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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

Combination of RIT with adoptive immunotherapy inhibits tumor growth and prolongs survival.(A), Animals were injected with 2x106 tumor cells subcutaneously and received the indicated treatment (n = 8 to 10 mice per group). Tumor volume was measured. Data points represent mean ± SD. * p<0,05, ** p<0,01, *** p<0,001 as determined by two-way ANOVA and Bonferonni post-tests. The combination of RIT + ACT or RIT alone or the ACT transfer alone significantly decrease tumor growth when compared with the control. The combination of RIT + ACT significantly decrease tumor growth when compared RIT alone or the ACT transfer alone. (B), Animals were injected subcutaneously with 2x106 tumor cells and received the indicated treatment. The percentage of surviving mice was evaluated when tumor volume reach end-point of 2500 mm3. The combination of RIT + ACT significantly increased survival (median survival of 31 days; log-rank, 0.0001) when compared with control or RIT alone (median survival of 28 days; log-rank, 0,0413) or the ACT transfer alone (median survival of 27 days; log-rank, 0,0391) cohorts. Statistical analysis were performed using non-parametric Mann-Whitney test.
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pone.0130249.g005: Combination of RIT with adoptive immunotherapy inhibits tumor growth and prolongs survival.(A), Animals were injected with 2x106 tumor cells subcutaneously and received the indicated treatment (n = 8 to 10 mice per group). Tumor volume was measured. Data points represent mean ± SD. * p<0,05, ** p<0,01, *** p<0,001 as determined by two-way ANOVA and Bonferonni post-tests. The combination of RIT + ACT or RIT alone or the ACT transfer alone significantly decrease tumor growth when compared with the control. The combination of RIT + ACT significantly decrease tumor growth when compared RIT alone or the ACT transfer alone. (B), Animals were injected subcutaneously with 2x106 tumor cells and received the indicated treatment. The percentage of surviving mice was evaluated when tumor volume reach end-point of 2500 mm3. The combination of RIT + ACT significantly increased survival (median survival of 31 days; log-rank, 0.0001) when compared with control or RIT alone (median survival of 28 days; log-rank, 0,0413) or the ACT transfer alone (median survival of 27 days; log-rank, 0,0391) cohorts. Statistical analysis were performed using non-parametric Mann-Whitney test.

Mentions: No significant difference was observed between tumor growth after α-RIT treatment alone or ACT treatment alone (Fig 5A). However, mice receiving the combination of α-RIT followed by ACT exhibited a significant decrease in tumor development compared to the control mice that received PBS or the ones that received RIT alone or ACT alone. Monitoring of those animals was also performed with regards to their survival after each treatment; the mice being sacrificed when tumour reached an endpoint volume of 2500 mm3 (Fig 5B). Once again, there was a significant difference in median survival of mice received the combination of RIT and ACT (31 days) compared to mice receiving ACT alone (28 days, p = 0.0391), or RIT alone (27 days, p = 0.0413). Altogether these data demonstrated that combining RIT and ACT was the most efficient therapeutic approach in terms of tumor development and survival. We investigated the impact of irradiation with α -particles on MHC class I or H2Kb/OVA257–264 complex expresssion on 5T33-OVA cells in vitro (S1 File). No clear variation in the overall MHC class I expression was observed (Figure A in S1 File), however irradiation resulted in a transient increase of the H2Kd/OVA257–264 complex expression (Figure B in S1 File) that is specifically recognized by OT-I CD8+ T cells and which might contribute to therapeutic efficacy of the combined treatment.


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)

Combination of RIT with adoptive immunotherapy inhibits tumor growth and prolongs survival.(A), Animals were injected with 2x106 tumor cells subcutaneously and received the indicated treatment (n = 8 to 10 mice per group). Tumor volume was measured. Data points represent mean ± SD. * p<0,05, ** p<0,01, *** p<0,001 as determined by two-way ANOVA and Bonferonni post-tests. The combination of RIT + ACT or RIT alone or the ACT transfer alone significantly decrease tumor growth when compared with the control. The combination of RIT + ACT significantly decrease tumor growth when compared RIT alone or the ACT transfer alone. (B), Animals were injected subcutaneously with 2x106 tumor cells and received the indicated treatment. The percentage of surviving mice was evaluated when tumor volume reach end-point of 2500 mm3. The combination of RIT + ACT significantly increased survival (median survival of 31 days; log-rank, 0.0001) when compared with control or RIT alone (median survival of 28 days; log-rank, 0,0413) or the ACT transfer alone (median survival of 27 days; log-rank, 0,0391) cohorts. Statistical analysis were performed using non-parametric Mann-Whitney test.
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Related In: Results  -  Collection

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

pone.0130249.g005: Combination of RIT with adoptive immunotherapy inhibits tumor growth and prolongs survival.(A), Animals were injected with 2x106 tumor cells subcutaneously and received the indicated treatment (n = 8 to 10 mice per group). Tumor volume was measured. Data points represent mean ± SD. * p<0,05, ** p<0,01, *** p<0,001 as determined by two-way ANOVA and Bonferonni post-tests. The combination of RIT + ACT or RIT alone or the ACT transfer alone significantly decrease tumor growth when compared with the control. The combination of RIT + ACT significantly decrease tumor growth when compared RIT alone or the ACT transfer alone. (B), Animals were injected subcutaneously with 2x106 tumor cells and received the indicated treatment. The percentage of surviving mice was evaluated when tumor volume reach end-point of 2500 mm3. The combination of RIT + ACT significantly increased survival (median survival of 31 days; log-rank, 0.0001) when compared with control or RIT alone (median survival of 28 days; log-rank, 0,0413) or the ACT transfer alone (median survival of 27 days; log-rank, 0,0391) cohorts. Statistical analysis were performed using non-parametric Mann-Whitney test.
Mentions: No significant difference was observed between tumor growth after α-RIT treatment alone or ACT treatment alone (Fig 5A). However, mice receiving the combination of α-RIT followed by ACT exhibited a significant decrease in tumor development compared to the control mice that received PBS or the ones that received RIT alone or ACT alone. Monitoring of those animals was also performed with regards to their survival after each treatment; the mice being sacrificed when tumour reached an endpoint volume of 2500 mm3 (Fig 5B). Once again, there was a significant difference in median survival of mice received the combination of RIT and ACT (31 days) compared to mice receiving ACT alone (28 days, p = 0.0391), or RIT alone (27 days, p = 0.0413). Altogether these data demonstrated that combining RIT and ACT was the most efficient therapeutic approach in terms of tumor development and survival. We investigated the impact of irradiation with α -particles on MHC class I or H2Kb/OVA257–264 complex expresssion on 5T33-OVA cells in vitro (S1 File). No clear variation in the overall MHC class I expression was observed (Figure A in S1 File), however irradiation resulted in a transient increase of the H2Kd/OVA257–264 complex expression (Figure B in S1 File) that is specifically recognized by OT-I CD8+ T cells and which might contribute to therapeutic efficacy of the combined treatment.

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