Abstract 3577: First-in-human phase I study of intraperitoneally administered interferon-activated autologous monocytes in platinum-resistant ovarian cancer
Authors: Cole Christopher B. , Green Daniel S. , Ning Franklin , Zoon Kathryn , Rosen Lindsey B. , Holland Steven M. , Annunziata Christina M. 
Published: June 2022

Abstract
Background: Ovarian cancer is the most lethal gynecologic cancer and is intrinsically resistant to immunotherapies. Previous work has demonstrated superior response rates with intraperitoneally (IP) directed therapies, providing the rationale for IP immunotherapy.
Methods: A previously published model system in which OVCAR ovarian cancer spheroids are killed by IFN-activated human monocytes was further characterized using confocal microscopy, global gene expression analysis, flow cytometry, and knockout/knockdown of key genes in the TRAIL-DR4/DR5 pathway. These results were translated into a phase I dose escalation trial in which 3-6 patients with platinum-resistant or refractory ovarian cancer were enrolled into 4 cohorts and treated IP q28 days with Peginterferon alfa-2b (25-250 mcg) and Interferon gamma-1b (5-50 mcg), with or without autologous monocytes (75-750 x 106 cells), in order to determine the recommended phase II dose (RP2D).
Results: Confocal microscopy of IFN-activated monocytes demonstrated migration into OVCAR spheroids and destruction of the spheroids and global gene expression analysis identified TRAIL as a ligand on monocytes upregulated by IFN treatment. Disruption of TRAIL receptors DR4/DR5 or deletion of CASPASE8 on OVCAR cells largely abrogated killing. IFN-activated human monocytes were able to kill IP-injected OVCAR tumor cells in a mouse xenograft model, and IFN-activated monocytes from ovarian cancer patients were able to kill OVCAR spheroids as effectively as those from healthy donors. 18 patients were subsequently enrolled on a phase I trial (median age, 61 years; median 5 prior therapies). 1 of 3 patients at the second dose level experienced a dose-limiting toxicity (grade 3 anemia) and no subsequent DLTs were observed. The RP2D was defined as 250mcg IFNa/50mcg IFNg/750 x 106 cells. The only treatment-related grade 3 or higher adverse events occurring in more than one patient were lymphocyte decrease (33.3%) and abdominal pain (11.1%). The best response observed was partial response (PR) in 2/9 RECIST-evaluable patients, and 1 additional patient had a CA-125 response with &gt;50% reduction. 4/9 patients had stable disease. Four patients were able to receive 5+ cycles (range 1-10 cycles). Biomarker analyses demonstrated that these long-term responders had a lower level of T-regulatory cells at baseline, but exhibited marked increase in myeloid derived suppressor cells (MDSC) at the time of tumor progression.
Conclusion: These findings characterize the mechanism of a novel cellular immunotherapy for ovarian cancer which is well tolerated with evidence of clinical activity in a heavily pretreated patient population. This therapy may serve as the backbone for a combination immunotherapy regimen incorporating additional agents targeting T-regulatory cells and/or MDSCs.
Citation Format: Christopher B. Cole, Daniel S. Green, Franklin Ning, Kathryn Zoon, Lindsey B. Rosen, Steven M. Holland, Christina M. Annunziata. First-in-human phase I study of intraperitoneally administered interferon-activated autologous monocytes in platinum-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3577.