Acquired resistance to immunotherapy in MMR-D pancreatic cancer

Abstract

BackgroundMMR-D pancreatic cancer have been reported to respond to checkpoint inhibitor therapy. Here, we report the first case of acquired resistance to immunotherapy in MMR-D pancreatic cancer.Case presentationA 45-year-old woman with unresectable MMR-D pancreatic cancer was initially treated with FOLFIRINOX, FOLFIRI, and stereotactic body radiation with stable disease burden. After 3 months, imaging showed progression of disease with an increase in CA19-9. She was subsequently enrolled in a clinical trial of an anti-PD-L1 antibody in combination with an IDO1 inhibitor. She demonstrated a partial response to therapy by RECIST 1.1 criteria with declining tumor markers. Twenty-two months after beginning immunotherapy, imaging revealed an increasing left ovarian cystic mass. There were no other sites of progressive disease. The patient underwent a total hysterectomy and bilateral salpingo-oophorectomy, appendectomy, omentectomy and pelvic lymphadenopathy. Pathology was consistent with a metastasis from the pancreas involving the endometrium and left ovary. Thereafter, the patient continued with PD-1 blockade therapy off protocol with no further progressive disease. Immune profiling showed high levels of CD8+ T cells and PD-1 positive immune cells infiltrating the tumor, with a moderate level of PD-L1 expression in both the immune cells and the tumor cells. Next generation sequencing found only the KRAS G12D and RNF43 G659Vfs*41 mutations were retained from the pre-treatment tumor in the treatment-resistant tumor.ConclusionsThis is the first report describing acquired resistance to immunotherapy in MMR-D pancreatic cancer with accompanying genomic and immune profiling. This case of oligoprogression in the setting of immunotherapy demonstrates the feasibility of localized treatment followed by continuation of immunotherapy to sustain ongoing response.

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

“…In a clinical trial of recurrent or metastatic colorectal cancer (CRC), patients with high MMR/MSI had better responses to immune checkpoint blockade [27]. MMR-D induction can reverse immunotherapy resistance in patients with pancreatic ductal adenocarcinoma [28]. The difference in MSI and the mutation load caused by MMR-D may explain differences in immunotherapy response.…”

Combination PD-1 and PD-L1 Blockade Promotes Durable Neoantigen-Specific T Cell-Mediated Immunity in Pancreatic Ductal Adenocarcinoma

“…A minor fraction (<1%) of PDA patients have abnormally high tumor mutational load because of defects in mismatch-repair genes (Hu et al, 2018b). Although few patients have been treated, a subset of these patients (five of eight) exhibited a clinical response following PD-1 blockade, yet most responses were transient, consistent with acquired resistance (Hu et al, 2018a(Hu et al, , 2018b.…”

Anti-PD1 therapy induces lymphocyte-derived exosomal miRNA-4315 release inhibiting Bim-mediated apoptosis of tumor cells

“…Anti-PD1 therapy is, to date, one of the most effective anticancer immunotherapies. Despite this success, a significant number of patients develop, or will develop, resistance to this therapy [2][3][4][5] . Innate resistance to anti-PD1 therapy is found in 60% of melanoma patients 6 , and 25% develop resistance after an initial phase of objective response 7 .…”

“…2 Equipe Apoptose et Progression Tumorale, LaBCT, Institut de Cancérologie de l'Ouest, Saint Herblain, France. 3 Cancéropole Grand-Ouest, Réseau Niches et Epigénétique des Tumeurs (NET), Saint Herblain, France. 4 EpiSAVMEN Network (Région Pays de la Loire), Saint Herblain, France.…”