The difference between ICI-responsive and non-ICI-responsive tumour types is merely a matter of degree – the former is “hot” or immune-cell inflamed, the latter is “cold” or non-immune-cell inflamed. This is somewhat of an oversimplification since not all hot tumours respond to ICIs and even those that initially respond may subsequently develop resistance; however, the fact remains that most human solid tumours are immunologically cold and are far less likely to respond to checkpoint inhibitors than immunologically hot ones.3
Figure 1: Follow the breadcrumbs strategy with AdAPT-001
There are currently nine approved checkpoint inhibitors. On the expectation that synergistic combination will improve outcomes relative to monotherapy, a multitude of trials have been attempted that pair other modalities with these ICI ‘backbones’ such as chemotherapy , surgery, radiotherapy, targeted agents, epigenetic modifiers, antiangiogenics and different ICIs. One of the most promising of these combination strategies, mechanistically speaking, is an ICI plus an inhibitor of transforming growth factor–β (TGF-β).
Table 1: Snapshot of TGF-β inhibitors in development
A main driver of tumour immunosuppression is the cytokine, TGF-β, which tumours produce at high levels and which deactivates T cells.4 Table 1 ) have taken bites of the TGF-β apple with several small molecular inhibitors and monoclonal antibody candidates that target TGF-β in clinical development. These include GSK’s bintrafusp alfa, a bifunctional antibody of PD-1 and TGF-β, Scholar Rock’s SRK-181, an anti-TGF-β1 monoclonal antibody, and BMS’ AVID200, an engineered TGF-β ligand trap. To date, results have been mixed to disappointing. One of the most advanced candidates, bintrafusp alfa, failed to meet its primary endpoints against standard of care in two randomised Phase II studies in lung and biliary tract cancer.5,6 7-9 10-12
EpicentRx’s AdAPT-001 is an oncolytic virus, currently in a Phase I/II anticancer trial called BETA PRIME (NCT04673942), which directly kills cancer cells. Due to defective antiviral response mechanisms, cancer cells are more susceptible to viral infection than healthy cells. As AdAPT-001 replicates, it expresses a proprietary TGF-β trap that is encoded in its DNA. This TGF-β trap binds to and neutralises the immunosuppressive TGF-β protein that most tumours express in excessive amounts and that is linked to escape from the immune system. Continuous replication of AdAPT-001 eventually leads to lysis of the cancer cells, thus leaving behind a metaphorical trail of breadcrumbs for immune cells to follow in the form of so-called ‘danger signals’ and tumour antigens, as illustrated in Figure 2 .
Figure 2: AdAPT-001 has the potential to turn cold tumours hot
Pre-clinical data has demonstrated – —and the preliminary clinical data from the ongoing BETA PRIME trial appears to suggest – that AdAPT-001 makes tumours hot and suitable for checkpoint inhibitor blockade, especially when those tumours are resistant to ICIs. The expectation based on experimental studies in mice is that the rate of cell destruction from AdAPT-001 will outpace tumour cell growth and that, combined with the stimulus of immune cell activation from TGF-β trap expression and ICI administration, will lead to excellent anticancer activity, even in tumours that were formerly resistant to the effects of ICIs.13
To thwart tumours, oncologists sometimes justifiably treat with toxic therapies – alone or in combination – if those therapies are thought to provide benefit. However, this often only reaps short-term gains, as the more toxicity the patient experiences, even if efficacy is improved, the greater the likelihood that treatment will be delayed, reduced or stopped altogether, which is ultimately associated with poorer outcomes.
Therefore, one potential advantage of an oncolytic adenovirus over many other therapies is that the side effects from it are mild and self-limiting, resulting in mostly cold-like symptoms, since adenoviruses are agents of the common cold. This is an especially important point in its favour since ICIs carry the risk of severe and sometimes even life-threatening toxicities, especially when used in combination. It is a common misconception that checkpoint inhibitors are less toxic than other therapies, when, in fact, their side effects are different than before and not necessarily better tolerated.14
Different from most other oncolytic viruses, which are constructed from a variety of different viral and non-viral elements, AdAPT-001 is de-targeted from normal cells, rather than specifically targeted to cancer cells, through the deletion of a small stretch of DNA in the virus. The premise behind this ‘less is more’ strategy is that viruses have been evolutionarily honed over thousands of years for simplicity and success so that the more viruses are tampered with or manipulated, the less well they replicate and perform. This is important not only for treatment, but also for manufacturing. AdAPT-001, which replicates almost as fast as original or wild-type virus, is manufactured in-house in an EpicentRx cleanroom instead of by a contract manufacturing organisation (CMO).
What also sets AdAPT-001 apart from other oncolytic viruses, the majority of which encode for the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), is the use of a TGF-β trap that, based on pre-clinical studies, overcomes multiple resistance mechanisms and turns cold tumours hot, thereby priming responses to checkpoint inhibitors that were previously inactive.
A testament to the game-changing potential of checkpoint inhibitors is a recent trial with the PD-1 inhibitor, dostarlimab, where an unprecedented 14/14 locally advanced rectal cancer patients with impaired DNA repair capacity due to mismatch repair (MMR) deficiency and microsatellite instability (MSI) went into remission.15
The problem – and the challenge going forward – is to develop combination strategies, which include well-tolerated therapies like AdAPT-001, that increase the likelihood of success with checkpoint inhibitors, not just for those with MMR deficiency and microsatellite instable (MSI) tumours, but for all cancer patients, even those with cold, non-immune-responsive tumours.
Dr Tony Reid
Tony is Chief Executive Officer at EpicentRx and holds a PhD focused in antiviral and antitumour activity from Stanford. Reid further pursued his MD at Stanford focusing on targeted viral vectors for cancer therapy and histone deacetylase inhibitors. In addition to his role at EpicentRx, Reid continues his 13 years as a Professor of Medicine at the University of California San Diego Moores Cancer Center as a medical oncologist focused on early phase clinical research while simultaneously developing an adenoviral platform.
Bryan is Chief Development Officer at EpicentRx and combines first-hand clinical experience with 17 years of pharmaceutical development experience. Before joining EpicentRx, Bryan worked as a Medical Officer at Intarcia Therapeutics. He has published over 100 peer-reviewed scientific articles, reviews and book chapters. He is also co-inventor of 10 issued patents and over 50 pending patents in the biomedical and device fields. Bryan was educated at Princeton University, Catholic University in Belgium and University of Miami Medical School.
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