A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer

Melissa A. Geller, Sarah Cooley, Patricia L. Judson, Rahel Ghebre, Linda F. Carson, Peter A. Argenta, Amy L. Jonson, Angela Panoskaltsis-Mortari, Julie Curtsinger, David McKenna, Kathryn Dusenbery, Robin Bliss, Levi S. Downs, Jeffrey S. Miller

Research output: Contribution to journalArticle

234 Citations (Scopus)

Abstract

Background. Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. Methods. Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m2 × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometry. Results. Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 3065) years. Mean NK cell dose was 2.16 × 107cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day 14 compared with pre-chemotherapy (P 0.03). Serum IL-15 levels increased after the preparative regimen (P <0.001). Patients receiving TBI had delayed hematologic recovery (P 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. Conclusions. Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.

Original languageEnglish (US)
Pages (from-to)98-107
Number of pages10
JournalCytotherapy
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2010

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Cell- and Tissue-Based Therapy
Natural Killer Cells
Ovarian Neoplasms
Breast Neoplasms
Whole-Body Irradiation
Tissue Donors
Chimerism
Regulatory T-Lymphocytes
Interleukin-2
Drug Therapy
Interleukin-15
Adoptive Transfer
Interleukin-10
Cyclophosphamide
Neoplasms
Flow Cytometry
Breast

Keywords

  • Breast cancer
  • Immunotherapy
  • Natural killer cells
  • Ovarian cancer

Cite this

A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. / Geller, Melissa A.; Cooley, Sarah; Judson, Patricia L.; Ghebre, Rahel; Carson, Linda F.; Argenta, Peter A.; Jonson, Amy L.; Panoskaltsis-Mortari, Angela; Curtsinger, Julie; McKenna, David; Dusenbery, Kathryn; Bliss, Robin; Downs, Levi S.; Miller, Jeffrey S.

In: Cytotherapy, Vol. 13, No. 1, 01.01.2010, p. 98-107.

Research output: Contribution to journalArticle

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abstract = "Background. Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. Methods. Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m2 × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometry. Results. Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 3065) years. Mean NK cell dose was 2.16 × 107cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69{\%}) patients without TBI and 6/7 (85{\%}) with TBI. T-regulatory cells (Treg) were elevated at day 14 compared with pre-chemotherapy (P 0.03). Serum IL-15 levels increased after the preparative regimen (P <0.001). Patients receiving TBI had delayed hematologic recovery (P 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. Conclusions. Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.",
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T1 - A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer

AU - Geller, Melissa A.

AU - Cooley, Sarah

AU - Judson, Patricia L.

AU - Ghebre, Rahel

AU - Carson, Linda F.

AU - Argenta, Peter A.

AU - Jonson, Amy L.

AU - Panoskaltsis-Mortari, Angela

AU - Curtsinger, Julie

AU - McKenna, David

AU - Dusenbery, Kathryn

AU - Bliss, Robin

AU - Downs, Levi S.

AU - Miller, Jeffrey S.

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N2 - Background. Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. Methods. Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m2 × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometry. Results. Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 3065) years. Mean NK cell dose was 2.16 × 107cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day 14 compared with pre-chemotherapy (P 0.03). Serum IL-15 levels increased after the preparative regimen (P <0.001). Patients receiving TBI had delayed hematologic recovery (P 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. Conclusions. Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.

AB - Background. Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. Methods. Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m2 × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometry. Results. Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 3065) years. Mean NK cell dose was 2.16 × 107cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day 14 compared with pre-chemotherapy (P 0.03). Serum IL-15 levels increased after the preparative regimen (P <0.001). Patients receiving TBI had delayed hematologic recovery (P 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. Conclusions. Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.

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KW - Ovarian cancer

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