Susceptibility of BRCA associated PDAC to immunotherapy strategies

Chani Stossel ^1,2,4 Dikla Atias ¹ Yulia Glick-Gorman ¹ Maria Raitses-Gurevich ¹ Sharon Halperin ¹ Michael Schvimer ³ Gal Markel ^2,4 Rob Denroche D ⁵ Steven Gallinger ^5,6 Raanan Berger ^1,2 Talia Golan ^1,2

¹Oncology Institute, Sheba Medical Center, Sheba Pancreatic Translational Lab, Israel
²Sackler Faculty of Medicine, Sackler Faculty of Medicine, Israel
³Pathology Department, Sheba Medical Center, Pathology Department, Israel
⁴Sheba Medical Center, Ella Lemelbaum Institute for Immuno-Oncology, Israel
⁵Ontario Institute for Cancer Research, Ontario Institute for Cancer Research, Canada
⁶Department of Surgery, University Health Network, Canada

Pancreatic-ductal-adenocarcinoma (PDAC) is a lethal malignancy. Germline-BRCA1/2 mutation carriers are the most well-defined DNA-damage-repair (DDR) deficient subgroup and present up-to ~15% of PDAC. Immunotherapy strategies have not shown significant clinical benefit in PDAC. DDR-deficient PDAC features increased mutational burden. Compared to the general PDAC population, BRCA1/BRCA2-mutated cases have higher incidence of PD-1/PD-L1 expression. We hypothesize that immuno-modulating strategies may have therapeutic value in BRCAmut PDAC, due-to the higher, neo-antigen-encoding mutational burden.

We developed unique patient-derived-xenograft (PDX) models from metastatic PDAC patients(n=64), resembling the morphologic and genomic characteristics of primary-PDAC(Golan,Oncotarget,2017). Seventeen PDX models were established from germline-BRCA-mutated patients obtained before treatment and at progression. Correlation between disease course at tissue acquisition and response to treatment was demonstrated in-vivo (Golan,IJC, 2018).

Sub-lethal irradiated 3-4week-old NSG mice were transplanted with CD34+ cells purified from umbilical–cord-blood. Peripheral hCD45 was detected from week 12. On week 18, cryopreserved tumor chunks from a germline-BRCA2-PDAC patient with high mutational and neoantigene load was subcutaneously transplanted to mice and thereafter treated with pembrolizumab(10mg/kg;q3-4) for 5-weeks(n=5-6/group). Weight and tumor volume were measured bi-weekly. Peripheral-blood was obtained every ~2-3-weeks. Decreased tumor growth rate was observed in the hCD45-engrafted pembrolizumab treated mice compared to hCD45-engrafted control treated mice, with one mice demonstrating complete response. hCD45,CD19,CD3,CD4 and CD8 cells were detected in splenocytes,bone-marrow and blood of engrafted mice. IHC-analysis with HLA/CD45/CD3/CD4 and CD8 demonstrated tumor-T-cells infiltration. A trend of correlation between hCD45-engraftment and tumor-growth inhibition was observed.

DDR-deficient PDAC patients may benefit from checkpoint-inhibition.