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Vantage Point – The new frontier in immuno-oncology: drug-device combos

Date March 28, 2017

Immuno-oncology drug combinations are still one of the hottest topics in cancer – but now there’s a new combo in town. An increasing focus on pairing up IO drugs with device-based interventional oncology procedures could help push this approach into the mainstream.

These interventional procedures could modify the tumour microenvironment and make certain cancers more susceptible to checkpoint inhibitors, some believe. “The idea is that if you have a procedure that produces necrotic tissue, like embolisation or ablation, that could potentially stimulate the immune system and lead to better results with a checkpoint inhibitor,” says Dr Joe Erinjeri, an interventional oncologist at the Memorial Sloan Kettering Cancer Center.

So far, his group has only carried out animal studies of these combination therapies, but a clinical trial is in the works at MSKCC that will evaluate Bristol-Myers Squibb’s PD-1 inhibitor Opdivo plus drug-eluting bead chemo-embolisation for advanced hepatocellular carcinoma.

Priming the immune system

Treatment with these beads, which are designed to deliver the chemotherapy doxorubicin directly to the liver, “leads to a bunch of different immunologic phenomena”, Dr Erinjeri says, including upregulating the PD-1/PD-L1 axis, dysregulating cytokines, and leading to increased CD4+ and CD8+ T cell populations.

In addition, the tumour necrosis triggered by the beads might expose the body to more tumour antigen. “Hopefully you’ve got a combination of effects that’s going to be very beneficial in turning on the immune system,” he concludes.

The combination approach could be useful in patients who do not respond to current immuno-oncology drugs, says Peter Stratford, chief technology officer at the UK interventional oncology specialist BTG.

Checkpoint inhibitors “have struggled in solid tumours because quite often there’s a significant mass and it’s hard for immunotherapies to address that”, he tells EP Vantage.

Local, device-based therapies could be harnessed “to debulk those tumours, and potentially stimulate the immune response”, and then IO drugs could be used “to address that residual viable tumour that’s left behind”.

BTG is looking at various combinations of drugs with interventional procedures, including cryoablation, which involves destroying a tumour by freezing it, internal radiation therapy delivered via an intra-arterial catheter, or using beads to deliver radiation or a chemo drug.

The effect on the patient’s immune system depends on how the tumours are killed, Mr Stratford adds. “We’re pretty excited about cryoablation, maybe more than others, because freezing obviously preserves protein structures, and it’s those protein structures that are really needed to stimulate the immune response.”

Early days

He admits that it is early days. Another hope for the drug-device combos – that they could be less toxic than the combination of anti-PD-1/PD-L1 drugs and CTLA4 inhibitors, such as Opdivo plus Yervoy – also remains to be proven.

Dr Erinjeri says: “We hope it will be [safer], but it could be rough on the patients. Maybe there’s going to be antigen overload. It might not be just tumour that becomes necrotic – what if you get antigen presentation of self-antigen?" This last interaction would lead to destruction of healthy tissue.

Showing the safety of the bead-Opdivo combo is therefore the primary goal of the upcoming MSKCC study, Dr Erinjeri stresses. But this will also look at overall response, progression-free survival and overall survival as secondary endpoints.

Other clinical trials are already underway using various interventional oncology approaches plus checkpoint inhibitors. Most of these studies are all relatively small, with fewer than 100 patients enrolled, but larger ones are in the development stage according to Dr Erinjeri.

Selected clinical trials of interventional oncology + IO drug combos 
Interventional procedure(s)  Drug(s)  Indication(s)  Sponsor  Trial ID  Data 
TACE or RFA  Tremelimumab  Advanced liver cancer  National Cancer Institute  NCT01853618  Jun 2017 (suspended*) 
Ablation  Opdivo  Advanced NSCLC  Brown University  NCT02469701  Oct 2017 
Cryosurgery  Keytruda  Oligo-metastatic prostate cancer  Sidney Kimmel Comprehensive Cancer Center  NCT02489357  Nov 2018 
Therasphere  Opdivo  Advanced liver cancer  Northwestern University  NCT02837029  Jul 2019 
Ablative therapies: TACE, RFA or cryosurgery  Durvalumab + tremelimumab  HCC and biliary tract carcinomas  National Cancer Institute  NCT02821754  Apr 2020 
Dendritic cell therapy + cryosurgery  Keytruda  Non-Hodgkin lymphoma  Mayo Clinic  NCT03035331  Feb 2021 
DEBTACE  Opdivo  HCC  Memorial Sloan Kettering Cancer Center  N/A  Not yet started 
*The NCI did not respond to enquiries about why this trial has been suspended.
DEBTACE: Drug-eluting bead chemo-embolisation; RFA: Radiofrequency ablation; TACE: transarterial catheter chemoembolisation.
 

BTG is doing its bit to increase the number of ongoing trials, recently teaming up with the Society of Interventional Oncology (SIO) to offer grant funding of up to $100,000 for promising combination projects.  

“There are at least a dozen groups out there working on various projects, and we’re hoping to get double that number by getting people interested via this call,” says Nahum Goldberg of the SIO.

The society hopes to announce the first round of winners in June, and two to four new projects could get funding depending on the quality of the applicants, he adds.

Mr Stratford hopes that the partnership with the SIO will help BTG formalise its combination strategy. “We get a lot of interest from physicians, which we’ve been addressing on a case-by-case basis. The purpose of tying up with the SIO is to bring some organisation to this and not just rely on individuals getting in touch to drive this work.”

He believes that the BTG-SIO-sponsored projects should start returning data in the next few years, and seems optimistic about the potential of the combination approach. “We have the opportunity to change that tumour microenvironment, and I think that genuinely becomes quite interesting.”

Mr Goldberg, meanwhile, stresses the early-stage nature of the research. “We’re in the infancy of this field. At this point of the game the discipline needs to figure out what each of the therapies is doing. We need to do this research to figure out where to ultimately take this.”

Dr Erinjeri is also cautious: “There’s the temptation to sprinkle immunotherapy on these different therapies, like you would sprinkle salt on a meal, hoping that the combination would work. But I think the rational development of these combinations is going to come from the results of these beginning studies.”

To contact the writer of this story email Madeleine Armstrong in London at madeleinea@epvantage.com or follow  @ByMadeleineA on Twitter

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