015) TGFβ is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res 75:2232–2242. https://doi.org/10.1158/0008-5472.can-14-3511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Barcellos-Hoff MH, Derynck R, Tsang ML, Weatherbee JA (1994) Transforming growth factor-beta activation in irradiated murine mammary gland. J Clin Invest 93:892–899. https://doi.org/10.1172/jci117045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Liu J et al (2012) TGF- blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci U S A 109:16618–16623. https://doi.org/10.1073/pnas.1117610109

    Article  PubMed  PubMed Central  Google Scholar 

  58. Rodríguez-Ruiz ME et al (2019) TGFβ blockade enhances radiotherapy abscopal efficacy effects in combination with anti-PD1 and anti-CD137 immunostimulatory monoclonal antibodies. Mol Cancer Ther 18:621–631. https://doi.org/10.1158/1535-7163.mct-18-0558

    Article  CAS  PubMed  Google Scholar 

  59. Demaria S et al (2005) Combining radiotherapy and immunotherapy: a revived partnership. Int J Radiat Oncol Biol Phys 63:655–666. https://doi.org/10.1016/j.ijrobp.2005.06.032

    Article  PubMed  PubMed Central  Google Scholar 

  60. Sharabi AB et al (2015) Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol Res 3:345–355. https://doi.org/10.1158/2326-6066.cir-14-0196

    Article  CAS  PubMed  Google Scholar 

  61. Wu L et al (2015) Targeting the inhibitory receptor CTLA-4 on T-cells increased abscopal effects in murine mesothelioma model. Oncotarget. https://doi.org/10.18632/oncotarget.3487

    Article  PubMed  PubMed Central  Google Scholar 

  62. Dovedi SJ et al (2014) Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 74:5458–5468. https://doi.org/10.1158/0008-5472.can-14-1258

    Article  CAS  PubMed  Google Scholar 

  63. Twyman-Saint VC et al (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373–377. https://doi.org/10.1038/nature14292

    Article  CAS  Google Scholar 

  64. Demaria S, Golden EB, Formenti SC (2015) Role of local radiation therapy in cancer immunotherapy. JAMA Oncol 1:1325. https://doi.org/10.1001/jamaoncol.2015.2756

    Article  PubMed  Google Scholar 

  65. Yu J et al (2021) Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med 27(1):152–164. https://doi.org/10.1038/s41591-020-1131-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ho AY et al (2020) A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer. Cancer 126(4):850–860. https://doi.org/10.1002/cncr.32599

    Article  CAS  PubMed  Google Scholar 

  67. Phase II pembrolizumab + palliative radiotherapy in breast cancer—full text view. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03051672. Accessed 10 Jun 2019

  68. Voorwerk L et al (2019) Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med 25:920–928. https://doi.org/10.1038/s41591-019-0432-4

    Article  CAS  PubMed  Google Scholar 

  69. Buchwald ZS et al (2018) Immune checkpoint blockade and the abscopal effect: a critical review on timing Dose and Fractionation. Front Oncol 8:612. https://doi.org/10.3389/fonc.2018.00612

    Article  PubMed  PubMed Central  Google Scholar 

  70. Young KH et al (2016) Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS ONE 11:e0157164. https://doi.org/10.1371/journal.pone.0157164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rudqvist NP et al (2018) Radiotherapy and CTLA-4 blockade shape the TCR repertoire of tumor-infiltrating T cells. Cancer Immunol Res 6(2):139–150. https://doi.org/10.1158/2326-6066.CIR-17-0134

    Article  CAS  PubMed  Google Scholar 

  72. Boutros C et al (2016) Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 13:473–486. https://doi.org/10.1038/nrclinonc.2016.58

    Article  CAS  PubMed  Google Scholar 

  73. Hassel JC et al (2017) Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions. Cancer Treat Rev 57:36–49. https://doi.org/10.1016/j.ctrv.2017.05.003

    Article  CAS  PubMed  Google Scholar 

  74. Perez-Ruiz E et al (2019) Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature 569:428–432. https://doi.org/10.1038/s41586-019-1162-y

    Article  CAS  PubMed  Google Scholar 

  75. Hwang WL et al (2018) Safety of combining radiotherapy with immune-checkpoint inhibition. Nat Rev Clin Oncol 15:477–494. https://doi.org/10.1038/s41571-018-0046-7

    Article  PubMed  Google Scholar 

  76. Martin AM et al (2018) Immunotherapy and symptomatic radiation necrosis in patients with brain metastases treated with stereotactic radiation. JAMA Oncol 4:1123. https://doi.org/10.1001/jamaoncol.2017.3993

