Monocytes: A Promising New TRAIL in Ovarian Cancer Cell Therapy

In this issue of Clinical Cancer Research, Green and colleagues investigated the clinical efficacy and tolerability of intraperitoneal treatment with autologous IFNα and IFNγ-activated monocytes in patients with platinum-resistant ovarian cancer (1). IFNs induced the expression of TRAIL in monocytes with subsequent activation of the extrinsic apoptotic pathway in ovarian cancer cells via death receptor 4 (DR4) and death receptor 5 (DR5) mediated signaling. Induction of apoptosis was crucially dependent on direct contact between monocytes and cancer cells. The adoptive transfer of activated monocytes resulted in clinical efficacy including RECIST measurable partial responses in this heavily pretreated cohort of ovarian cancer patients. Among the translational endpoints, lower baseline levels of peripheral regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) were associated with clinical benefits. Long-term responders showed increasing levels of peripheral classical monocytes and MDSCs upon disease progression. The treatment was overall well tolerated with patients receiving up to 10 intraperitoneal infusions. Of note, this adoptive cell transfer of monocytes did not require lymphodepletion in contrast to T-cell receptor or chimeric antigen receptor (CAR) T-cell therapy.

Single-agent IFN therapy of ovarian cancer has been studied in prior clinical trials. In an early trial conducted by Berek and colleagues, patients with recurrent high-grade epithelial ovarian cancer received intraperitoneal IFNα2. The treatment resulted in a 43% overall response rate with five complete responses and induced an inflammatory tumor microenvironment (TME) including an increase in monocytes (2). Follow-up studies using intraperitoneal IFNα in combination with upfront chemotherapy and as first-line maintenance treatment confirmed clinical efficacy (3–8). Similarly, IFNγ treatment has been shown to promote an immune-stimulatory peritoneal environment, generating clinical responses in ovarian cancer patients with persistent disease after first-line chemotherapy (9), in combination with standard chemotherapy (10), and as salvage therapy in platinum-resistant disease (11). Despite the promising clinical benefits of recombinant IFN therapy in ovarian cancer, there is no FDA-approved indication at this time.

Monocytes are a fundamental component of innate immunity and can elicit cytotoxic activity against cancer cells through phagocytosis or expression of immune modulating cytokines like IFNγ (12). Only a few prior clinical studies have explored the antitumor effects of monocytes in ovarian cancer patients. Andreesen and colleagues used autologous macrophages generated in vitro from serum monocytes in 5 patients with ovarian carcinoma and observed regression of ascites in 2 patients (13). In a separate trial, monocytes activated ex vivo by liposomal muramyltripeptide phosphatidylethanolamine (L-MTP-PE) administered intraperitoneally resulted in an inflammatory systemic and loco-regional response, which included symptoms of fever and abdominal pain, respectively.

The Phase I clinical trial reported by Green and colleagues combines the various antitumor properties of IFNs and monocytes. The investigators reported in prior systematically conducted preclinical studies that IFN-activated monocytes elicit synergistic antitumor effects in ovarian cancer cell lines and mouse models (14, 15). Furthermore, the differentiation of monocytes into macrophages and polarization into a more tumoricidal M1 phenotype was greatly enhanced by the combination treatment with both IFNα and IFNγ (12, 15). In the current study, upregulation of TRAIL within IFN-activated monocytes was identified as an important mechanism for inducing ovarian cancer cell death (Fig. 1). Activation of the extrinsic apoptotic pathway via DR4 and caspase 8 suggested a potentially preferred pathway. The requirement for cell-to-cell contact in this process is an important aspect and an excellent rationale for intraperitoneal treatment. In a majority of ovarian cancer patients, the disease is confined to the abdomen with distribution on the peritoneal surfaces, providing an opportunity for direct contact between activated monocytes and cancer cells. It will be of interest to study the dynamics of intraperitoneally infused monocytes including the trafficking to metastatic sites in the peritoneal cavity, the ability of monocytes to generate M1 macrophages, and the antitumor activity of transferred monocytes in the presence of an immunosuppressive TME.

While TRAIL is a potent inducer of apoptosis, it is important to consider possible tumor promoting effects, which may negatively impact the clinical efficacy of IFN-activated monocytes. TRAIL induces signaling of various oncogenic pathways including PI3K, protein kinase B (AKT), MTOR, and MAPKs resulting in increased cell proliferation, migration, and invasion (16, 17). Activation of the PI3K/AKT/MTOR pathway was described in breast and ovarian cancer cells to cause TRAIL resistance (18). In addition, activation of noncanonical TRAIL signaling, including via NF-κB, has been reported to inhibit apoptosis induced by TRAIL, resulting in enhanced survival in various cancer cells (19). Among the effects on immune cells, TRAIL inhibits CD8+ T-cell proliferation while stimulating the proliferation of CD4+ T cells including CD4+ Treg cells. The antigen presenting function of dendritic cells is decreased by blocking cytokine secretion and preventing the generation of MHC class I-antigen peptide complexes. In the current trial, the cyclical treatment with IFN-activated monocytes every 28 days rather than continuous exposure of cancer and immune effector cells to TRAIL may mitigate these possible pro-tumoral effects.

The antitumor effects of activated monocytes are likely enhanced by the induction of a pro-inflammatory environment as suggested by the upregulation of several cytokines within the peripheral blood of treated patients. IFNγ levels showed an 8.8-fold increase after intraperitoneal infusion of monocytes with concomitant higher levels of IL6, IL10, and TNFα. It is conceivable that this systemic cytokine profile reflects an IFN and monocyte induced inflammatory TME with activated cellular immune responses, including enhanced antigen presentation and higher levels of active CD8+ T cells. This modulation of the TME might improve the response to immunotherapy including immune checkpoint inhibitors, which have shown low response rates in ovarian cancer when used as single agents.

It will be important to identify predictors of response to IFN-treated monocytes. The presence of Treg cells, cancer-associated fibroblasts, or immune-suppressive cytokines like TGFβ in the ovarian cancer TME might be associated with non-response, while the presence of CD8+ T cells or an IFNγ signature might be predictors of response. The genomic background, in particular the presence of BRCA mutations, might convey more favorable responses due to increased STING signaling and IFN expression in cells with defects in homologous recombination. In addition, mutations in DR5 and DR4 have been described as a resistance mechanism to TRAIL-induced apoptosis and are present in about 7% of ovarian cancers. A comprehensive analysis of the biological changes induced by IFN-activated monocytes in the TME as planned by the investigators will provide important insights for the development of biomarkers.

The molecular and immunologic heterogeneity, a high level of immune-suppression, and a low tumor mutational burden all contribute to the challenges of any ovarian cancer immunotherapy. IFN-activated monocyte treatment is a promising new strategy with the potential to overcome these obstacles. Further refinement, including the identification of an effective combination treatment, will be crucial to enhance clinical benefits. The lack of target specificity of monocytes might be overcome, for example, by introducing CARs to target ovarian cancer associated antigens such as NY-ESO1 or mesothelin. The monocytes have choices on their TRAIL forward to becoming an effective ovarian cancer cell therapy.

O. Dorigo reports grants from BioEclipse, IMV, EMD Serono, Novartis, AstraZeneca, Millenium Pharma, Clovis Oncology, EISAI, Agenus, Merck, Epsila Bio, and R-Pharm US and personal fees from Clovis Oncology outside the submitted work. No disclosures were reported by the other author.