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Combinatorial Approaches With Checkpoint Inhibitors to Enhance Anti-tumor Immunity.

ABSTRACT: Treatment of cancer patients has been recently revolutionized by the application of various immunotherapeutics. However, the response rates are still limited ranging between approximately 20 and 40% suggesting that combinations of immunotherapy with conventional treatment, like chemotherapy, radiation, epigenetic modulators, targeted therapies using small molecules as well as other (immuno) therapeutics, might be an option to increase systemic anti-tumor immunity. It is postulated that different non-immune based therapies in combination with immunotherapies could reprogram the immune suppressive tumor microenvironment and enhance the immunogenicity of tumor cells leading to an improved therapeutic efficacy and a better patients' outcome. Despite there exist various examples of increased objective responses achieved by adding these different therapies to immunotherapies, strategies for rational and evidence-based design of checkpoint inhibitor combinations to maximize the clinical benefit for patients are urgently required. Therefore, the main purpose of this review is to summarize recent results obtained from experimental models and clinical trials to enhance tumor immunogenicity by combining immunotherapy with other therapeutic options to maximize patients' outcome and minimize adverse events.

SUBMITTER: Seliger B

PROVIDER: S-EPMC6538766 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Combinatorial Approaches With Checkpoint Inhibitors to Enhance Anti-tumor Immunity.

Seliger Barbara B

Frontiers in immunology 20190522

Treatment of cancer patients has been recently revolutionized by the application of various immunotherapeutics. However, the response rates are still limited ranging between approximately 20 and 40% suggesting that combinations of immunotherapy with conventional treatment, like chemotherapy, radiation, epigenetic modulators, targeted therapies using small molecules as well as other (immuno) therapeutics, might be an option to increase systemic anti-tumor immunity. It is postulated that different ...[more]

PMID: 31178856

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Project description:BackgroundTumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity.MethodsMultiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens.ResultsWhile genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient.ConclusionsThis comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

Dataset Information

Combinatorial Approaches With Checkpoint Inhibitors to Enhance Anti-tumor Immunity.

Publications

Combinatorial Approaches With Checkpoint Inhibitors to Enhance Anti-tumor Immunity.

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