Immunotherapy for cancer, whereby the immune system is harnessed as a means to target and neutralise tumour cells, is heralded as a promising approach for the treatment of a range of cancers. The Journal for ImmunoTherapy of Cancer (JITC) – official journal for the Society for Immunotherapy of Cancer – is dedicated to disseminating the latest insights in this field, from tumour immunology to cancer immunotherapy. Highlighting the best research in this area, the journal recognises the best scientific research article and the best clinical application research article in its annual awards. This year Stefani Spranger from the University of Chicago, USA, won best science study for their research article on tumour rejection, whilst Shailender Bhatia from the University of Washington, USA, and colleagues won best clinical application study for their investigation into the treatment of metastatic renal cell carcinoma. Phil Dooner, Senior Journal Development Editor for JITC asked both Spranger and Bhatia more about their award-winning research findings and what’s next for their research.
First off, we hear from Spranger discussing her research into combination therapies for the blockade of immune inhibitory pathways, which have been implicated to have a role in cancer. Spranger specifically looks at how this blockade restores interleukin-2 production and the proliferation of CD8+ T cells directly within the tumour microenvironment…
What first got you into tumour immunology studies?
SS: It was basically back when I was a senior undergraduate, starting off graduate school in Germany. I was at a seminar with Dolores Schendeland she gave me a study from Steve Rosenberg to discuss. It was so amazing to discover that T cells actually can induce meltdown of a tumour that I wanted to investigate further. So I then did my diploma thesis and my PhD in her lab.
In your study you used a variety of combinations of compounds (IDO inhibitor INCB23843,anti-CTLA-4 mAb and anti-PD-L1 mAb) to achieve blockade of immune inhibitory mechanisms. Why did you choose these agents?
SS: Those three agents were basically in the clinic at the University of Chicago. Also anti-CTLA-4 mAb is approved by the US Food and Drug Administration, as is anti-PD-L1 mAb, so it was basically the rationale of taking the three compounds that are most likely to be approved for future use.
Why did you choose to focus your study on the murine B16.SIY melanoma model?
SS: So SIY is basically just our antigen where we have all the tools to track the immune response against it. B16 in general is an inflamed tumour that is tough to treat. So it’s a fairly robust model for this type of therapy.
Did anything surprise you when you started analysing your data?
SS: It actually surprised me that all three combinations had the same effect. We were expecting one to work better, and maybe have different mechanisms of action. It’s very striking that they all work directly in the same way. We probably have to investigate more if the molecular pathways that lead to the activation of the T cells are the same or if there are just different molecular mechanisms but they all end up in the same effect that we see.
What kind of impact do you hope these findings will have on the clinic?
SS: We really think and we suggest that probing interleukin-2 (IL-2) production in tumour infiltrating lymphocytes is a biomarker for how effective the therapy is. Maybe if you just probe over time when you get therapy and you see this patient has a good IL-2 response, keep on treating, while the other patient doesn’t, so maybe you have to switch your checkpoint inhibitor or do something different.
What’s next for your research?
SS: I am focusing now on the other part of the tumours that are not inflamed, and how we can tackle those tumours that are not responding to checkpoint blockade right now.
Moving from fundamental research into clinical application, we now hear from Bhatia on how the combination of the drug sorafenib with recombinant interleukin-21 (IL-21) could prove beneficial in the treatment of metastatic renal cell carcinoma (mRCC)…
What is recombinant IL-21 therapy and how has it previously been used in the treatment of mRCC?
SB: IL-21 is a cytokine that is secreted by our immune cells and helps them talk to each other. Recombinant means that it’s created in a way outside of the human body, very similar to the form that exists in the human body, and it can be administered for therapeutic purposes. It has been tested for cancer therapy as a monotherapy in multiple studies. Most of those studies were in melanoma, but actually the very first study of IL-21 also had a sizeable proportion of patients with metastatic kidney cancer.
In this study you use intravenous IL-21 with oral sorafenib. What gave you this idea?
SB: The field of kidney cancer was revolutionised by the arrival of these new oral drugs, which were a significant improvement over prior intravenous chemotherapies, which never used to work really well. Around 2004 the first drug for stage four advanced renal cancer was approved – that was sorafenib – and it was followed almost immediately by another drug, sunitinib. When these two drugs were approved, there was a lot of excitement in the field and a lot of efforts to try and improve the effectiveness of these drugs by combining them with other agents. Now my particular interest has been immunotherapy of cancer, so I was always trying to use immunotherapies to build up on the treatments that were already existing for cancer.
What were your key findings and were you surprised by any of your results?
SB: This was a phase one and phase two study. The phase one portion of the study wanted to test the safety of combining this novel drug, IL-21, with an already existing drug, sorafenib. We found that doses of IL-21 combined safely with this agent. The phase two study tested the final dose combination in a larger number of patients to get a sense of how effective it is.
Did any results surprise you?
SB: We were not exactly surprised by any of the results but it actually confirmed some of our beliefs in the power of immunotherapy. There were a couple of patients in our study who had long-term responses, which is seldom seen with chemotherapies. But I think the combination of immunotherapy with an existing targeted therapy also resulted in the same kind of result, which was a remarkable gain. Our study demonstrates that combinations of immunotherapies with other targeted therapies are feasible, and those combinations have the potential to improve outcomes.
How could these results affect future therapies for mRCC?
SB: This study is unique in that it combines a novel immunotherapy with an already existing targeted therapy for kidney cancer, and that’s important because most of the drugs that are available for kidney cancer are very similar to each other, most of them are targeted chemotherapies, and they work fairly similarly, and when they work, the effectiveness is limited, with most patients eventually progressing on those therapies. What we really need is a novel way to approach this disease, and I think the power of immunotherapy in resulting in long term responses adds that extra dimension.