Editors' ChoiceCancer

When instability is a good thing

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Science Translational Medicine  17 Jun 2015:
Vol. 7, Issue 292, pp. 292ec100
DOI: 10.1126/scitranslmed.aac7154

Among the tumor types found to be most responsive to PD-1 blockade are tumors rich in somatic mutations as a result of exposure to environmental mutagens, such as melanoma and lung cancer. The peptides derived from proteins encoded by mutated genes serve as effective cancer rejection antigens; these neoantigens circumvent central T cell tolerance and are more efficiently recognized by the immune system. Therefore, one would expect that tumors with higher mutation rates would have more neoantigen formation and hence would be more sensitive to immunotherapy.

Tumors with mutations in mismatch repair genes also have elevated mutation rates. As a proof of concept, Le et al. conducted a phase 2 clinical trial in 41 patients with and without mismatch deficient tumors who were treated with the anti–PD-1 antibody pembrolizumab. None of the patients with mismatch repair–proficient colorectal cancers (CRC) had an objective response to therapy; in contrast, the disease control rate in mismatch repair–deficient tumors was 90% (9 of 10 patients) in CRC and 71% (5 of 7 patients) in non-CRC patients. Further, the authors applied tumor somatic exome sequencing data combined with each patient’s major histocompatibility complex (MHC) class I HLA haplotype to an epitope prediction algorithm. A higher number of potential mutation-associated neoantigens was identified from mismatch repair–deficient versus proficient tumors (mean 578 versus 21 neoantigens) and this was associated with a longer progression-free survival and a greater density of CD8+ lymphoid infiltrates, especially at invasive tumor fronts.

Anti–PD-1 therapies rely on the ability of activated CD8 T cells to recognize cancer cells; it is therefore quite plausible that the subset of patients who are more likely to respond have a reactive endogenous T cell compartment and that neoantigens contribute to this reactivity. Immune checkpoint inhibitors are promising drugs, but their benefit is restricted to certain patient populations. Future interventions to boost neoantigen-specific T cell reactivity may increase the range of human cancers that respond to these immunotherapeutic agents.

D. T. Le et al., PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 10.1056/NEJMoa1500596 (2015). [Abstract]

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