PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon

Abstract

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and sensitize tumors to checkpoint blockade immunotherapy. However, many POLE mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we. prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with specific single base substitution signature, high T-cell infiltrates, and high response rate to anti-PD1 monotherapy. This study illustrates how specific DNA repair defects can sensitize to immunotherapy, POLE proofreading deficiency representing a novel tumor agnostic biomarker for response to PD-1 checkpoint blockade therapy.

Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability

“…Following a few pioneer case reports [ 55 ], the biological hypothesis that, in POLE -mutated tumors, the accumulation of mutations caused by replicative errors leads to high TMB and ultimately could result in sensitivity to ICIs, was confirmed by the promising activity of PD-1 blockade in a small cohort of pre-treated patients with MSS/pMMR advanced tumors harboring selective POLE pathogenic mutations in the DNA-binding or catalytic site of the exonuclease domain [ 56 ].…”

Interplay between the DNA Damage Response and Immunotherapy Response in Cancer

“…Consistent with these observations, HRD was found to be a superior biomarker of response in a study conducted on patients enrolled in a phase I/II trial of niraparib and pembrolizumab in ovarian cancer [ 122 ]. More recently, loss-of-function mutations in the DNA binding or exonuclease domains on polymerase epsilon, associated with hypermutated tumors and increased TMB, have also been reported to respond well to anti-PD-(L)1 therapies [ 123 ].…”

Cancérogenèse et variants faux sens pathogènes du domaine exonucléasique des ADN polymérases ε et δ

“…Ainsi, les variants pathogènes de POLE pourraient être un biomarqueur de la réponse aux immunothérapies. C'est ce que montre la récente publication des résultats d'un premier essai clinique prospectif utilisant une immu-nothérapie anti-PD1 chez des patients ayant des tumeurs avec mutation de POLE, à un stade avancé [11]. Un bénéfice thérapeutique a été constaté chez les patients porteurs d'un variant pathogène du domaine exonucléase de POLE, mais pas chez ceux qui avaient d'autres types de variants (variants du domaine exonucléase n'affectant pas l'activité correctrice de l'enzyme ou variants localisés hors de ce domaine protéique).…”