Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model
An effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with temozolomide and irinotecan, supporting a role for chemo-immunotherapy in NB. γδ T cells are an attractive anti-tumor immunotherapy because of...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2019-08-01
|
| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2019.1593804 |
| _version_ | 1811210101874229248 |
|---|---|
| author | Jaquelyn T. Zoine Kristopher A. Knight Lauren C. Fleischer Kathryn S. Sutton Kelly C. Goldsmith Christopher B. Doering H. Trent Spencer |
| author_facet | Jaquelyn T. Zoine Kristopher A. Knight Lauren C. Fleischer Kathryn S. Sutton Kelly C. Goldsmith Christopher B. Doering H. Trent Spencer |
| author_sort | Jaquelyn T. Zoine |
| collection | DOAJ |
| description | An effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with temozolomide and irinotecan, supporting a role for chemo-immunotherapy in NB. γδ T cells are an attractive anti-tumor immunotherapy because of their direct cytotoxic activity mediated through cell surface receptors NKG2D and CD16. NKG2D facilitates the innate recognition of stress-induced ligands whereas CD16 recognizes antibody bound to tumors and activates mechanisms of antibody-dependent cellular cytotoxicity (ADCC). This study demonstrates an efficient method for expanding and storing γδ T cells from NB patient-derived apheresis products at clinically relevant amounts. The expanded patient-derived γδ T cells were cytotoxic against the K562 cell line and multiple NB cell lines. Combining γδ T cells with dinutuximab led to a 30% increase in tumor cell lysis compared to γδ T cells alone. Furthermore, low-dose temozolomide in combination with expanded γδ T cells and dinutuximab resulted in increased IFNγ secretion and increased γδ T-cell surface expression of FasL and CD107a. IMR5 NB cell line xenografts established subcutaneously in NSG mice were treated with a regimen of dinutuximab, temozolomide, and γδ T cells. This combination caused targeted killing of NB xenografts in vivo, reducing tumor burden and prolonging survival. These data support the continued preclinical testing of dinutuximab and temozolomide in conjunction with γδ T-cell immunotherapy for patients with recurrent/refractory NB. |
| first_indexed | 2024-04-12T04:50:33Z |
| format | Article |
| id | doaj.art-c49d9607fe3b4710974be40de0fcdfb1 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-04-12T04:50:33Z |
| publishDate | 2019-08-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-c49d9607fe3b4710974be40de0fcdfb12022-12-22T03:47:20ZengTaylor & Francis GroupOncoImmunology2162-402X2019-08-018810.1080/2162402X.2019.15938041593804Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine modelJaquelyn T. Zoine0Kristopher A. Knight1Lauren C. Fleischer2Kathryn S. Sutton3Kelly C. Goldsmith4Christopher B. Doering5H. Trent Spencer6Emory University School of MedicineEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineAn effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with temozolomide and irinotecan, supporting a role for chemo-immunotherapy in NB. γδ T cells are an attractive anti-tumor immunotherapy because of their direct cytotoxic activity mediated through cell surface receptors NKG2D and CD16. NKG2D facilitates the innate recognition of stress-induced ligands whereas CD16 recognizes antibody bound to tumors and activates mechanisms of antibody-dependent cellular cytotoxicity (ADCC). This study demonstrates an efficient method for expanding and storing γδ T cells from NB patient-derived apheresis products at clinically relevant amounts. The expanded patient-derived γδ T cells were cytotoxic against the K562 cell line and multiple NB cell lines. Combining γδ T cells with dinutuximab led to a 30% increase in tumor cell lysis compared to γδ T cells alone. Furthermore, low-dose temozolomide in combination with expanded γδ T cells and dinutuximab resulted in increased IFNγ secretion and increased γδ T-cell surface expression of FasL and CD107a. IMR5 NB cell line xenografts established subcutaneously in NSG mice were treated with a regimen of dinutuximab, temozolomide, and γδ T cells. This combination caused targeted killing of NB xenografts in vivo, reducing tumor burden and prolonging survival. These data support the continued preclinical testing of dinutuximab and temozolomide in conjunction with γδ T-cell immunotherapy for patients with recurrent/refractory NB.http://dx.doi.org/10.1080/2162402X.2019.1593804γδ t cellsneuroblastomatargeted immunotherapytemozolomidedinutuximab |
| spellingShingle | Jaquelyn T. Zoine Kristopher A. Knight Lauren C. Fleischer Kathryn S. Sutton Kelly C. Goldsmith Christopher B. Doering H. Trent Spencer Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model OncoImmunology γδ t cells neuroblastoma targeted immunotherapy temozolomide dinutuximab |
| title | Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model |
| title_full | Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model |
| title_fullStr | Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model |
| title_full_unstemmed | Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model |
| title_short | Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model |
| title_sort | ex vivo expanded patient derived γδ t cell immunotherapy enhances neuroblastoma tumor regression in a murine model |
| topic | γδ t cells neuroblastoma targeted immunotherapy temozolomide dinutuximab |
| url | http://dx.doi.org/10.1080/2162402X.2019.1593804 |
| work_keys_str_mv | AT jaquelyntzoine exvivoexpandedpatientderivedgdtcellimmunotherapyenhancesneuroblastomatumorregressioninamurinemodel AT kristopheraknight exvivoexpandedpatientderivedgdtcellimmunotherapyenhancesneuroblastomatumorregressioninamurinemodel AT laurencfleischer exvivoexpandedpatientderivedgdtcellimmunotherapyenhancesneuroblastomatumorregressioninamurinemodel AT kathrynssutton exvivoexpandedpatientderivedgdtcellimmunotherapyenhancesneuroblastomatumorregressioninamurinemodel AT kellycgoldsmith exvivoexpandedpatientderivedgdtcellimmunotherapyenhancesneuroblastomatumorregressioninamurinemodel AT christopherbdoering exvivoexpandedpatientderivedgdtcellimmunotherapyenhancesneuroblastomatumorregressioninamurinemodel AT htrentspencer exvivoexpandedpatientderivedgdtcellimmunotherapyenhancesneuroblastomatumorregressioninamurinemodel |