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Exploring optimal sequencing of radiation and immunotherapy combinations.

ABSTRACT: Purpose:The purpose of this article is to assemble, review, and provide a synopsis of the historical and current literature regarding optimal sequencing of radiation (RT) and immunotherapy combination treatments. Materials and methods:A review of the literature was performed using PubMed with the query "radiation" and "Immunotherapy", "PD1", "PDL1", "CTLA4", "OX40", "checkpoint", "vaccine", "macrophage", "STING", and "TGFbeta". Studies that included sequencing of therapy were evaluated and the studies were included at the authors discretion. Results:A paucity of primary literature exists examining the best order of radiation and immunotherapy, most of which was performed in the pre-clinical setting. The observations are that optimal sequencing of various radiation plus immune therapy combinations is dependent on the mechanism(s) of activation by the combination treatment. Immunosuppressive molecules tend to be better inhibited prior to RT while engagement of costimulatory genes is better activated concomitantly with RT. Conclusions:These data should compel more basic research into both the direct investigation of sequencing efficacy and studies on the mechanisms of immune mediated cell death potentiated by radio-therapy.

SUBMITTER: Gunderson AJ

PROVIDER: S-EPMC6200887 | biostudies-literature | 2018 Oct-Dec

REPOSITORIES: biostudies-literature

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Exploring optimal sequencing of radiation and immunotherapy combinations.

Gunderson Andrew J AJ Young Kristina H KH

Advances in radiation oncology 20181023 4

<h4>Purpose</h4>The purpose of this article is to assemble, review, and provide a synopsis of the historical and current literature regarding optimal sequencing of radiation (RT) and immunotherapy combination treatments.<h4>Materials and methods</h4>A review of the literature was performed using PubMed with the query "radiation" and "Immunotherapy", "PD1", "PDL1", "CTLA4", "OX40", "checkpoint", "vaccine", "macrophage", "STING", and "TGFbeta". Studies that included sequencing of therapy were eval ...[more]

PMID: 30370348

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Project description:The FITExP profiling approach was used to identify protein hits from cells incubated with RAPTA-T or RAPTA-EA. Validation experiments with paclitaxel and cisplatin underlined the reliability of the method and hit lists for both test compounds (and?) gave physiologically viable anti-cancer mechanisms. The hit proteins for paclitaxel match with those published and the ones obtained for cisplatin were related to DNA repair, which is in line with the principal mechanism of cisplatin cytotoxicity involving the formation of nuclear DNA lesions. RAPTA-T treatment leads to upregulation of multiple hits suggesting a broad mechanism of action involving both metastasis and tumorigenicity. In contrast, hit proteins identified after incubation with RAPTA-EA are linked to regulation of the oxidative stress response and are therefore thought to be conferred by the EA moiety in the drug. From a therapeutic standpoint, RAPTA-EA could be explored in cancers where EA alone has shown potency, such as chronic lymphocytic leukemias,91 or where EA combined with another agent shows synergy, such as the combination of EA with afatinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitors for breast cancers.92 On the other hand, due to its broad mechanism of action, RAPTA-T could potentially be more useful if used concomitantly with drugs that target specific cancer pathways and could also play a role in therapies for later stage cancers due to its anti-metastatic properties. Here, application of the FITExP allowed us to gauge the mechanistic pathways involved in the action of two novel ruthenium(II) metallodrugs with very different phenotypic characteristics and from this knowledge infer their role in therapy. Potentially, future application of the FITExP approach in this manner could be useful for identification of cancer chemotherapy drug combinations, where commonly cancer clinical trials fail at phase II where drug combinations are first tried and tested.

Dataset Information

Exploring optimal sequencing of radiation and immunotherapy combinations.

Publications

Exploring optimal sequencing of radiation and immunotherapy combinations.

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