Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer

Arlene L. Oei, Preethi Korangath, Kathleen Mulka, Mikko Helenius, Jonathan B. Coulter, Jacqueline Stewart, Esteban Velarde, Johannes Crezee, Brian Simons, Lukas J.A. Stalpers, H. Petra Kok, Kathleen Gabrielson, Nicolaas A.P. Franken, Robert Ivkov

Research output: Contribution to journalArticle

Abstract

Purpose: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model.Methods: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3 × 8 Gy)±local HT, mild (HTM, 43 °C/20 min) or partially ablative (HTAbl, 45 °C/5 min plus 43 °C/15 min),±IT with anti-PD-1 and anti-CTLA-4 antibodies (both 4 × 10 mg/kg, i.p.). Tumor growth was measured daily. Two weeks after treatment, lungs and livers were harvested for histopathology evaluation of metastases.Results: Compared to untreated controls, all treatment groups demonstrated a decreased tumor volume; however, when compared against surgical resection, only RT + HTM+IT, RT + HTAbl+IT and RT + HTAbl had similar or smaller tumors. These cohorts showed more infiltration of CD3+ T-lymphocytes into the primary tumor. Tumor growth effects were partially reversed with T-cell depletion. Combinations that proved most effective for primary tumors generated modest reductions in numbers of lung metastases. Conversely, numbers of lung metastases showed potential to increase following HT + IT treatment, particularly when compared to RT. Compared to untreated controls, there was no improvement in survival with any treatment.Conclusions: Single-fraction MION HT added to RT + IT improved local tumor control and recruitment of CD3+ T-lymphocytes, with only a modest effect to reduce lung metastases and no improvement in overall survival. HT + IT showed potential to increase metastatic dissemination to lungs.

Fingerprint

Radiation Effects
Nanoparticles
Fever
Radiotherapy
Breast Neoplasms
Lung
Neoplasms
Triple Negative Breast Neoplasms
Neoplasm Metastasis
T-Lymphocytes
Therapeutics
Induced Hyperthermia
Human Mammary Glands
Growth
Tumor Burden
Antibodies
Liver

Keywords

  • immune checkpoint therapy
  • ionizing radiation
  • Magnetic nanoparticle hyperthermia
  • metastatic cancer
  • triple negative breast cancer

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cancer Research

Cite this

Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer. / Oei, Arlene L.; Korangath, Preethi; Mulka, Kathleen; Helenius, Mikko; Coulter, Jonathan B.; Stewart, Jacqueline; Velarde, Esteban; Crezee, Johannes; Simons, Brian; Stalpers, Lukas J.A.; Kok, H. Petra; Gabrielson, Kathleen; Franken, Nicolaas A.P.; Ivkov, Robert.

In: International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, Vol. 36, 01.11.2019, p. 47-63.

Research output: Contribution to journalArticle

Oei, Arlene L. ; Korangath, Preethi ; Mulka, Kathleen ; Helenius, Mikko ; Coulter, Jonathan B. ; Stewart, Jacqueline ; Velarde, Esteban ; Crezee, Johannes ; Simons, Brian ; Stalpers, Lukas J.A. ; Kok, H. Petra ; Gabrielson, Kathleen ; Franken, Nicolaas A.P. ; Ivkov, Robert. / Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer. In: International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. 2019 ; Vol. 36. pp. 47-63.
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abstract = "Purpose: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model.Methods: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3 × 8 Gy)±local HT, mild (HTM, 43 °C/20 min) or partially ablative (HTAbl, 45 °C/5 min plus 43 °C/15 min),±IT with anti-PD-1 and anti-CTLA-4 antibodies (both 4 × 10 mg/kg, i.p.). Tumor growth was measured daily. Two weeks after treatment, lungs and livers were harvested for histopathology evaluation of metastases.Results: Compared to untreated controls, all treatment groups demonstrated a decreased tumor volume; however, when compared against surgical resection, only RT + HTM+IT, RT + HTAbl+IT and RT + HTAbl had similar or smaller tumors. These cohorts showed more infiltration of CD3+ T-lymphocytes into the primary tumor. Tumor growth effects were partially reversed with T-cell depletion. Combinations that proved most effective for primary tumors generated modest reductions in numbers of lung metastases. Conversely, numbers of lung metastases showed potential to increase following HT + IT treatment, particularly when compared to RT. Compared to untreated controls, there was no improvement in survival with any treatment.Conclusions: Single-fraction MION HT added to RT + IT improved local tumor control and recruitment of CD3+ T-lymphocytes, with only a modest effect to reduce lung metastases and no improvement in overall survival. HT + IT showed potential to increase metastatic dissemination to lungs.",
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T1 - Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer

