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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

Adoptive OT-I T cell transfer.(A), Dose response of 5T33-OVA tumor cells to adoptive transfer of OT-I CD8+ T cells treatment. Animals were injected subcutaneously with 2x106 tumor cells and received the indicated doses of OT-I CD8+ T cells (n = 10 mice per group). Tumor volume was determined by using a caliper. Data points represent mean ± SD of 10 measures. *** p<0,001 as determined by two-way ANOVA and Bonferonni post-tests. (B), Tumors were explanted and single cell suspensions were prepared by grinding tumors in a tissu grinder. Cells were stained with monoclonal anti-CD8b PE and anti-CD45.1 FITC. Histograms represent the percentage of CD45.1+ in CD8+ cells.
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pone.0130249.g004: Adoptive OT-I T cell transfer.(A), Dose response of 5T33-OVA tumor cells to adoptive transfer of OT-I CD8+ T cells treatment. Animals were injected subcutaneously with 2x106 tumor cells and received the indicated doses of OT-I CD8+ T cells (n = 10 mice per group). Tumor volume was determined by using a caliper. Data points represent mean ± SD of 10 measures. *** p<0,001 as determined by two-way ANOVA and Bonferonni post-tests. (B), Tumors were explanted and single cell suspensions were prepared by grinding tumors in a tissu grinder. Cells were stained with monoclonal anti-CD8b PE and anti-CD45.1 FITC. Histograms represent the percentage of CD45.1+ in CD8+ cells.

Mentions: To assess the impact of ACT on tumor growth, 1x106, 2x106 or 5x106 OT-I CD8+ T cells were injected intravenously in the mice tail vein, 11 days after subcutaneous tumor engraftment. As shown in Fig 4A, at day 25, mice injected with 2 or 5x106 OT-I CD8+ T cells exhibited a significant tumor growth reduction compared with mice receiving no treatment or receiving 1x106 OT-I CD8+ T cells (p< 0.001). There was no significant difference between untreated mice and those receiving 1x106 OT-I CD8+ T cells (p>0.05).


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)

Adoptive OT-I T cell transfer.(A), Dose response of 5T33-OVA tumor cells to adoptive transfer of OT-I CD8+ T cells treatment. Animals were injected subcutaneously with 2x106 tumor cells and received the indicated doses of OT-I CD8+ T cells (n = 10 mice per group). Tumor volume was determined by using a caliper. Data points represent mean ± SD of 10 measures. *** p<0,001 as determined by two-way ANOVA and Bonferonni post-tests. (B), Tumors were explanted and single cell suspensions were prepared by grinding tumors in a tissu grinder. Cells were stained with monoclonal anti-CD8b PE and anti-CD45.1 FITC. Histograms represent the percentage of CD45.1+ in CD8+ cells.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130249.g004: Adoptive OT-I T cell transfer.(A), Dose response of 5T33-OVA tumor cells to adoptive transfer of OT-I CD8+ T cells treatment. Animals were injected subcutaneously with 2x106 tumor cells and received the indicated doses of OT-I CD8+ T cells (n = 10 mice per group). Tumor volume was determined by using a caliper. Data points represent mean ± SD of 10 measures. *** p<0,001 as determined by two-way ANOVA and Bonferonni post-tests. (B), Tumors were explanted and single cell suspensions were prepared by grinding tumors in a tissu grinder. Cells were stained with monoclonal anti-CD8b PE and anti-CD45.1 FITC. Histograms represent the percentage of CD45.1+ in CD8+ cells.
Mentions: To assess the impact of ACT on tumor growth, 1x106, 2x106 or 5x106 OT-I CD8+ T cells were injected intravenously in the mice tail vein, 11 days after subcutaneous tumor engraftment. As shown in Fig 4A, at day 25, mice injected with 2 or 5x106 OT-I CD8+ T cells exhibited a significant tumor growth reduction compared with mice receiving no treatment or receiving 1x106 OT-I CD8+ T cells (p< 0.001). There was no significant difference between untreated mice and those receiving 1x106 OT-I CD8+ T cells (p>0.05).

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