Tumors With High Levels of Microsatellite Instability Responded Well to Treatment With PD-1 Inhibitors

A new study has provided further information on whether certain patients are likely to benefit from anti–PD-1 immunotherapy, suggesting that the level of microsatellite instability (MSI) and subsequent insertion/deletion mutations (indels) may be a crucial predictor of response.¹

The new research used 2 mouse cancer cell lines, B16F10 (melanoma) and CT26 (colon cancer). Using CRISPR-Cas9, they knocked out MSH2, 1 of 4 key DNA mismatch repair (MMR) genes commonly mutated in MMR-deficient cancers. The MMR-deficient cell lines, along with their parental, MMR-proficient cell lines were then cultured over 1 month and 4 months to produce MSI-intermediate and MSI-high cell lines, respectively. The parental cell lines were cocultured for similar periods of time and termed MSI-stable. Both MMR-deficient cell lines had an increased number of mutations generally and indel coding mutations, characteristic of MSI tumors.

Both the modified MMR-deficient and parental MMR-proficient cell lines were engrafted into mice and then treated with antibodies against PD-1. Anti–PD-1 treated mice showed a small, statistically significant effect in reducing melanoma tumor volume in the parental MSI-stable and MSI-intermediate engrafted mice, 24 days postimplantation.

For mice injected with MSI-stable or MSI-intermediate colon cancer cells, there was no effect on the tumor. However, in both sets of mice engrafted with the high-MSI cells, the anti–PD-1 antibody had a substantial, significant effect in reducing tumor volume, accompanied by a substantial increase in T-cell tumor infiltration.