Alpha Radiation Brachytherapy Acts as in situ Vaccination and Activates Systemic- and Specific- Anti-Tumor Immunity

Introduction: Diffusing Alpha emitters Radiation Therapy (DaRT) is an innovative brachytherapy treatment for solid tumors. Ra-224 loaded wires (seeds) disperse short-lived alpha-emitting atoms, which destroy the primary tumor, sparing the healthy tissue surrounding it. In solid tumor mice-models, DaRT resulted in retardation of tumor growth, extended survival, reduced lung metastases, and stimulated anti-tumor immunity. DaRT is currently tested under clinical trials. DaRT seeds cured 80% of cancer patients with SCC of the skin and oral cavity without adverse effects.

Here, we explored approaches to boost systemic- and specific- antitumor immunity by combining DaRT with several immunomodulatory strategies.

Materials and Methods: Subcutaneous tumors implanted in Balb/C mice, were treated with DaRT seeds with/without immunomodulatory agents. Non-radioactive seeds (inert) served as control.

(I) in the colon carcinoma model (CT26) DaRT was combined with: (a) viral RNA mimic polyIC or (b) immunoadjuvant XS15 or (c) MDSC inhibitor (sildenafil), combined with Treg inhibitor (cyclophosphamide), and the immunoadjuvant CpG. (II) in the breast cancer model (4T1) DaRT was combined with polyIC intratumural treatment.

Results and discussion: (I) CT26-breaing mice treated with DaRT in combination with (a) polyIC, showed reduced tumor volume compared to DaRT alone or to polyIC alone. (b) XS15, reduced tumor volume, increased host survival, and tumor-free mice, compared to DaRT alone (c) CpG, sildenafil and cyclophosphamide significantly retarded tumor development, showing 56% complete response, and 32.5% partial response, within 13-52 days following DaRT treatment. The control group (inert seeds + immunomodulators) showed 12% complete response and 65% partial response.

Cured mice were reinjected with either CT26 or DA3 (breast carcinoma) cells. All DA3 tumors developed within 10 days, while the CT26 cells did not developed tumors within 52 days. Splenocytes from CT26 bearing mice cured by DaRT combined with immunomodulators protected naïve mice from developing CT26 tumors, suggesting the involvement of a specific immune response. (II) 4T1-brearing mice treated with DaRT in combination with polyIC showed reduced tumor growth, compared to DaRT alone.

Conclusions: We propose DaRT as a safe and efficient treatment, not only for tumor ablation, but also for in situ vaccination. DaRT provides tree pivotal aspects as a novel therapeutic strategy: 1) efficient destruction of the primary tumor 2) not harming the healthy tissue 3) systemic activation of a specific- and distant anti-tumor immunity.