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E - Disease Models and Clinical Applications -> Cancer – Oncolytic Viruses

Replication Competent Adenovirus-mediated cytotoxic and Interleukin-12 Gene Therapy in Stage IV Pancreatic Cancer: 36 Month Follow-Up Data from a Phase I Clinical Trial

Type: Oral Abstract Session

Presentation Details
Session Title: Late-Breaking Abstracts II
Location: Ballroom C
Start Time: 5/18/2022 8:15
End Time: 5/18/2022 8:30

Introduction: Pancreatic cancer (PC) is the fourth leading cause of death from cancer in the United States. Metastatic PC (mPC) has a median survival of less than 9 months. The tumor immune microenvironment (TIME) of mPC is marked by an immunosuppressive network which contributes to immunotherapy resistance. There is an urgent clinical need to develop novel therapeutic approaches that improve survival for mPC patients. We conducted a phase I clinical trial in mPC using replication-competent (RC) Ad5-yCD/mutTKSR39rep-hIL12 adenovirus in combination with chemotherapy. The primary endpoints of this dose escalation study were maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) at Day 21, secondary endpoint was rates of grade 3 CTCAE and exploratory endpoints were viral distribution, level of immunological cytokines and clinical outcomes. Overall survival was not a study end point. Method: This was a single site, nonrandomized, dose-escalation phase 1 trial of a replication competent adenovirus harboring two suicide genes (HSV-TK, yCD) and an IL-12 expression cassette for treatment of metastatic pancreatic cancer patients (men and women older than 18 yrs). Patients were enrolled between October 2017 and May 2019. Each subject received a single endoscopic ultrasound guided intratumoral injection of the IL-12 adenovirus. The three patient cohorts received either 1X1011 virus particles, vp (N=3), 3X1011 vp (N=3) or 1X1012 vp (N=6). Two days later, subjects were administered 7 days of 5-fluorocytosine (150 mg/kg/day, orally) prodrug therapy. Fourteen days after completion of the 5-FC prodrug therapy course, subjects initiated chemotherapy at the discretion of the treating physician. Toxicity, viral load, immunological cytokines, and immune cell activation was measured up to day 21. Overall survival analysis was conducted on March 9th, 2022. One patient is still alive 35.7 months after adenoviral injection and chemotherapy. Results and conclusion: This trial demonstrated that Ad5-yCD/mutTKSR39rep-hIL12 adenovirus was safe and well tolerated by mPC patients. Moreover, intratumoral injection of this virus showed viral load in several patients for up to 2 weeks post-injection, led to increased serum cytokines (IL12, IFNγ, and CXCL10), and increased CD4+, CD8+ T-cells indicative of immune system activation. MTD was not reached in the study. Additionally, this non-randomized, phase I trial demonstrated that higher doses (1X1012 vp, cohort 3) of the Ad5-yCD/mutTKSR39rep-hIL12 gene therapy virus provided a clinically meaningful median OS benefit of 18.4 months (Figure 1) compared with 4.2 months for patients receiving low doses (1X1011 and 3X1011vp, cohorts 1 and 2) of the adenovirus. Log-rank (Mantel-Cox) test P values were 0.01 while Logrank test for trend were 0.009 (Figure 1). To our knowledge this is the first phase-1 trial which indicated median OS ~18 months for mPC patients. Our future plans include conducting a Phase II trial in the same patient population to establish efficacy of this therapeutic approach.



Shyam Nyati1, Farzan Siddiqui1, Kenneth Barton1, Robert Pompa2, Svend O. Freytag1, Gazala Khan3, Irina Dobrosotskaya3, Munther Ajlouni1, Yingshu Zhang1, Jingfang Cheng1, Stephen Brown1, Benjamin Movsas1, David Kwon4

1Radiation Oncology, Henry Ford Health System, Detroit, MI,2Gastroenterology, Henry Ford Health System, Detroit, MI,3Oncology, Henry Ford Health System, Detroit, MI,4Henry Ford Pancreatic Cancer Center, Henry Ford Health System, Detroit, MI
 S. Nyati: None.

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