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Dissertation Defense: Novel Approaches in Pancreatic Cancer Treatment: Bridging Mechanics, Cells, and Immunity

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Jasmine Johnson

Dissertation Defense: Novel Approaches in Pancreatic Cancer Treatment: Bridging Mechanics, Cells, and Immunity


Khan Mohammad Imran

Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Allen Lab
Nov. 29, 2023 at 12 p.m.
In person: VA-MD College of Veterinary Medicine, Phase II, Classroom 125

About this Dissertation

The heterogeneity of pancreatic cancer renders many available general therapies ineffective holding the five-year survival rate close to 10% for decades. Surgical resection eligibility, resistance to chemotherapy and limited efficacy of immunotherapy emphasize the dire need for diverse and innovative treatments to combat this challenging disease. This study evaluates co-therapy strategies that combine non-thermal, minimally invasive ablation technology and targeted drug delivery to enhance treatment efficacy.

Our research begins by uncovering the multifaceted potential of Irreversible Electroporation (IRE), a cutting-edge non-thermal tumor ablation technique. This study demonstrates IRE-mediated ability to trigger programmed necrotic cell death, induce cell cycle arrest, and modulate immune cell populations within the tumor microenvironment. This transformation from a pro-tumor state to a proinflammatory milieu, enriched with cytotoxic T lymphocytes and neutrophils. IRE-induced proinflammation in the tumor site renders immunologically “cold” tumor into immunologically “hot” tumor and holds significant promise of improving treatment efficacy. Notably, IRE-treated mice exhibited an extended period of progression-free survival, implying clinical potential. The transient nature of these effects suggests potential mechanisms of tumor recurrence highlighting the need for further studies to maximize the efficacy of IRE. Our mechanistic studies evaluated the IFN-STAT1-PD-L1 feedback loop as a possible reason for pancreatic tumor recurrence. Our data also suggest a stronger IFN-PD-L1 feedback loop compared to mammary, osteosarcoma and glioblastoma tumors rendering pancreatic cancer immunologically “cold”.

This study also investigates the use of histotripsy (a non-thermal, noninvasive, nonionizing ultrasound-guided ablation modality) to treat pancreatic cancer utilizing a novel immunocompromised swine model. We successfully generated human orthotopic pancreatic tumors in the immune deficient pigs, which allowed for consequent investigation of clinical challenges presented by histotripsy. While rigorous clinical studies are indispensable for validation, the promise of histotripsy offers new hope for patients.

In parallel, we used our immunocompromised swine model of orthotopic pancreatic cancer to investigate the SonoTran system, which employs ultrasound-activated oscillating particles to enhance drug delivery within hard-to-reach tumors. Our study demonstrates that SonoTran significantly enhances the intratumoral penetrance of therapeutic agents, including commonly used chemotherapy drugs like paclitaxel and gemcitabine. Additionally, SonoTran improved delivery of the anti-epidermal growth factor (EGFR) monoclonal antibody, cetuximab- which is frequently used in cancer immunotherapy. Together, our findings address challenges in the delivery of a range of therapeutics while simultaneously exposing challenges like off-target damage.

In conclusion, this study presents a multifaceted approach to confront the complex characteristics of pancreatic cancer. Given the variations in patient response and the complexity of the disease, it is clear that a singular solution is unlikely. Our research, which combines IRE, histotripsy, and SonoTran, to interrogate a promising array of tools to tackle different challenges to provide tailored treatments. In the ever-evolving landscape of pancreatic cancer therapy, this research opens new avenues to investigate deeper into molecular mechanisms, co-therapy treatment options, future preclinical and clinical studies which eventually encourage the potential for improved patient outcomes.

More About the Candidate and Project


Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate

Soonchunhyang University, M.S., Medical Sciences

University of Dhaka-Bangladesh, B.S., M.S., Microbiology


Graduate Research Assistant, Allen Lab


Irving Coy Allen, MBA, Ph.D., Professor, Biomedical Sciences and Pathobiology

Committee Members


Imran KM, Gannon J, Morrison HA, Tupik JD, Tintera B, Nagai-Singer MA, Ivester H, Madanick JM, Hendricks-Wenger A, Uh K, Luyimbazi DT. Successful In Situ Targeting of Pancreatic Tumors in a Novel Orthotopic Porcine Model Using Histotripsy. Ultrasound in Medicine & Biology. 2023 Aug 16.

Imran KM, Ganguly A, Paul T, Powar M, Vlaisavljevich E, Cho CS, Allen IC. Magic bubbles: utilizing histotripsy to modulate the tumor microenvironment and improve systemic anti-tumor immune responses. International Journal of Hyperthermia. 2023 Dec 31;40(1):2244206.

Imran KM, Tintera B, Morrison HA, Tupik JD, Nagai-Singer MA, Ivester H, Council-Troche M, Edwards M, Coutermarsh-Ott S, Byron C, Clark-Deener S. Improved Therapeutic Delivery Targeting Clinically Relevant Orthotopic Human Pancreatic Tumors Engrafted in Immunocompromised Pigs Using Ultrasound-Induced Cavitation: A Pilot Study. Pharmaceutics. 2023 May 24;15(6):1585.

Imran KM, Nagai-Singer MA, Brock RM, Alinezhadbalalami N, Davalos RV, Allen IC. Exploration of Novel Pathways Underlying Irreversible Electroporation Induced Anti-Tumor Immunity in Pancreatic Cancer. Front Oncol. 2022 Mar 18;12:853779. doi: 10.3389/fonc.2022.853779. PMID: 35372046; PMCID: PMC8972192.

Hay AN, Imran KM#, Hendricks-Wenger A#, Gannon JM, Sereno J, Simon A, Lopez VA, Coutermarsh-Ott S, Vlaisavljevich E, Allen IC, Tuohy JL*. Ablative and immunostimulatory effects of histotripsy ablation in a murine osteosarcoma model. Biomedicines. Accepted 10/02/23.

Gannon J, Imran KM, Hendricks-Wenger A, Edwards M, Covell H, Ruger L, Singh N, Nagai-Singer M, Tintera B, Eden K, Mendiratta-Lala M. Ultrasound-guided noninvasive pancreas ablation using histotripsy: feasibility study in an in vivo porcine model. International Journal of Hyperthermia. 2023 Dec 31;40(1):2247187.

Alinezhadbalalami N, Graybill PM, Imran KM, Verbridge SS, Allen IC, Davalos RV. Generation of Tumor-activated T cells Using Electroporation. Bioelectrochemistry. 2021 Dec;142:107886. doi: 10.1016/j.bioelechem.2021.107886. Epub 2021 Jul 13. PMID: 34303065; PMCID: PMC8504467.

Nagai-Singer, M.A., Woolls, M.K., Leedy, K., Hendricks-Wenger, A., Brock, R.M., Coutermarsh-Ott, S., Paul, T., Morrison, H.A., Imran, K.M., Tupik, J.D. and Fletcher, E.J., 2023. Cellular Context Dictates the Suppression or Augmentation of Triple-Negative Mammary Tumor Metastasis by NLRX1. The Journal of Immunology.