    Article  PubMed  PubMed Central  Google Scholar 

  77. Fang P et al (2017) Radiation necrosis with stereotactic radiosurgery combined with CTLA-4 blockade and PD-1 inhibition for treatment of intracranial disease in metastatic melanoma. J Neurooncol 133:595–602. https://doi.org/10.1007/s11060-017-2470-4

    Article  CAS  PubMed  Google Scholar 

  78. Colaco RJ et al (2016) Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases. J Neurosurg 125:17–23. https://doi.org/10.3171/2015.6.jns142763

    Article  CAS  PubMed  Google Scholar 

  79. Diao K et al (2018) Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects. J Neurosurg 129:1397–1406. https://doi.org/10.3171/2017.7.jns171286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. McArthur H et al (2017) Abstract 4705: CTLA4 blockade with HER2-directed therapy (H) yields clinical benefit in women undergoing radiation therapy (RT) for HER2-positive (HER2+) breast cancer brain metastases (BCBM). Cancer Res. https://doi.org/10.1158/1538-7445.AM2017-4705

    Article  PubMed  Google Scholar 

  81. Stereotactic Radiation and Immunotherapy in Patients with Advanced Triple Negative Breast Cancer—full text view. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03464942. Accessed 6 Jun 2019

  82. Atezolizumab + stereotactic radiation in triple-negative breast cancer and brain metastasis—full text view. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03483012. Accessed 6 Jun 2019

  83. Pembrolizumab and stereotactic radiosurgery (SRS) of selected brain metastases in breast cancer patients—full text view. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03449238. Accessed 6 Jun 2019

  84. Pusztai L et al (2018) Abstract OT1-02-04: SWOG S1418/NRG -BR006: A randomized, phase III trial to evaluate the efficacy and safety of MK-3475 as adjuvant therapy for triple receptor-negative breast cancer with > 1 cm residual invasive cancer or positive lymph nodes (>pN1mic) after neoadjuvant chemotherapy. Cancer Res. https://doi.org/10.1158/1538-7445.SABCS17-OT1-02-04

    Article  Google Scholar 

  85. Mougalian SS et al (2015) Ten-year outcomes of patients with breast cancer with cytologically confirmed axillary lymph node metastases and pathologic complete response after primary systemic chemotherapy. JAMA Oncol 2(4):508–516. https://doi.org/10.1001/jamaoncol.2015.4935

    Article  Google Scholar 

  86. Neoadjuvant Chemotherapy Combined with Stereotactic Body Radiotherapy to the Primary Tumour +/- Durvalumab, +/- Oleclumab in Luminal B Breast Cancer: full text view. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03875573. Accessed 26 Feb 2021

  87. P-RAD: A randomized study of preoperative chemotherapy, pembrolizumab and no, low or high dose radiation in node-positive, HER2-negative breast cancer—full text view. https://www.clinicaltrials.gov/ct2/show/NCT04443348. Accessed 26 Feb 2021.

  88. McArthur H et al (2020) Pre-operative pembrolizumab (pembro) with radiation therapy (RT) in patients with operable triple-negative breast cancer (TNBC). Presented at 2020 virtual San Antonio breast cancer symposium (SABCS), 8–11 December 2020. Abstract PS12-09

  89. Li X et al (2011) Preliminary safety and efficacy results of laser immunotherapy for the treatment of metastatic breast cancer patients. Photochem Photobiol Sci 10(5):817–821

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Li X et al (2010) Clinical effects of in situ photoimmunotherapy on late-stage melanoma patients: a preliminary study. Cancer Biol Ther 10(11):1081–1087

    Article  PubMed Central  PubMed  Google Scholar 

  91. Zerbini A et al (2006) Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res 66:1139–1146

    Article  CAS  PubMed  Google Scholar 

  92. Fietta AM et al (2009) Systemic inflammatory response and downmodulation of peripheral CD25+Foxp3+ T-regulatory cells in patients undergoing radiofrequency thermal ablation for lung cancer. Hum Immunol 70:477–486

    Article  CAS  PubMed  Google Scholar 

  93. Hansler J et al (2006) Activation and dramatically increased cytolytic activity of tumor specific T lymphocytes after radio-frequency ablation in patients with hepatocellular carcinoma and colorectal liver metastases. World J Gastroenterol 12:3716–3721

    Article  PubMed Central  PubMed  Google Scholar 

  94. Ito F et al (2015) Immune adjuvant activity of pre-resectional radiofrequency ablation protects against local and systemic recurrence in aggressive murine colorectal cancer. PLoS ONE 10:e0143370

