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

BackgroundOvarian 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.MethodsPatient 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.DiscussionWe 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

Monocyte heterogeneity and functions in cancer

“…Despite these challenges, a Phase I clinical trial was recently initiated to explore autologous transfer of monocytes collected by apheresis to patients with recurrent chemotherapy-resistant ovarian cancer. 143 Results from this clinical trial will be informative for future directions in clinical monocyte transfer therapies.…”

“…Unlike chimeric Ag receptor (CAR) T cells that have been successful in the clinic for treatment of leukemia and lymphomas, monocytes display limited proliferative capacity ex vivo and can be a challenging target for gene editing. Despite these challenges, a Phase I clinical trial was recently initiated to explore autologous transfer of monocytes collected by apheresis to patients with recurrent chemotherapy‐resistant ovarian cancer . Results from this clinical trial will be informative for future directions in clinical monocyte transfer therapies.…”

Driving Immune Responses in the Ovarian Tumor Microenvironment

“…reinforced the ability of monocytes and IFNs to kill tumor cells synergistically, although sensitivity varied between lines ( 118 ). A Phase 1 clinical trial was created to evaluate the intraperitoneal administration of autologous monocytes treated ex vivo with pegylated inteferon α-2b and interferon γ-1b ( 119 ). Preliminary results showed a well-tolerated treatment with two PRs and four patients with SD ( 120 ).…”

Aggregation-prone peptides modulate activity of bovine interferon gamma released from naturally occurring protein nanoparticles

“…In recent years, IFN- has been investigated in approximately 80 clinical trials for a number of indications, mainly related to immune system disorders, infectious diseases and cancer (https://www.clinicaltrials.gov). Recombinant IFN- is administered either as a unique drug in these clinical trials [35][36][37][38][39][40][41] or in combination with other products [42][43][44]. Therefore, the central key role of IFN- in immunostimulatory and immunomodulatory effects will lead to an increase in the use of this cytokine in the coming years in human health.…”