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

Jérémie Ménager,Jean-Baptiste Gorin,Alain Faivre-Chauvet,Frank Bruchertseifer,Cédric Louvet,Yannick Guilloux,Lucile Drujont,Michel Chérel,Catherine Maurel,Sébastien Gouard,Joëlle Gaschet,Alfred Morgenstern,François Davodeau,Hiroshi Shiku

doi:10.1371/journal.pone.0130249

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.

Highlights

Radiation therapy is one of the most efficient form of cancer therapy, and is used in the treatment of more than half of all cancer patients [1,2]
Adoptive T-cell transfer (ACT) is a passive immunotherapy consisting in the infusion of large number of autologous or allogeneic lymphocytes with antitumor activity which have been amplified ex vivo [17]
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)

Summary

Introduction

Radiation therapy is one of the most efficient form of cancer therapy, and is used in the treatment of more than half of all cancer patients [1,2]. Several studies have demonstrated that radiation therapy can induce tumor regression through the development of an adaptive immune response dependent on tumor-specific T-lymphocytes [8,13,14,15] These studies gave the first hints that radiation therapy and immunotherapies which had been so far envisioned as separate cancer treatment approaches could be combined to provide an enhanced anti-tumor response. Adoptive T-cell transfer (ACT) is a passive immunotherapy consisting in the infusion of large number of autologous or allogeneic lymphocytes with antitumor activity which have been amplified ex vivo [17] Such approach has been largely investigated in melanoma patients through reinfusion of autologous tumor infiltrating lymphocytes (TIL) [18]. Besides inducing lymphodepletion, ionizing radiation was shown to enhance ACT efficacy by raising tumor immunogenicity and by promoting an abscopal effect which consists in the inhibition of distant tumors after local irradiation [8,20,22]

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