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Combining α-Radioimmunotherapy and Adoptive T Cell Therapy to Potentiate Tumor Destruction.

Ménager J, Gorin JB, Maurel C, Drujont L, Gouard S, Louvet C, Chérel M, Faivre-Chauvet A, Morgenstern A, Bruchertseifer F, Davodeau F, Gaschet J, Guilloux Y - PLoS ONE (2015)

Bottom Line: Then we evaluated the therapeutic efficacy in the mice treated with α-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells).We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment.These results demonstrate the efficacy of combining α-RIT and ACT in the MM model we established.

View Article: PubMed Central - PubMed

Affiliation: CRCNA-UMR 892 INSERM, Nantes, France; 6299 CNRS, Nantes, France; Université de Nantes, Nantes, France.

ABSTRACT
Ionizing radiation induces direct and indirect killing of cancer cells and for long has been considered as immunosuppressive. However, this concept has evolved over the past few years with the demonstration that irradiation can increase tumor immunogenicity and can actually favor the implementation of an immune response against tumor cells. Adoptive T-cell transfer (ACT) is also used to treat cancer and several studies have shown that the efficacy of this immunotherapy was enhanced when combined with radiation therapy. α-Radioimmunotherapy (α-RIT) is a type of internal radiotherapy which is currently under development to treat disseminated tumors. α-particles are indeed highly efficient to destroy small cluster of cancer cells with minimal impact on surrounding healthy tissues. We thus hypothesized that, in the setting of α-RIT, an immunotherapy like ACT, could benefit from the immune context induced by irradiation. Hence, we decided to further investigate the possibilities to promote an efficient and long-lasting anti-tumor response by combining α-RIT and ACT. To perform such study we set up a multiple myeloma murine model which express the tumor antigen CD138 and ovalbumine (OVA). Then we evaluated the therapeutic efficacy in the mice treated with α-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells). We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment. These results demonstrate the efficacy of combining α-RIT and ACT in the MM model we established.

No MeSH data available.


Related in: MedlinePlus

5T33-OVA phenotypic analysis after transduction by a lentiviral vector encoding cytoplasmic ovalbumin (A) 5T33 and 5T33-OVA staining with PE-conjugated antibody 25-D1.16, which specifically recognizes the OVA peptide ‘SIINFEKL’ bound to the MHC class I molecule H-2Kb and (B) staining of 5T33 and 5T33-OVA with APC-conjugated anti-mouse CD138 mAb.Flow cytometry was performed on a BD FACSCalibur Flow Cytometry System.
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pone.0130249.g001: 5T33-OVA phenotypic analysis after transduction by a lentiviral vector encoding cytoplasmic ovalbumin (A) 5T33 and 5T33-OVA staining with PE-conjugated antibody 25-D1.16, which specifically recognizes the OVA peptide ‘SIINFEKL’ bound to the MHC class I molecule H-2Kb and (B) staining of 5T33 and 5T33-OVA with APC-conjugated anti-mouse CD138 mAb.Flow cytometry was performed on a BD FACSCalibur Flow Cytometry System.

Mentions: The prerequisite to evaluate the therapeutic effect of α -RIT and ACT combination was to develop a suitable tumor model expressing two antigens, the first one allowing targeting with a radiolabeled antibody (CD138) and the second one for specific OT-I CD8+ T cell recognition (H2Kb/OVA257–264 complexes). To do so, we transduced the 5T33 cells with the cytoplasmic ovalbumin gene and the resulting 5T33-OVA cells were purified by FACS sorting based on the expression of H2Kb/OVA257–264 complexes on the plasma membrane. The purity of the sorting was controlled by cell labeling with the 25-D1.16 antibody specific for H2Kb/OVA257–264 complexes. As shown in Fig 1A, 73.4% of 5T33-OVA cells expressed this MHC-peptide complex compared to parental 5T33 cells. Endogeneous CD138 expression was also controlled to ensure that the transduction did not modify its expression on the 5T33-OVA cells. As shown in Fig 1B, respectively 96.4% and 97.1% of 5T33 and 5T33-OVA cells respectively were labeled by the anti-CD138 antibody. Together, these data demonstrate that 5T33-OVA cells express H2Kb/OVA257–264 complexes without altering the expression of CD138 antigen at the cell surface.


