E195: Irreversible Electroporation in Combination with Adjuvant PD-1 Versus TIGIT Checkpoint Inhibition in an Orthotopic Pancreatic Cancer Model

ePoster Abstract Author(s)

Jorge R. de la Torre Medina, MD

Resident Physician
UC San Diego
San Diego, California, United States

Submitter(s)

Jorge R. de la Torre Medina, MD

Resident Physician
UC San Diego
San Diego, California, United States

Author(s)

Jorge R. de la Torre Medina, MD

Resident Physician
UC San Diego
San Diego, California, United States
RW

Rebekah White, MD

Professor Surgery
UC San Diego, United States
UJ

Utsav Joshi, PhD

Post-Doctoral Fellow
UC San Diego, United States
KN

Kim Nguyen-Ta, MD

Resident Physician
UC San Diego, United States
JS

Jaynath Shankara Narayanan, PhD

Post-Doctoral Fellow
UC San Diego, United States

Introduction: Immune checkpoint inhibitors have shown promising results against a great variety of solid tumors. Unfortunately, results utilizing these agents in pancreatic adenocarcinoma (PDAC) have been disappointing. Irreversible electroporation (IRE) is a non-thermal form of tumor ablation in clinical use for locally advanced PDAC. We have previously shown that IRE can induce systemic immune responses in murine PDAC models. We hypothesized that combination of IRE with checkpoint inhibition would have synergistic effects. In this study, we specifically compared two different checkpoint inhibitors (anti-PD-1 & anti-TIGIT antibodies) as adjuvant therapy following IRE in an orthotopic PDAC model that consistently produces liver metastases.

Methods: All studies utilized a murine PDAC organoid line (KPC46) derived from a liver metastasis in a genetically engineered (KPC) mouse model. Tumors were implanted orthotopically into the tail of the pancreas in syngeneic, immunocompetent mice. Following tumor implantation, mice were surveilled by ultrasound until tumors reached 7 mm in diameter, then randomized to one of three treatment groups: IRE + vehicle control (n=5), IRE + anti-TIGIT (n=6) or IRE + anti-PD-1 (n=5). IRE treatment consisted of 150 x 500 microsecond pulses at 1500 V/cm using tweezer-style electrodes. Treatment with anti-TIGIT and anti-PD-1 was provided with 100 micrograms every 48 hours for 2 weeks starting day 1 post-procedure. Mice were allowed to survive until they met humane endpoints requiring euthanasia. Complete response was defined as 2 months of observation without evidence of disease.

Results: We observed a trend toward improved survival in the IRE + anti-TIGIT group (median 4.3 weeks, Figure). Median survival in the IRE + anti-PD-1 group (3.4 weeks) was slightly but not significantly worse than IRE alone (4 weeks). There was one complete response (1/6, 17%) in the IRE + anti-TIGIT group.

Conclusions: In this pilot study, we combined IRE with two clinically relevant checkpoint inhibitors. Consistent with prior studies in humans, we observed no benefit with anti-PD-1 therapy. In contrast, the addition of anti-TIGIT therapy to IRE was associated with a trend toward increased survival and one complete response to therapy, even in this highly aggressive model. Further experiments are ongoing to explore the possible synergism of IRE and anti-TIGIT therapy.

Learning Objectives:

Understand the role of irreversible electroporation in solid tumors
Combination of IRE with immunotherapeutic agents may provide benefit in solid tumors
Orthotopic implantation murine models for pancreatic cancer offer a feasible way to explore treatments.