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

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.

SUBMITTER: Li M

PROVIDER: S-EPMC8345035 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rates of malignant melanoma are continuing to increase, and until recently effective treatments were lacking. However, since 2011 three immunotherapeutic agents, known as checkpoint inhibitors, have been approved. This review aims to establish whether these three drugs - ipilimumab, nivolumab, and pembrolizumab - offer greater efficacy and tolerability compared to control interventions (placebo, immunotherapy, or chemotherapy) in patients with stage III or IV unresectable cutaneous melanoma.A search on four major medical and scientific databases yielded 7,553 records, of which seven met the inclusion criteria, with a total study population of 3,628. Only prospective Phase II or III randomized controlled trials on checkpoint inhibitors for patients with unresectable cutaneous melanoma that reported data on survival (overall or progression-free), tumor response, or adverse events were included. Three meta-analyses were carried out.The hazard ratio for progression or death was 0.54 (95% confidence interval [CI]: 0.44-0.67), and the odds ratio for best overall response rate was 4.48 (95% CI: 2.77-7.24), both in favor of checkpoint inhibitors. However, control treatments were associated with an insignificantly lower rate of discontinuation of treatment due to adverse effects or treatment-related adverse events (odds ratio =1.63 [95% CI: 0.55-4.88]).This study finds that checkpoint inhibitors are more effective than control interventions, both in terms of survival and tumor response, and yet no less tolerable. PD1 therapies (nivolumab and pembrolizumab) appear to offer greater efficacy than CTLA4 therapy (ipilimumab). The combination of nivolumab and ipilimumab was, however, the most effective, but significantly less tolerable than monotherapy. The lack of published clinical data does, however, limit this study. Further research is needed in two areas in particular: 1) to determine the optimal use of checkpoint inhibitors, specifically in terms of combination therapy, and 2) to identify reliable biomarkers to predictive responders and guide treatment assignment.

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

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