    Article  PubMed Central  PubMed  Google Scholar 

  95. Hu Z et al (2007) Investigation of HIFU-induced anti-tumor immunity in a murine tumor model. J Transl Med 5:34. https://doi.org/10.1186/1479-5876-5-34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yu Z et al (2015) Treatment of osteosarcoma with microwave thermal ablation to induce immunogenic cell death. Oncotarget 5(15):6526–6539

    Article  Google Scholar 

  97. Eranki A et al (2020) High-intensity focused ultrasound (HIFU) triggers immune sensitization of refractory murine neuroblastoma to checkpoint inhibitor therapy. Clin Cancer Res 26(5):1152–1161

    Article  CAS  PubMed  Google Scholar 

  98. Mouratidis PXE, Costa M, Rivens I, Repasky EE, Ter Haar G (2021) Pulsed focused ultrasound can improve the anti-cancer effects of immune checkpoint inhibitors in murine pancreatic cancer. J R Soc Interface 18(180):20210266

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Zhu J et al (2018) Enhanced antitumor efficacy through microwave ablation in combination with immune checkpoints blockade in breast cancer: A pre-clinical study in a murine model. Diagn Interv Imaging 99(3):135–142

    Article  CAS  PubMed  Google Scholar 

  100. Li L et al (2017) Microwave ablation combined with OK-432 induces Th1-type response and specific antitumor immunity in a murine model of breast cancer. J Transl Med 15(1):23

    Article  PubMed Central  PubMed  Google Scholar 

  101. Gameiro SR et al (2016) Tumor cells surviving exposure to proton or photon radiation share a common immunogenic modulation signature, rendering them more sensitive to T cell-mediated killing. Int J Radiat Oncol Biol Phys 95(1):120–130

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Durante M et al (2013) Immunologically augmented cancer treatment using modern radiotherapy. Trends Mol Med 19(9):565–582

    Article  CAS  PubMed  Google Scholar 

  103. Lee K et al (2014) Metastatic potential in MDA-MB-231 human breast cancer cells is inhibited by proton beam irradiation via the Akt/nuclear factor-κB signaling pathway. Mol Med Rep 10:1007–1012

    Article  CAS  PubMed  Google Scholar 

  104. Hashimoto S et al (2018) Recovery from sublethal damage and potentially lethal damage: proton beam irradiation vs X-ray irradiation. Strahlenther Onkol 194(4):343–351

    Article  PubMed  Google Scholar 

  105. Sabel MS et al (2005) Immunologic response to cryoablation of breast cancer. Breast Cancer Res Treat 90(1):97–104. https://doi.org/10.1007/s10549-004-3289-1

    Article  CAS  PubMed  Google Scholar 

  106. Gage AA et al (2009) Experimental cryosurgery investigations in vivo. Cryobiology 59:229–243. https://doi.org/10.1016/j.cryobiol.2009.10.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Waitz R et al (2012) Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy. Cancer Res 72:430–439. https://doi.org/10.1158/0008-5472.CAN-11-1782

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Cox Level 3, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA

    Alice Y. Ho, Shervin Tabrizi & Samantha A. Dunn

  2. Harvard Radiation Oncology Program, Boston, MA, USA

    Shervin Tabrizi

  3. Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    Heather L. McArthur

Authors
  1. Alice Y. Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shervin Tabrizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samantha A. Dunn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heather L. McArthur
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AYH, SAD, and ST contributed to conception and execution of the review. AYH, SAD, and ST wrote sections of the manuscript and HLM critically reviewed the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Corresponding author

Correspondence to Alice Y. Ho.

Ethics declarations

Conflict of interest

Dr. Ho reports grants from Merck & Co., grants from GSK, Inc., personal fees from Amgen, outside the submitted work. Dr. McArthur reports grants and personal fees from Merck, Lilly, and Bristol-Myers Squibb as well as personal fees from AstraZeneca, Seattle Genetics, Genentech, Pfizer, Immunomedics, Genomic Health, Puma Biotechnology, and Daiichi-Sankyo, outside the submitted work. Dr. Tabrizi and Ms. Dunn have nothing to disclose.

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

Ho, A.Y., Tabrizi, S., Dunn, S.A. et al. Current advances in immune checkpoint inhibitor combinations with radiation therapy or cryotherapy for breast cancer. Breast Cancer Res Treat 191, 229–241 (2022). https://doi.org/10.1007/s10549-021-06408-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-021-06408-z

Keywords

Search

Navigation