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Colorectal

Colorectal Parallel Session

24: Phase 1b Randomized Controlled Trial of Perioperative Tadalafil and Influenza Vaccination in Cancer Patients Undergoing Major Surgical Resection of a Primary Abdominal Malignancy (PERIOP-04)

Friday, March 22, 2024
11:12am – 11:22am ET
Location: C101
Disclosure(s):
Rebecca C. Auer, MD, MSc, FRCSC, FACS: Enhanced Medical Nutrition: Research Grant (Terminated); Incyte: Consultant (Ongoing), Research Grant (Ongoing); Leo Pharma Inc.: Research Grant (Terminated); NK Gen: Research Grant (Ongoing); Qu Biologics: Contracted Research (Ongoing)
Introduction: Natural Killer (NK) cells kill malignant cells and prevent cancer metastases. We have previously demonstrated that abdominal surgery results in expansion of surgery-induced Myeloid Derived Suppressor Cells (sx-MDSC) that directly inhibit NK cell function, leading to metastatic recurrence. This effect is attenuated with perioperative administration of PDE-5 inhibitors, such as tadalafil, which reverses suppressive activity of sx-MDSCs, in combination with the influenza vaccine, a non-specific activator of NK cells. In this Phase Ib open label RCT we investigated the safety and efficacy of this combined regimen to prevent the immunosuppressive effects of surgery on NK cell function.


Methods: Participants were randomized to standard of care (SOC, n=11) or intervention (tadalafil daily for 5 days pre- and 10 days postoperatively and an influenza vaccine immediately prior to surgery, n=13). Safety was assessed with the NCI Common Terminology Criteria for Adverse Events toxicity criteria and Clavien Dindo classification. Peripheral blood samples were taken at baseline, day of surgery (POD0) and postoperative day (POD) 1, 3, 10 and 35. The primary endpoint was change in NK cytotoxicity (NKC) from POD0 to POD1. Secondary endpoints included NK IFNγ secretion, NK markers of activation (DNAM1, NKG2D), and sx-MDSC suppression. Statistical comparisons were conducted on SAS® using t-test or Mann-Whitney test.


Results: Compliance in the intervention arm was 95%. There were no serious adverse events (SAEs) related to intervention and postoperative AEs were < grade 2 and similar in both arms.  In the SOC arm, NKC was significantly reduced by 45% on POD1 (p=0.01), with 10/11 patients having lower NKC on POD1 vs. POD0. In contrast, NKC in the intervention arm was only reduced by 22% (p=NS) and 4/13 patients had higher NKC on POD1 vs. POD0. NK cell IFNγ secretion was below the limit of detection in all patients on POD1 but was higher on POD3 in the intervention arm (256pg/mL) compared to the SOC arm (60pg/mL, p=0.2) but this did not reach statistical significance. There was no significant change in NK cell proportions or activation markers between the two arms. The intervention regimen did not affect suppression by sx-MDSC on POD1, as measured in a NK cell cytotoxicity assay co-cultured with sx-MDSCs.


Conclusions: Perioperative tadalafil and influenza vaccination was well tolerated and improved NK cell function, without a measurable reduction in sx-MDSC suppressive activity. 

Learning Objectives:

  • define the effects of major surgery on NK cell function.
  • describe the tolerability of a combination immunotherapy with influenza vaccination and a PDE-5 inhibitor and the effect on postoperative complications.
  • describe the impact of a combination immunotherapy with influenza vaccination and a PDE-5 inhibitor in preventing postoperative NK cell dysfunction.