Using T cell engineering plus triple checkpoint blockade to enhance the efficacy of adoptive immunotherapy in ovarian cancer

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Published: 15 Apr 2019
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Dr Kristin Anderson - Fred Hutchinson Cancer Research Center, Seattle, USA

Dr Kristin Anderson speaks to ecancer at the 2019 American Association for Cancer Research (AACR) meeting about a study looking at using T cell engineering plus triple checkpoint blockade to enhance the efficacy of adoptive immunotherapy in ovarian cancer.

Dr Anderson explains that finding an immunotherapeutic approach for treating ovarian cancer is very important as most treatments to date work only in particular subsets of patients, with immunotherapy having the potential to work in all patients.

She reports that they found the need to use three different checkpoint blockade antibodies together in order to reinvigorate the T cells.

 

My research, I basically do engineered adaptive T-cell immunotherapy. That means that I take T-cells either out of someone’s blood or out of the spleen of a mouse and I engineer them to be able to see and kill cancer more effectively.

Why is it important to develop immunotherapeutic strategies for ovarian cancer?

It’s really important for us to develop immunotherapy for ovarian cancer because we don’t have any that work yet. Right now we’ve seen a lot of success with chemotherapies and drugs like PARP inhibitors in certain subsets of patients but we really need some strategies that are going to work in all the patients that we end up seeing and immunotherapy actually offers a lot of potential to do that.

How did you go about doing this?

The way we went about this was basically to figure out what tumour antigens are expressed in many, many ovarian cancer patients. We focussed on high grade serous ovarian cancer because that one is incredibly aggressive and it’s one that we see in the majority of our patients. There was actually a really great study done by the NCI several years ago where they characterised tumour antigens that are overexpressed in tumours but lowly expressed in healthy tissue and mesothelin was one of those. So we developed a T-cell receptor that could target mesothelin and basically made a human version and a mouse version and that’s what we’re looking at in this study.

What did you find?

In this study what we found was that the T-cells that we engineered end up migrating beautifully into tumours but they eventually become dysfunctional and a lot of work has gone into checkpoint blockade, this idea that you can find a brake on a T-cell and block it so that the T-cells are released to exhibit functional efficacy against the tumour. So we tried one or two different checkpoint antibodies in our study with our T-cells to see if we could reinvigorate them, make them better at killing cancer. Single agents alone and double agent combinations didn’t work; we only saw improved anti-tumour efficacy or tumour killing when we used three different checkpoint blockade antibodies together.

Why do you think there is this inhibition?

We think in this particular situation these tumours have lots of mechanisms that are turning T-cells off. Each T-cell expresses more than one pathway that can be blocked. So by simply taking the brakes off one of them there are other mechanisms still at play so we have to actually overcome more than one of those simultaneously to really release the potential of these T-cells.

Is there any worry that this could target normal human tissue?

There is a slight concern that we might be exhibiting or seeing on-target but off-tumour effects. One of the great things about targeting with a T-cell receptor, though, is that we can actually tailor the specific component of mesothelin we’re targeting. So, for example, CAR T-cell therapy targets the protein itself; what we’re doing with a T-cell receptor is actually targeting a peptide, so just a piece of the protein that’s presented in a special presentation molecule. So if healthy tissue, for example, presents one peptide and cancer presents a different one, if we engineer our T-cell receptor to only see the one that’s presented in cancer then we’ve actually made our targeting much safer. So that’s what we’re really hoping to see when we take this into patients.

Can this be used in other cancers as well?

This can be used in other cancers and that’s what makes this really awesome to be working on is that mesothelin is overexpressed in mesothelioma, so lung cancer, ovarian cancer, pancreatic cancer. So the idea that this strategy can help one subset of patients is not true, it could potentially help many types of patients with many kinds of cancer.

Is there the possibility to be able to improve targeting by personalisation to the patient?

I would love to see in the future a situation where a patient could come in and have their blood taken or have a biopsy of their tumour done and off the shelf we could say, ‘Your tumour expresses antigens a, b and c and your tumour has obstacles d, e and f and so we’re going to engineer your cells with the tools that we already have available, specifically to get around the issues in your tumour.’ I would love to see that, it’s still years in the future but in a perfect world we’d be able to tailor therapy based on a broad toolset that works in lots of people.

When and how do you see this progressing into the clinic?

I see this going to the clinic relatively quickly, actually. The T-cell receptor that we’ve engineered to target mesothelin is already in processing, it’s in the clinical vector processing plants. So it’s being made for clinical trials as we speak; checkpoint blockade is already in the clinic as well. So once both the antibodies that are used in checkpoint are proved to be safe and the T-cell receptor itself is proven to be very safe it’s very quick for us to suggest a trial where we put the two together.

What will be the implications of this?

The implications for cancer therapy for patients using this strategy are huge. Not only do we have one patient subset we have many.

Are you excited about the future of immunotherapy?

I’m incredibly excited to be involved in immunotherapy right now. I feel really fortunate that I got to be involved in immunotherapy now that it’s taking off. There are pioneers who spent decades trying to get this to work and they fought an uphill battle, arguing that synthetic biology could actually be used as a treatment. Now we’re really seeing pay-off for all of that work that they did so I feel very honoured to be able to work in their field and to get to push it forward into patients even faster.