Checkpoint Inhibition Failure

Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy

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 Genomic defects in the interferon pathway genes reduce the chance of response to immune…

UCLA study finds why some cancers stop responding to immunotherapy

Researchers have for the first time identified mechanisms that enable advanced melanoma to become resistant to a new class of drugs, known as…|By Deena Beasley

Figure 1.
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Better understanding of the steps in the immune response to specific tumour cells will allow for smarter (less trial-&-error), more effective and more individualised combination immunotherapy.

For example, combination of checkpoint inhibitors similarly involved in T-cell activation and survival (eg anti-CTLA4 with anti-PD-1) may give rise to more autoimmune toxicity without a commensurate augmentation in tumour kill. More illogical (and redundant) will be to combine inhibitors targeting the same checkpoint ligation (eg anti-PD-1 with anti-PD-L1).

Instead, combining a checkpoint inhibitor involved in cytotoxic/helper T-cell activation with checkpoint inhibitor involved in regulatory T-cell activation, or with dendritic cell antigen presentation, should be more synergistic. And combining “weaker” checkpoint inhibitors like anti-PD-L1 with anti-TIGIT may deliver better safety without compromising response and survival.