Combining α-Radioimmunotherapy and Adoptive T Cell Therapy to Potentiate Tumor Destruction.

Ménager J, Gorin JB, Maurel C, Drujont L, Gouard S, Louvet C, Chérel M, Faivre-Chauvet A, Morgenstern A, Bruchertseifer F, Davodeau F, Gaschet J, Guilloux Y - PLoS ONE (2015)

5T33-OVA phenotypic analysis after transduction by a lentiviral vector encoding cytoplasmic ovalbumin (A) 5T33 and 5T33-OVA staining with PE-conjugated antibody 25-D1.16, which specifically recognizes the OVA peptide ‘SIINFEKL’ bound to the MHC class I molecule H-2Kb and (B) staining of 5T33 and 5T33-OVA with APC-conjugated anti-mouse CD138 mAb.Flow cytometry was performed on a BD FACSCalibur Flow Cytometry System.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476754&req=5

pone.0130249.g001: 5T33-OVA phenotypic analysis after transduction by a lentiviral vector encoding cytoplasmic ovalbumin (A) 5T33 and 5T33-OVA staining with PE-conjugated antibody 25-D1.16, which specifically recognizes the OVA peptide ‘SIINFEKL’ bound to the MHC class I molecule H-2Kb and (B) staining of 5T33 and 5T33-OVA with APC-conjugated anti-mouse CD138 mAb.Flow cytometry was performed on a BD FACSCalibur Flow Cytometry System.
Mentions: The prerequisite to evaluate the therapeutic effect of α -RIT and ACT combination was to develop a suitable tumor model expressing two antigens, the first one allowing targeting with a radiolabeled antibody (CD138) and the second one for specific OT-I CD8+ T cell recognition (H2Kb/OVA257–264 complexes). To do so, we transduced the 5T33 cells with the cytoplasmic ovalbumin gene and the resulting 5T33-OVA cells were purified by FACS sorting based on the expression of H2Kb/OVA257–264 complexes on the plasma membrane. The purity of the sorting was controlled by cell labeling with the 25-D1.16 antibody specific for H2Kb/OVA257–264 complexes. As shown in Fig 1A, 73.4% of 5T33-OVA cells expressed this MHC-peptide complex compared to parental 5T33 cells. Endogeneous CD138 expression was also controlled to ensure that the transduction did not modify its expression on the 5T33-OVA cells. As shown in Fig 1B, respectively 96.4% and 97.1% of 5T33 and 5T33-OVA cells respectively were labeled by the anti-CD138 antibody. Together, these data demonstrate that 5T33-OVA cells express H2Kb/OVA257–264 complexes without altering the expression of CD138 antigen at the cell surface.

Bottom Line: Then we evaluated the therapeutic efficacy in the mice treated with α-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells).We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment.These results demonstrate the efficacy of combining α-RIT and ACT in the MM model we established.

View Article: PubMed Central - PubMed

Affiliation: CRCNA-UMR 892 INSERM, Nantes, France; 6299 CNRS, Nantes, France; Université de Nantes, Nantes, France.

ABSTRACT
Ionizing radiation induces direct and indirect killing of cancer cells and for long has been considered as immunosuppressive. However, this concept has evolved over the past few years with the demonstration that irradiation can increase tumor immunogenicity and can actually favor the implementation of an immune response against tumor cells. Adoptive T-cell transfer (ACT) is also used to treat cancer and several studies have shown that the efficacy of this immunotherapy was enhanced when combined with radiation therapy. α-Radioimmunotherapy (α-RIT) is a type of internal radiotherapy which is currently under development to treat disseminated tumors. α-particles are indeed highly efficient to destroy small cluster of cancer cells with minimal impact on surrounding healthy tissues. We thus hypothesized that, in the setting of α-RIT, an immunotherapy like ACT, could benefit from the immune context induced by irradiation. Hence, we decided to further investigate the possibilities to promote an efficient and long-lasting anti-tumor response by combining α-RIT and ACT. To perform such study we set up a multiple myeloma murine model which express the tumor antigen CD138 and ovalbumine (OVA). Then we evaluated the therapeutic efficacy in the mice treated with α-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells). We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment. These results demonstrate the efficacy of combining α-RIT and ACT in the MM model we established.

No MeSH data available.


Related in: MedlinePlus