Improved tumor responses with sequential targeted alpha followed by IL2 immunocytokine therapies in treatment of CEA positive breast and colon tumors in CEA transgenic mice

Abstract

Rationale: Targeted alpha therapy (TAT) delivers high linear transfer energy alpha particles to tumors with the potential to generate tumor immune responses that may be augmented by antigen targeted immunotherapy. Methods: This concept was evaluated in immunocompetent carcinoembryonic antigen (CEA) transgenic mice bearing CEA positive mammary or colon tumors. Tumors were targeted with humanized anti-CEA antibody M5A labeled with ²²⁵Ac for its 10-day half-life and emission of 4 alpha particles, and the immunocytokine M5A-IL2. Results: A dose response (3.7, 7.4 and 11.1 kBq) of TAT only, for orthotopic CEA positive mammary tumors, was observed with a tumor growth delay of 30d and an increase in median survival from 20d to 36d at the highest dose. ICK (4x daily) monotherapy gave a tumor growth delay of 20d that was not improved by addition of 7.4 kBq of TAT 5d after the start of immunocytokine. However, TAT (7.4 kBq) followed by ICK 10d later led to a tumor growth delay of 38d with an increase of median survival to 45d. Similar results were seen for TAT followed by immunocytokine at 5d vs 10d. When a similar study was performed with subcutaneous implanted CEA positive MC38 colon tumors, TAT (7.4 kBq) monotherapy gave an increase in median survival from 29d to 42d. The addition of ICK 10d post 7.4 kBq TAT increased median survival to 57d. Immunophenotyping showed increased tumor infiltrating IFNγ+CD8+ T-cells and an increased ratio of these cells to Foxp3+CD4+ Tregs with sequential therapy. Immunohistochemistry confirmed there was an increase in tumor-infiltrating CD8+ T-cells in the sequential therapy group, strongly suggesting that ICK augmented TAT can lead to an immune response that improves tumor therapy. Conclusion: Low dose (7.4 kBq) TAT followed by a 4 dose immunocytokine regimen 5 or 10 days later gave superior tumor reductions and survival curves compared to either monotherapy in breast and colon cancer tumor models. Reversing the order of therapy to immunocytokine followed by TAT 10 days later was equivalent to either monotherapy in the breast cancer model.