text: Dr Amrik Basran, Chief Scientific Officer at Avacta, explains the current state of cancer immunotherapy and the challenges of moving into combinations of these innovative treatments.
  What is the current landscape like for cancer immunotherapy?
  With the success of the monotherapy checkpoint inhibitors, researchers are starting to look at combinations of immunotherapies, and also at combinations of chemotherapy and immune checkpoint blockade.
  Depending on which combinations and when they’re administered, these can have increased benefits for the patient in a wide range of cancers compared to monotherapy, mainly because you’re hitting two different mechanisms to get a broader effect.
  The holy grail is to have therapies that are more effective in a wider group of cancer patients and having sustained efficacy or cure, but still have manageable safety profiles. All these drugs come with their risks, and it’s a fine line between managing the risk and the toxicity you can see in the patient.
  Would you say that immunotherapy has lived up to its expectations or do they still have some way to go?
  I think there is some way to go. We still want to push patient survival rates up and effectively take cancer from being an acute disease to a chronic disease that can be managed over long periods of time. The ultimate goal would be curative treatments, but cure is very difficult to achieve in most types of cancer.
  Many patients on the first-generation immunotherapies are still being followed to see how the disease has been modified or progressed, so we’ll have to see how long these patients survive for – but in many cases it’s been several years of extended life where it usually would have been six to eight months. From that perspective immunotherapy has been very significant, but what we’re all striving for is making these therapies work better and have fewer side effects for patients, in a broad range of cancer types.
  At the moment, yes, immunotherapy has clearly delivered a fundamental change to patients compared to chemotherapy, but I still think there’s a long way to go in the sense of understanding the tumour biology in the patient. There are also many different kinds of immune cells involved in immunosurveillance in the body and understanding why, for example, in certain tumours they don’t enter the tumour or ignore the cancer cells and not kill them is very challenging. Even one tumour type itself may have very different types of damaged cells growing in it and so a single therapeutic agent may not work. That makes understanding what disease processes are going on in the patient and how to treat the cancer difficult. But I do think in the long-term, once people understand the biology and have better model systems to test drug combinations, we may be able to do target combinations that give better efficacy for the patient in the long-term.
  What are the main challenges in trying to address multiple targets?
  Classically, antibodies just recognise and block one target, like PD-1, to reactivate the immune system to the presence of cancer cells. But what people are really interested in at the moment is whether we can we combine blocking one pathway with another. The problem is, if you give patients, for example, anti-CTLA-4 therapy and an anti-PD-1 therapeutic antibodies, the efficacy is improved, but the side effects are worse.
  Secondly, each one of these antibodies individually has a very high price tag in the hundreds of thousands of dollars. The balance between justifying the cost of the therapy and patient survival is always going to be a challenge for healthcare providers.
  Researchers have been looking at whether you can make molecules called bi-specifics, where we engineer two different targeting sites in the same molecule. Instead of giving two monotherapies, you just give one drug that will hit both targets.
  On paper that sounds great. It should also be cheaper to manufacture a single biological drug than two and more convenient for the patient. But the reality is that biotech and pharma companies have struggled to do this over the last 10 years; there’s only a couple of approved bi-specifics on the market. The problem is not only whether you can manufacture these molecules and produce them at scale for a clinical study as they sometimes have stability issues – it’s also the underlying target biology, which target combinations go together? How predictive are the in vivo models used to test the molecules to indicate what may happen in a patient? Are you going to see other side effects which you didn’t see in the models when you give them to a patient?
  For small biotech, target selection and validation is a challenge, because it is expensive and time intensive. The knowledge and data about which target combinations may be successful to target in the clinic has mainly been researched in academia with large pharma funding the work. With smaller biotechs they tend to follow combinations others are working on in the industry or with academia.
  How is Avacta hoping to address these challenges?
  We are developing next-generation cancer immunotherapies combining our two proprietary platforms – Affimer® biotherapeutics and pre|CISIONTM pro-drugs which are specifically activated in the tumour microenvironment.
  Our Affimer technology is based on a fully human protein. The parent molecule that we’ve designed this on is called Stefin A, a naturally occurring human protease inhibitor found in the cell lysosome. It’s a very small protein and its main function is to regulate the way the cells break down other proteins within the cell.
  We have engineered two additional peptide loops into the surface of the molecule, and each of those loops has nine amino acids, so we have 18 amino acids that we can play with. Then we use phage display to identify binders to the target of interest for example, the immune checkpoint PD-L1.
  Due to the biophysical properties of the Affimer scaffold, it is relatively straightforward to join multiple Affimer proteins together and make dimers and trimers. So far, we’ve managed to put five of these Affimers together, which means we can bind to multiple targets in one molecule that should be developable as a drug.
  We’re really interested in the potential of making multi-specific immunotherapies, because this has been so much easier to do with Affimer technology. Our aim is to extend the benefits of cancer immunotherapy to a wider number of patients, including those who do not experience a durable response to current single immune checkpoint inhibitors.
  The pre|CISION technology incorporates a chemotherapeutic agent that is chemically modified using a linker, which we refer to as a pro-drug. In this format, the pro-drug is inactive and cannot enter cells and so should have very low toxicity when given to the patient. The linker is specifically cleaved by the protease, fibroblast activation protein alpha (FAP-?), and not by any other enzymes. FAP? is expressed at 10-100-fold above background levels in many solid tumors. In the circulation and tissues where there is no or low FAP-?, the pro-drug should remain inactive and so show low toxicity. As the pro-drug enters and accumulates in the tumour, the linker will be specifically cleaved by FAP-?, releasing the chemotherapeutic agent which can now enter and kill the cancer cells. By this mechanism, we expect be able to give the patient higher doses of the pro-drug, show improved tumour cell killing and efficacy, with lower systemic toxicity. This should allow the pro-drugs to expand the therapeutic window and enable broader use in oncology, particularly in combinations with other Affimer protein or antibody based immuno-oncology therapeutics.