Combination Image-Guided and Antibody-Targeted α-Therapy Before Targeted Immunotherapy for Treatment of Solid Tumors

Abstract

The rationale of this study was to evaluate the efficacy of 3 types of targeted therapy for solid tumors, comprising image-guided radiation therapy (IGRT), low-dose targeted α-therapy (TAT), and antibody-targeted interleukin-2 immunocytokine therapy, with the expectation that the combination of 2 types of targeted radiation therapy would perform better than either monotherapy with immunocytokine therapy. Methods: Carcinoembryonic antigen (CEA)-positive syngeneic breast and colon tumors in CEA transgenic animals were treated with single-dose IGRT (10 Gy) and 2 different regimens of fractionated IGRT (4 doses of 2.5 Gy or 4 doses of 3.65 Gy), with and without low-dose TAT (37 kBq of ²²⁵Ac-DOTA-anti-CEA) to optimize doses and tumor models for the combination of 2 types of IGRT plus TAT with immunocytokine therapy. Results: In preliminary PET imaging in the breast cancer model, fractionated IGRT (4 doses of 2.5 Gy) provided better antibody tumor penetration than did single-dose IGRT (10 Gy). Similarly, tumor regression and survival were superior with IGRT when combined with low-dose TAT, followed with best rechallenge responses in the groups treated with 4 doses of 2.5 Gy combined with TAT. Since comparable results were obtained in the colon cancer model, triple therapy (fractionated IGRT plus low-dose TAT followed by immunocytokine therapy) was studied in the colon cancer model, demonstrating complete cures in the majority of mice and rejection of all rechallenges. When the study was repeated for immunophenotyping 2 d after the completion of therapy, significant increases in natural killer and CD8-positive/interferon-gamma-positive cells were observed with triple therapy. Moreover, the changes in the tumor microenvironment, as reflected by the reduction of macrophages and infiltration of granulocytes and monocytes, was an important feature of these therapies. The memory phenotypes of the CD8-positive cells in tumor-draining lymph nodes and tumors showed significant increases of T cells with central memory versus naïve phenotypes in untreated controls. Interestingly, in contrast to the spleens and tumor-draining lymph nodes, there was almost a complete lack of naïve CD4-positive cells in the control tumors, a situation that was reversed by all 3 types of therapy, with the combination of IGRT, TAT, and immunocytokine therapy exhibiting the highest increase. Conclusion: Triple targeted therapy had the best therapeutic effects in a solid tumor model as evidenced by tumor cures, rejection of tumor rechallenge, and immunophenotyping.

Keywords: image-guided radiotherapy; radioimmunoimaging; radionuclide therapy; targeted immunotherapy; targeted α-therapy.