AU - Oei, Arlene L.

AU - Korangath, Preethi

AU - Mulka, Kathleen

AU - Helenius, Mikko

AU - Coulter, Jonathan B.

AU - Stewart, Jacqueline

AU - Velarde, Esteban

AU - Crezee, Johannes

AU - Simons, Brian

AU - Stalpers, Lukas J.A.

AU - Kok, H. Petra

AU - Gabrielson, Kathleen

AU - Franken, Nicolaas A.P.

AU - Ivkov, Robert

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Purpose: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model.Methods: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3 × 8 Gy)±local HT, mild (HTM, 43 °C/20 min) or partially ablative (HTAbl, 45 °C/5 min plus 43 °C/15 min),±IT with anti-PD-1 and anti-CTLA-4 antibodies (both 4 × 10 mg/kg, i.p.). Tumor growth was measured daily. Two weeks after treatment, lungs and livers were harvested for histopathology evaluation of metastases.Results: Compared to untreated controls, all treatment groups demonstrated a decreased tumor volume; however, when compared against surgical resection, only RT + HTM+IT, RT + HTAbl+IT and RT + HTAbl had similar or smaller tumors. These cohorts showed more infiltration of CD3+ T-lymphocytes into the primary tumor. Tumor growth effects were partially reversed with T-cell depletion. Combinations that proved most effective for primary tumors generated modest reductions in numbers of lung metastases. Conversely, numbers of lung metastases showed potential to increase following HT + IT treatment, particularly when compared to RT. Compared to untreated controls, there was no improvement in survival with any treatment.Conclusions: Single-fraction MION HT added to RT + IT improved local tumor control and recruitment of CD3+ T-lymphocytes, with only a modest effect to reduce lung metastases and no improvement in overall survival. HT + IT showed potential to increase metastatic dissemination to lungs.

AB - Purpose: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model.Methods: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3 × 8 Gy)±local HT, mild (HTM, 43 °C/20 min) or partially ablative (HTAbl, 45 °C/5 min plus 43 °C/15 min),±IT with anti-PD-1 and anti-CTLA-4 antibodies (both 4 × 10 mg/kg, i.p.). Tumor growth was measured daily. Two weeks after treatment, lungs and livers were harvested for histopathology evaluation of metastases.Results: Compared to untreated controls, all treatment groups demonstrated a decreased tumor volume; however, when compared against surgical resection, only RT + HTM+IT, RT + HTAbl+IT and RT + HTAbl had similar or smaller tumors. These cohorts showed more infiltration of CD3+ T-lymphocytes into the primary tumor. Tumor growth effects were partially reversed with T-cell depletion. Combinations that proved most effective for primary tumors generated modest reductions in numbers of lung metastases. Conversely, numbers of lung metastases showed potential to increase following HT + IT treatment, particularly when compared to RT. Compared to untreated controls, there was no improvement in survival with any treatment.Conclusions: Single-fraction MION HT added to RT + IT improved local tumor control and recruitment of CD3+ T-lymphocytes, with only a modest effect to reduce lung metastases and no improvement in overall survival. HT + IT showed potential to increase metastatic dissemination to lungs.

KW - immune checkpoint therapy

KW - ionizing radiation

KW - Magnetic nanoparticle hyperthermia

KW - metastatic cancer

KW - triple negative breast cancer

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