Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma

Mengshi Li; Dijie Liu; Dongyoul Lee; Yinwen Cheng; Nicholas J Baumhover; Brenna M Marks; Edwin A Sagastume; Zuhair K Ballas; Frances L Johnson; Zachary S Morris; Michael K Schultz

doi:10.3390/cancers13153676

Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma

Cancers (Basel). 2021 Jul 22;13(15):3676. doi: 10.3390/cancers13153676.

Authors

Mengshi Li^{1

2}, Dijie Liu^{1

2}, Dongyoul Lee², Yinwen Cheng^{3

4}, Nicholas J Baumhover^{1

2}, Brenna M Marks¹, Edwin A Sagastume¹, Zuhair K Ballas⁵, Frances L Johnson^{1

5}, Zachary S Morris⁶, Michael K Schultz^{1

2

3

7

8}

Affiliations

¹ Viewpoint Molecular Targeting, Inc., Coralville, IA 52241, USA.
² Department of Radiology, University of Iowa, Iowa City, IA 52242, USA.
³ Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA.
⁴ Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
⁵ Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
⁶ Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁷ Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
⁸ Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA.

Abstract

Radiotherapy can facilitate the immune recognition of immunologically "cold" tumors and enhance the efficacy of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors (ICIs) in melanoma. Systemic administration of receptor-targeted radionuclide therapy has the potential to selectively deliver radionuclides to multiple tumors throughout the body in metastatic settings. By triggering immunologic cell death and increasing the immune susceptibility of surviving tumor cells in these locations, targeted radionuclide therapies may overcome resistance to ICIs and render immunologically "cold" tumors throughout the body responsive to ICIs and immunologically "hot". Here, we show the anti-tumor cooperation of targeted α-particle radionuclide therapy (α-TRT) and ICIs in preclinical models of melanoma. Melanocortin 1 receptor (MC1R)-targeted radiopeptide [²¹²Pb]VMT01 was employed to deliver α-radiation to melanoma tumors in mice. A single injection of 4.1 MBq [²¹²Pb]VMT01 significantly slowed the tumor growth of B16-F10 melanoma and the combination of [²¹²Pb]VMT01 and ICIs induced a cooperative anti-tumor effect leading to 43% complete tumor response with no sign of malignancy on autopsy. Animals with complete response developed anti-tumor immunity to reject further tumor inoculations. This therapeutic cooperation was completely abolished in RAG1 KO mice, which are deficient in T-cell maturation. In addition, the anti-tumor cooperation was compromised when fractionated [²¹²Pb]VMT01 was used in the combination. We also demonstrated that [²¹²Pb]VMT01 induced immunogenic cell death in tumor vaccination assays and in vitro exposure to [²¹²Pb]VMT01 sensitized immunotolerant melanoma to ICIs treatment in vivo. Enhanced tumor infiltrating CD3⁺, CD4⁺, CD8⁺ lymphocytes were observed following injection of 1.4 MBq [²¹²Pb]VMT01. Overall, we demonstrated anti-tumor cooperation between α-TRT and ICIs in melanoma that is mediated by tumor specific immunity.

Keywords: alpha-particle radiotherapy; immune checkpoint inhibitors; immunogenic cell death; immunotherapy; melanoma.

Grants and funding

1R43CA232954-01A1/Small Business Innovation Research