Immunotherapy could transform systemic power of locoregional IO treatments

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Muneeb Ahmed, S Nahum Goldberg and Nir Rozenblum

Many physicians now believe that immunotherapy is a disruptive field in cancer medicine. Interventional oncology can either “snooze and lose” as one prominent interventional radiologist put it on a recent podium presentation, or wake up and do the research needed on how best to harness the potential of this field when using interventional oncology treatments.

 

Immunotherapy involves stimulating the cancer patient’s immune system so that it can robustly fight the disease. There could be a time, not far away, when interventional radiologists no longer perform procedures to destroy tumour tissue alone—they might be ablating to provoke the patient’s immune system to powerfully destroy cancer cells.

When asked why immunotherapy is becoming a subject of interest within interventional oncology, Bradford Wood, director, Center for Interventional Oncology, chief of Interventional Radiology, and a senior researcher with the National Institutes of Health (NIH) Clinical Center and National Cancer Institute, said: “Good things happen when we think outside the box, leave our comfort zone, and embrace the success stories of other disciplines. So goes it with interventional oncology and immunotherapy.

“Immunotherapy could prove to be the ‘Trojan horse’ inside cancer, turning the patient’s own immune system against the tumour. Immunotherapy has recently had significant impact upon the approaches to a broad variety of cancers, including melanoma, lung and kidney cancer, and is the topic of an even wider spectrum of studies and clinical trials. It is the latest biologic therapy to be added to the pharmaceutical arsenal against cancer. In order to optimise the impact of interventional oncology, we need to embrace and integrate novel approaches from the other more traditional pillars of oncology (such as medical, surgical, and radiation oncology). Combining interventional oncology with immunotherapies may be a rational approach,” he added.

There have been ongoing preclinical and translational efforts in harnessing immune power with radiofrequency ablation, microwave ablation, cryoablation, irreversible electroporation, high intensity focused ultrasound, and chemoembolization with drug-eluting beads.

A term that is much used when talking about immunotherapy is “abscopal effect”. Abscopal simply means “off target” and abscopal effects are off target cancer responses to locoregional therapy, said Joseph P Erinjeri, interventional oncologist, Memorial Sloan Kettering Cancer Center, New York, USA, at the Society of Interventional Radiology’s (SIR’s) Annual Scientific Meeting (2–7 April, Vancouver, Canada).

Erinjeri explained that when cancer cells are killed, they act like antigens, and [locoregional therapies such as] ablation brings tumour antigen in close contact with immune cells/cytokines and growth factors. “Antigen, immune cells and immune stimulating drugs are necessary to optimally create abscopal effects and antitumour immunity. Ablation leads to increased tumour antigen exposure, increased quality of immune cells such as CD8 and CD4 cells, and dendritic cells,” he noted.

Wood explained: “The local or regional therapy in this case acts like a sort of ‘super-vaccine’, where tumour antigens are deposited into an inflammatory ‘cytokine soup’, with regional hyperaemia enhanced by local hyperthermia, enhanced extravasation and enhanced immune response that is tumour-specific. When this is combined with new drugs that stop the body’s off-system (thus stimulating the ability to recognise tumour as foreign), then good things may happen in terms of these drugs’ effects, namely enhanced T-cell activation and enhanced antigens for antigen presenting cells (APCs). Those drugs in the family of “check-point inhibitors” (anti-CTLA4 and Anti-PD) are the drugs that have received the most interest in the cancer research community. The immune system often recognises tumour as ‘foreign’ but the response is usually not robust enough to result in meaningful effects. So along come interventional oncology and checkpoint inhibitors.”

Commenting on the potential of immunotherapy in interventional oncology, Wood said: “Immunotherapy combined with interventional oncology has the potential to change the nature of how we practice on a daily basis. Specifically, if radiofrequency ablation, microwave ablation, laser, cryoablation, irreversible electroporation, high-intensity focused ultrasound and chemoembolization become standard methods for augmentation of antigen presentation for many cancers, then the potential applications and impact could dwarf our current collective practices.

If it proves to be valid, this approach may be the tip of a paradigm-shifting iceberg. It is possible that many approaches to cancer
immunotherapy may be augmented by enhanced antigen presentation and enhanced T-cell activation provided by sub-lethal ablation, for example. Interventional radiologists are not used to leaving tumour tissue behind, since we often try to ablate an entire tumour and a margin of normal tissue. In the case of ablation plus immunotherapies, although this is speculative, we may find ourselves in the unusual role of intentionally and incompletely treating a piece of a large tumour, simply for antigen presentation (“radiofrequency or cryovaccination).”


Enigmatic balance

Some data suggest that interventional oncology procedures such as ablation sometimes have an immunogenic effect and, conflictingly, also a tumourigenic effect.

Two of the three Best Interventional Oncology Papers of 2015 selected for presentation at the European Conference on Interventional Oncology (ECIO, 17–20 April, Dublin, Ireland) focused on the systemic effects of local therapies and reported on these effects.

Muneeb Ahmed, chief, Division of Vascular and Interventional Radiology, Beth Israel Deaconess Medical Center/Harvard, Boston, USA, presented on hepatic radiofrequency ablation induced stimulation of distant tumour growth being suppressed by c-Met inhibition.

