Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other Than Abscopal Effect: A Systematic Review

Vito Longo, Oronzo Brunetti, Amalia Azzariti, Domenico Galetta, Patrizia Nardulli, Francesco Leonetti, Nicola Silvestris, Vito Longo, Oronzo Brunetti, Amalia Azzariti, Domenico Galetta, Patrizia Nardulli, Francesco Leonetti, Nicola Silvestris

Abstract

Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitourinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response such as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a higher expression of immune checkpoint molecules, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors in order to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve the response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitory receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.

Keywords: angiogenesis; chemotherapy; immune checkpoint inhibitors; tyrosine kinase inhibitors.

Conflict of interest statement

The Authors declare no conflicts of interests.

Figures

Figure 1
Figure 1
Research strategy with PRISMA flow diagram.
Figure 2
Figure 2
Summarizes the mechanisms implicated in improving the efficacy of immune checkpoint inhibitors (ICIs): The influence of microbiota on dendritic cell (DC) maturation and activation; the correct trafficking of T cells to the tumor bed due to the normalization of endothelium by anti-angiogenic drugs and the VEGF immunosuppressive activity; the impact of chemotherapy on immunosuppressive cells and on DC maturation; release of damaged molecular patterns after oncolytic viruses induce tumor cell lysis.
Figure 3
Figure 3
Summary of the mechanisms involved in improving of ICI efficacy by oncolytic viruses: Release of damage-associated molecular patterns after tumor cell lysis, transfer of genes encoding INF-α, GM-CSF and others cytokines, DC maturation and activation, natural killer (NK) cell activation, and increase in PD-L1 expression. The main studies evaluating the combination of oncolytic viruses are also reported.

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