Intraarterial therapies for priming the immune system: rationale and clinical results

Interventional oncologists (IOs) are playing an ever-increasing role in the management of various types of solid tumors. In fact, numerous in situ tumor destruction techniques (e.g., percutaneous ablation, transarterial therapy, radiation therapy, etc.) can successfully kill tumors, lead to increased overall survival and result in an improved quality of life. [1] While good results have been seen in patients with early-stage disease or in those with oligometastases, outcomes for patients with advanced disease remain poor.

Immunotherapy also has an important role in the management of malignant tumors. Despite the recent improvements of systemic chemotherapy and biologics, immune checkpoint inhibitors have yielded promising clinical applications. It has now been shown that monotherapy only benefits some patients. Therefore, combinations of immune checkpoint inhibitors with different mechanisms of action have been used with agents targeting programmed cell death protein 1 (PD-1) & cytotoxic lymphocyte-associated antigen 4 (CTLA-4). This has been shown to significantly increase overall response rates and overall survival in patients with malignant melanoma. [2] Unfortunately, these combined therapies increase the incidence of immune-related adverse events. [3] Therefore, it has become necessary to adopt a comprehensive treatment strategy based on immune checkpoint inhibitors that can then both increase overall response rates and reduce treatment-related adverse events. [4]

In recent years, there has been substantial interest in stimulating the immune system to reduce local tumor recurrence and the development of distant metastases by utilizing various locoregional therapies. The immune system and its interactions with locoregional therapies is very complex and there are numerous ways that each targeted therapy contributes to the interplay with the immune system. The locoregional therapies are typically used to treat the primary tumor and they have specific immunomodulatory responses that can then be stimulated or suppressed based on the mechanism of action of the chosen immunotherapy. In fact, IOs have been using immunotherapeutic strategies for more than two decades that combine transarterial embolotherapy with an immunostimulant drug (e.g., interferon, GM-CSF, OK-432, etc.). This approach, called immuno-embolization, was found in patients with HCC [5] and uveal melanoma metastases [6] to be reasonably effective at stimulating an immune response at off-target sites but resulted in less tumor necrosis in the target tumor than standard chemoembolization (TACE) approaches.

We now know that transarterial therapies such as TACE and transarterial radioembolization (TARE) have both immunostimulatory and immunosuppressive effects. [7] Transarterial approaches are used to achieve necrosis of the tumor tissue, reduce the release of immunosuppressive factors, and alter peripheral immune cell phenotypes while reducing the number of peripheral T helper cells and induce a hypoxic microenvironment. They can also upregulate HIF-1α and PD-L1 expression and damage the normal liver tissue. On the other hand, ablative therapies can stimulate the immune system by reducing immunosuppression, increasing the exposure of tumor antigens and enhances the immunogenicity of tumor antigens, active antigen presenting cells and increase tumor-specific T cells while suppressing the immune system by increase the production of IL-6, HIF-1α,HGF and its receptor c-MET and upregulating PD-L1 expression. Lastly, like brachytherapy I125 seeds, TARE can act to induce in situ vaccination and re-program the tumor microenvironment while increasing PD-L1 expression and infiltration of Treg into the tumor microenvironment. Based on some positive results from locoregional therapies and immune checkpoint inhibitors in HCC, separately, many clinical trials have been initiated to test the combination of immune checkpoint blockade (and other types of immunotherapy) plus locoregional therapies.

This talk will, therefore, introduce the rationale for using transarterial therapies to prime the immune system and allow the audience to understand the various specific immune change that will be induced by transarterial therapies. [8,9] Furthermore, the mechanisms of immune stimulation with the various intra-arterial therapies and the available data on immune system stimulation with intra-arterial therapies will be reviewed. [10,11]