“Radiofrequency ablation of normal liver can stimulate distant extrahepatic subcutaneous c-Met and tumour growth, proliferation and angiogenesis. Off target pro-oncogenic effects of hepatic radiofrequency ablation are mediated by activation of human growth factor/c-Met locally and with downstream VEGF activation in distant tumours. Adjuvant c-Met and VEGF inhibitors can variably block off target distant tumour stimulation after hepatic radiofrequency ablation. Hepatic radiofrequency ablation did not stimulate distance growth in c-Met negative tumours,” he said at the session. Ahmed et al’s study concluded that radiofrequency ablation of normal liver may incite off-target distant tumour stimulation for some tumour types. Off target tumourigenic effects can be blocked by c-Met and VEGF inhibitors given within a short window after treatment. “Tumour receptor positivity may be a biomarker to predict which tumours may be more susceptible to off-target cytokine/factor mediated effects of hepatic radiofrequency ablation,” he said.

Nir Rozenblum, Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel, then reported on inflammatory changes in the radiofrequency periablative zone inducing global organ effects, including regeneration. Rozenblum and team concluded that radiofrequency ablation induces both focal changes in the border zone and global changes including hepatocyte proliferation in the ablated lobe and the untreated lobe. The cellular response to radiofrequency ablation include both resident hepatic cell population as well as infiltrating cells (innate immune cells). “Radiofrequency ablation induces an asynchronous liver regeneration dependent on IL-6 and HGF. Blockading the c-Met/HGF axis attenuates hepatocellular carcinoma recurrence post radiofrequency ablation in a genetic model,” Rozenblum said.

S Nahum Goldberg, head of Interventional Oncology Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel and Department of Radiology, Beth Israel Deaconess Medical Center, Boston, USA, an author on both the papers commented in the session: “There is no question that our ablative therapies induce all kinds of changes that could be immunologic and could be used for further therapy. Thus, our next pressing challenge is to determine how to induce the immunologic, and not the tumorigenic, systemic effects.”

Commenting on the enigmatic balance between immunogenic and tumourigenic (or pro-metastatic) effects, Wood explains: “There may be subtle, and thankfully not too common, processes at the edge of an ablation zone (sublethally heated and stressed zone) whereby the stress or hypoxia phenomenon and molecular cascades stimulate pro-growth factors or molecular events that speed up tumour cell growth rates (locally, or possibly even systemically). On other occasions, the abscopal effect may be seen in which remote, but otherwise untreated, tumours shrink after a local ablation elsewhere. Presumably this is immune mediated. We saw this occur in a patient in 1999–2000 where remote untreated tumours mysteriously shrank after a radiofrequency ablation of one renal cell metastasis to the liver. We (and others) then went to the lab and proved that a tumour-specific response can be documented following sub-total radiofrequency ablation in a mouse model, and that this tumour-specific response stimulates gamma-interferon secreting immunocytes turned on by exposure to the same tumour. The immunity can also be conferred to another mouse (“adoptive transfer”), rendering the second mouse immune to later implantation with that cancer.

Radiofrequency can also upregulate immune responses when combined with other immunotherapies like vaccines or dendritic cell administration. Curing a pre-engineered mouse model of cancer is easy, but what about real patients? Our medical oncology colleagues, Tim Greten and Austin Duffy, at NIH/National Cancer Institute along with our Center for Interventional Oncology interventional radiology team reported intriguing interim early results at the American Society for Clinical Oncology (ASCO) meeting from our clinical trial combining checkpoint inhibitors with radiofrequency ablation, cryoablation or chemoembolization with drug-eluting beads in patients with heavily pre-treated hepatocellular carcinomas (manuscript under review). Reaching the truth of whether there is potential for this combined approach will require years of multidisciplinary collaborative team science.”


Immunotherapy and radioembolization

Speaking at a dedicated session on immunotherapy and local treatment held at ECIO, Jens Ricke, professor, Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg, Germany, at the outset noted that he wanted to downplay the expectations surrounding immunotherapy. “I am not sure that we are really finished with antiangiogenesis, and targeted therapies, but we are focusing on the new kid on the block, immunotherapy.

Ricke explained: “In radiation therapy, there have been some clinical case reports of abscopal effects, and this is resulting in an effect in the radiotherapy literature. The question is: is Y-90 a suitable inducer of in vivo tumour vaccination?” He alluded to an ambitious approach that seeks to use Y-90 for in-vivo tumour vaccination. “Is this feasible and can the effect be enhanced by adding checkpoint inhibitors?”

“Y-90 is a very specific type of radiation compared to fractionated radiation as seen with stereotactic body radiation therapy (SBRT). Abscopal effects have been published only with SBRT so far. Radiation induces immunologic cell death, and thereby promotes endogenous vaccination.
Immune checkpoint modulators outperform immunogenic tumour shielding. There is a need for further basic science to be undertaken before a combination can be proposed. Also, the toxicity of the therapy is unclear,” he explained.

Ricke then reported on the AROMA study that was first approved by the local ethics committee on 16 January 2016. AROMA seeks to understand if radioembolization induces a measurable immune response to untreated tumour cells. The first patient was treated in February, with there being a plan for 20 patients to be enrolled.


Next steps

Wood told Interventional News: “The time for optimisation and refinement is now, before this approach becomes more common. There are a host of preclinical and translational questions yet to be answered in order to optimise the approach and determine how to do this right. We are lucky to be interventional oncologists in an era of transformation, and to see first-hand the changes brought about by minimally invasive image-guided therapies. It is an even greater honour to hope to play some small part in the evolution of interventional oncology, as we close the gaps between diagnosis and therapy without scalpels, without blood loss, with patients often as outpatients. This is a time of huge opportunity and equally huge challenges.”

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