Radiation enhanced the local and distant anti-tumor efficacy in dual immune checkpoint blockade therapy in osteosarcoma

Abstract

Radiation therapy has been long utilized as localized cancer treatment. Recent studies have also demonstrated that it has a distant effect by the enhanced immunity, but it rarely occurs. The purpose of this study was to investigate whether X-ray irradiation combined with anti-PD-L1 and anti-CTLA-4 antibodies (P1C4) provides a higher probability of this distant effect as well as enhanced local antitumor efficacy for osteosarcoma. LM8 mouse osteosarcoma cells were inoculated into both legs of C3H mice assigned to one of four groups, namely no treatment (No Tx), P1C4, X-ray irradiation (RAD) to the leg of one side, and combination (COMB) groups. Survival and treatment-related immune molecular changes were analyzed. Administration of P1C4 produced a tumor growth delay on day 30 in 18% of the mice. In contrast, combination therapy produced the strongest tumor growth inhibition not only at the irradiated tumor but also at unirradiated tumor in 67% of the mice. Accordingly, lung metastasis in the COMB group was strongly reduced by 98%, with a significant survival benefit. Unirradiated tumor in mice in the COMB group significantly recruited CD8 + tumor-infiltrating lymphocytes with a moderate reduction of Treg, producing a significant increase in the CD8/ Treg ratio. These results suggest that radiation enhances the efficacy of P1C4 treatment against distant metastasis as well as local control in osteosarcoma. Our data suggest that radiation therapy combined with dual checkpoint blockade may be a promising therapeutic option for osteosarcoma.

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

“…What can we do to make immune therapies effective in these tumors and patients? [77][78][79][80] Despite this preclinical evidence of immune checkpoint inhibitor activity, the response to these agents in clinical trials has been underwhelming. Background OS has been considered to be immunogenic and amenable to immune therapies since the early 19th century when William Coley, considered to be the "Father of Immunotherapy," observed responses after injecting patients with bone and soft tissue sarcomas with streptococcalderived toxins (ie, Coley's toxins).…”

“…75 Preclinical studies in immunocompetent mouse models suggest that blockade of immune checkpoint pathways alone or in combination with chemotherapy (trabectedin) or radiation can reduce both primary and metastatic tumor burden in bone and soft tissue sarcomas. [77][78][79][80] Despite this preclinical evidence of immune checkpoint inhibitor activity, the response to these agents in clinical trials has been underwhelming. In the SARC028 study, only 1 of the 22 patients with OS had an objective response to single agent pembrolizumab.…”

“…Efforts have been underway within the COG to develop clinical trials of immune checkpoint inhibitors in combination with chemoradiotherapy based on intriguing preliminary evidence suggesting that radiation might immunosensitize these tumors. 79 Other efforts to identify novel therapies that effectively modulate the immune response to OS, such as targeting IDO, B7-H3, or certain chemokines (eg, CXCL12) are also under consideration. If designed with the proper integrated correlative biology experiments, these trials could significantly enrich our understanding of the role of the immunity in this disease.…”

Animal Models in Microbeam Radiation Therapy: A Scoping Review

“…Similarly, superficial or cutaneous lesions, as well as those of the appendicular musculoskeletal system [96], would be ideal candidates for the first human trials of MRT. Therefore, future animal models for MRT research could include murine models of cutaneous T-cell lymphoma [97][98][99], locally recurrent breast cancer [100], soft-tissue sarcoma [101,102] and osteosarcoma [103][104][105]. These are diseases which can be highly radio-resistant and are often refractory to conventional radiotherapy.…”

Proteomic profiling and identification of significant markers from high-grade osteosarcoma after cryotherapy and irradiation

“…become a gold standard procedure for patients with sarcomas 6 . In order to eliminate the residual tumor cells from recycled autografts extracorporeal irradiation (ECIR) and cryotherapy/liquid nitrogen (LN)freezing are the two commonly used treatment methods employed in the biological reconstruction 7,8 . This technique can improve the regeneration of the bone, help to attain union and subsequent remodeling, and especially it restores limb function by supplying blood, osteogenic cells and proteins to the graft interface.…”