Combining alpha radiation-based brachytherapy with immunomodulators promotes complete tumor regression in mice via tumor-specific long-term immune response

Vered Domankevich,Michael Schmidt,Itzhak Kelson,Hans-Georg Rammensee,Adi Cohen,Sujit S Nair,Ashutosh Tewari,Yona Keisari,Margalit Efrati

doi:10.1007/s00262-019-02418-5

Abstract

Diffusing alpha-emitters radiation therapy (DaRT) is the only known method for treating solid tumors with highly destructive alpha radiation. More importantly, as a monotherapy, DaRT has been shown to induce a systemic antitumor immune response following tumor ablation. Here, immunomodulatory strategies to boost the antitumor immune response induced by DaRT, and the response specificity, were investigated in the colon cancer CT26 mouse model. Local treatment prior to DaRT, with the TLR3 agonist poly I:C, was sufficient to inhibit tumor growth relative to poly I:C or DaRT alone. DaRT used in combination with the TLR9 agonist CpG, or with the TLR1/2 agonist XS15 retarded tumor growth and increased tumor-rejection rates, compared to DaRT alone, curing 41% and 20% of the mice, respectively. DaRT in combination with CpG, the Treg inhibitor cyclophosphamide, and the MDSC inhibitor sildenafil, cured 51% of the animals, compared to only 6% and 0% cure when immunomodulation or DaRT was used alone, respectively. Challenge and Winn assays revealed that these high cure rates involved a specific immunological memory against CT26 antigens. We suggest that DaRT acts in synergy with immunomodulation to induce a specific and systemic antitumor immune response. This strategy may serve as a safe and efficient method not only for tumor ablation, but also for in situ vaccination of cancer patients.

Highlights

Ablation strategies are non-surgical procedures that destroy solid tumors in situ, thereby releasing tumor antigens and damage-associated molecular pattern (DAMP) molecules, which promote a systemic antitumor immune response
Combined treatment with diffusing alpha-emitters radiation therapy (DaRT) and the TLR3 agonist poly I:C retards CT26 tumor development compared to each treatment alone
Combined treatment with DaRT and the TLR9 agonist CpG, or the TLR1,2 agonist XS15, retards CT26 tumor development and increases tumor‐rejection rates compared to DaRT alone

Summary

Introduction

Ablation strategies are non-surgical procedures that destroy solid tumors in situ, thereby releasing tumor antigens and damage-associated molecular pattern (DAMP) molecules, which promote a systemic antitumor immune response (for review, see [1]). A unique method for solid tumor ablation using highly destructive alpha radiation was developed in our laboratories, termed diffusing alpha-emitters radiation therapy (DaRT) [2, 3]. By widening the range of the alphaemitting atoms’ distribution inside the tumor, this method provides the only known application for alpha-based brachytherapy of solid tumors. Synergy between radiotherapy and immunotherapy has been demonstrated in preclinical trials, and a mechanistic rationale to combine both therapies has been suggested. Enhances MHC1 expression, and promotes phagocytosis by

Methods

Results

Conclusion