Title : The development of an integrated novel alpha radiation based- radiotherapy and immunotherapy cancer treatment: From pre-clinical to clinical trials
Introduction: Ablation strategies are non-surgical debulking procedures that can destroy solid tumors and release tumor antigens and damage associated molecular pattern molecules (DAMPs) for the induction of systemic anti-tumor immunity. Such anti-tumor immune responses can destroy residual malignant cells in primary tumors and distant metastases. In this way, the tumor can serve as its own antigenic vaccine after ablation. We developed a unique intra-tumoral alpha radiation based tumor ablation treatment termed, Diffusing Alpha emitters Radiation Therapy (DaRT). We use of radium-224 loaded wires, which release by recoil short-lived alpha-emitting atoms into the tumor. These atoms disperse in the tumor, and spray it with highly destructive alpha radiation.
Materials and methods: Subcutaneous tumors from squamous cell carcinoma (SCC), pancreatic, colon, prostate, breast and lung carcinoma origin were treated with stainless steel Ra-224 loaded wire(s) with or without chemotherapeutic drugs, and immune modulating agents. Tumor progression was recorded and radioactivity dose distribution was measured. The sensitivity of the various cancer cells was determined by their ability to form colonies after irradiation in vitro with alpha particles.
Results and discussion: I. Insertion of Ra-wires (DaRT) into solid tumors resulted in significant retardation of tumor growth, extended survival, reduced lung metastases and cured animals bearing murine squamous cell carcinoma (SCC), lung, pancreatic, colon, prostate and breast mouse derived tumors, and human derived tumors. Tumor local control was dependent on tumor size and the amount of radioactivity of the wires. II. An augmented level of local control was achieved when a combined treatment of Ra-224 wires and chemotherapy was applied III. Intratumoral tissue necrosis and tumor growth retardation were in correlation with the distribution of released alpha emitting isotopes and with the radiosensitivity of tumor cells IV. The radiosensitivity of tumor cells to alpha radiation was in correlation with their ability to avoid or repair double strand breaks V. Applied as a monotherapy, tumor ablation by DaRT boosted systemic anti-tumor immune responses. The treatment also reduced the fraction of lung metastasis bearing mice from 93% (control) to only 56% (DaRT treated). VI. Intratumoral insertion of DaRT sources in combination with inhibition of myeloid derived suppressor cells by sildenafil, inhibition of regulatory T cells (Tregs), and immunostimulation with CpG, reduced tumor growth, and several tumors completely regressed. Tumor bearing mice treated with DaRT and the immunomodulators displayed a significant resistance to the growth of a tumor re-challenge, and had a reduced lung metastatic burden as compared to the control. The combined treatment protocol reinforced both local and systemic anti-tumor immune responses.