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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

In vitro recognition of 5T33-OVA.Cytotoxic T-cell-mediated lysis of 5T33-OVA targets. T cells isolated from OT-I mice were activated using irradiated splenocytes loading with OVA257–264 (SIINFEKL) peptide. In vitro T-cell-mediated cytotoxicity against 5T33-OVA was determined using a standard four-hour 51Cr release assay at several effector-to-target ratios (E:T Ratio).
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pone.0130249.g002: In vitro recognition of 5T33-OVA.Cytotoxic T-cell-mediated lysis of 5T33-OVA targets. T cells isolated from OT-I mice were activated using irradiated splenocytes loading with OVA257–264 (SIINFEKL) peptide. In vitro T-cell-mediated cytotoxicity against 5T33-OVA was determined using a standard four-hour 51Cr release assay at several effector-to-target ratios (E:T Ratio).

Mentions: To further characterize the 5T33-OVA cells, we performed a cytotoxicity assay to evaluate the recognition efficiency by OT-I CD8+ T cells. For this experiment, we primed OT-I CD8+ T-cells in vitro for 5 days. As shown in Fig 2, primed OT-I CD8+ lymphocytes did not kill parental 5T33 cells (<5%), whereas 5T33-OVA cells and 5T33 pulsed with OVA257–264 peptide were killed, with lysis of 17% to 59% and 28% to 73% respectively at the different E:T ratios. These data indicate that the 5T33-OVA express enough H2Kb/OVA257–264 complexes to be recognized by the OT-I T-cells. Moreover, we observe an efficient recognition of 5T33-OVA cells by OT-I T-cells of 5T33-OVA cells in association with the high level of H2Kb/OVA257–264 expression on 5T33-OVA cells seen by flow cytometry (Fig 1A).


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)

In vitro recognition of 5T33-OVA.Cytotoxic T-cell-mediated lysis of 5T33-OVA targets. T cells isolated from OT-I mice were activated using irradiated splenocytes loading with OVA257–264 (SIINFEKL) peptide. In vitro T-cell-mediated cytotoxicity against 5T33-OVA was determined using a standard four-hour 51Cr release assay at several effector-to-target ratios (E:T Ratio).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130249.g002: In vitro recognition of 5T33-OVA.Cytotoxic T-cell-mediated lysis of 5T33-OVA targets. T cells isolated from OT-I mice were activated using irradiated splenocytes loading with OVA257–264 (SIINFEKL) peptide. In vitro T-cell-mediated cytotoxicity against 5T33-OVA was determined using a standard four-hour 51Cr release assay at several effector-to-target ratios (E:T Ratio).
Mentions: To further characterize the 5T33-OVA cells, we performed a cytotoxicity assay to evaluate the recognition efficiency by OT-I CD8+ T cells. For this experiment, we primed OT-I CD8+ T-cells in vitro for 5 days. As shown in Fig 2, primed OT-I CD8+ lymphocytes did not kill parental 5T33 cells (<5%), whereas 5T33-OVA cells and 5T33 pulsed with OVA257–264 peptide were killed, with lysis of 17% to 59% and 28% to 73% respectively at the different E:T ratios. These data indicate that the 5T33-OVA express enough H2Kb/OVA257–264 complexes to be recognized by the OT-I T-cells. Moreover, we observe an efficient recognition of 5T33-OVA cells by OT-I T-cells of 5T33-OVA cells in association with the high level of H2Kb/OVA257–264 expression on 5T33-OVA cells seen by flow cytometry (Fig 1A).

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