A Phase 1 trial of autologous monocytes stimulated ex vivo with Sylatron® (Peginterferon alfa-2b) and Actimmune® (Interferon gamma-1b) for intra-peritoneal administration in recurrent ovarian cancer

Abstract

Background: Ovarian cancer has no definitive second line therapeutic options, and largely recurs in the peritoneal cavity. Locoregional immune therapy using both interferons and monocytes can be used as a novel approach. Interferons have both cytostatic and cytotoxic properties, while monocytes stimulated with interferons have potent cytotoxic properties. Due to the highly immune suppressive properties of ovarian cancer, ex vivo stimulation of autologous patient monocytes with interferons and infusion of all three agents intraperitoneally (IP) can provide a strong pro-inflammatory environment at the site of disease to kill malignant cells.

Methods: Patient monocytes are isolated through counterflow elutriation and stimulated ex vivo with interferons and infused IP through a semi-permanent catheter. We have designed a standard 3 + 3 dose escalation study to explore the highest tolerated dose of interferons and monocytes infused IP in patients with chemotherapy resistant ovarian cancer. Secondary outcome measurements of changes in the peripheral blood immune compartment and plasma cytokines will be studied for correlations of response.

Discussion: We have developed a novel immunotherapy focused on the innate immune system for the treatment of ovarian cancer. We have combined the use of autologous monocytes and interferons alpha and gamma for local-regional administration directly into the peritoneal cavity. This therapy is highly unique in that it is the first study of its type using only components of the innate immune system for the locoregional delivery consisting of autologous monocytes and dual interferons alpha and gamma. Trial Registration ClinicalTrials.gov Identifier: NCT02948426, registered on October 28, 2016. https://clinicaltrials.gov/ct2/show/NCT02948426.

Keywords: Cellular therapy; Immunotherapy; Interferons; Intraperitoneal; Monocytes; Ovarian cancer.

Fig. 1

Diagram of treatment. Prior to the start of the trial patients will have an implantable port that access the peritoneum placed surgically. Patients will have their monocytes isolated by counter-flow elutriation and stimulated with Sylatron^® (Peginterferon alfa-2b) and Actimmune^® (Interferon gamma-1b) ex vivo. The monocytes and interferons will be infused IP by gravity in 250 mL Plasmalyte A, followed by a 250 mL saline wash. The patient will rotate from the supine position to left prostrate, followed by left prostrate, every 15 min for 2 h to ensure movement of the product within the peritoneum

Fig. 2

Time line of treatment: After assessment and consent, the patients will be enrolled on Day-1 for line placement and research bloods. On Day 0 the patient will undergo apheresis. The Sylatron^® (Peginterferon alfa-2b) and Actimmune^® (Interferon gamma-1b) will be added to the monocytes and the product will be infused on Day 1. The patient will be monitored for 24 h and released. This schedule will repeat for Cycle 2. Prior to cycle the patient will have disease re-staging based on a CT scan. If the patient is eligible for cycle three, they will receive the product infusion and be released 3 h post infusion