The questions of if, how and when to combine interventional oncological procedures with systemic immunotherapy are on the tip of everyone’s tongue, from multidisciplinary tumour boards to industry executive boardrooms, writes Ryan Hickey, New York, USA.
Immunotherapy has transformed the landscape of cancer care in the last several years. It has not only introduced an entire new class of anti-cancer agents into the treatment paradigms of nearly every cancer, it has also led to an entirely new understanding of the interplay between our immune systems and cancers. As testament to the excitement behind this new mode of cancer treatment, the US Food and Drug Administration has been approving the use of immunotherapeutic agents at an unprecedented rate, in certain circumstance even lowering the threshold for the level of evidence traditionally required to gain approval.
As my co-authors and I discussed in a recent article published in Journal of Vascular and Interventional Radiology (JVIR), the molecular biology driving the efficacy of immunotherapeutic agents, particularly the immune checkpoint inhibitors, suggests that interventional oncologic procedures could offer tremendous potential for synergy with these immunotherapeutic agents.
Immune checkpoint inhibitors, such as the anti-CTLA-4 antibody ipilimumab and the series of antibodies against the PD-1 receptor or its ligands, including pembrolizumab, nivolumab and atezolimumab, function by blocking the “off-switch” of cytotoxic and regulatory immune cells, in a sense “re-activating” the immune system against cancer cells.
The combination of an inflammatory response and tumour antigen exposure results in proliferation of tumour-specific cytotoxic T cells, yet any significant antitumour response is typically impeded by activation of these “off-switches,” either by the tumour cells themselves, or the tissue immediately surrounding the tumour cells (tumour microenvironment). By combining the inflammatory response and antigenic exposure inherent to interventional oncology procedures with a blockade of these immune system “off-switches,” the science suggests that we could achieve far greater results than we might achieve with either modality alone.
Furthermore, as we learn more about the relationship between cancer cells and the cytotoxic and regulatory components of the immune system, we are discovering that our local therapies have important, and possibly detrimental, systemic effects. For example, percutaneous ablation has been shown to change the expression of these very same “off-switches,” not only on lymphocytes, but also on tumour and tumour microenvironment cells far from the site of ablation. An increase in certain circulating cytokines and growth factors has been implicated as a factor in the changing phenotype of these remote cells. Interestingly—and concerning—many of these same cytokines and growth factors are upregulated as a result of transarterial embolotherapies as well.
Radiation is a potent initiator of an immune response, although mechanistically in a different manner than seen with the immediate necrosis effects of percutaneous ablation and hypoxia inducing transarterial embolotherapies. The combination of external beam radiotherapy with immune checkpoint inhibitors has already been shown to provide synergistic effects on certain cancers, such as prostate cancer and melanoma. What effect, therefore, might the brachytherapeutic mechanism of radioembolization have when combined with systemic immunotherapy?
The questions of if, how and when to combine interventional oncologic procedures with systemic immunotherapy are on the tip of everyone’s tongue, from multidisciplinary tumour boards to industry executive boardrooms. There has arguably been no greater opportunity for interventional radiologists to cement interventional oncology as a central pillar of cancer care. We must rise to the challenge, drive the investigation of these questions and own the synergistic treatments that result.
Ryan Hickey is director, Interventional Oncology and Transplant Interventions, NYU Langone Health, New York, USA. He has reported no disclosures pertaining to this article.