Paul and Brett's Alpha

Our missives are intended to be thought provoking and (hopefully) interesting to read. It is thus welcome when they generate some debate with our readers. All ideas progress through challenge; there is no such thing as a “safe space” for ideas and we welcome all discussions on the topics we raise, and the Trust in general, even if you disagree with our views and the decisions that we take based upon them.

Given how emotive cancer is as a subject, and how much money has been invested in tackling it, one should not be surprised that suggesting there are other, better things to invest in might draw some disagreement. Few can argue with our core tenet that classical chemotherapy sucks – it surely stands in perfect opposition to Hippocrates suggestion from his Epidemics essays: “first do no harm”. The credo of chemo seems more like “do as much harm as possible without killing the patient”; a crude weapon of mass destruction with scant regard for collateral damage.

If the R&D outcomes of recent years have not lived up to the hype, and failed to banish this particular approach from the armamentarium, surely that does not mean there is nothing to hope for? We pointedly did not say this, we merely argued that the field was too crowded and too uncertain to make the risk reward favourable from an investment standpoint. “But what about personalised cancer vaccines?” some of you asked, noting that topic drew nary a mention.

This is a fair point and we are actually somewhat enthusiastic about this field of study. We would again emphasise (apropos last month’s missive), that a ‘field of study’ is a worthy area of research that should receive grant funding; this is not the same as a sound basis for a positive investment case.

Indeed, we would argue that our optimistic view on this as an area of research supports the previous argument not to invest widely into oncology R&D (including those companies conducting such cancer vaccine research). We shall endeavour to explain why in the following paragraphs (which presume a degree of familiarity with the content of last month’s factsheet).

Let us first describe (in very simplistic terms) the principles and history of therapeutic cancer vaccines before moving into the modern era and the prospects for the next generation of products to actually work. We must draw a distinction between therapeutic vaccines and those against cancer-inducing (‘oncogenic’) pathogens (e.g. vaccination against the HPV virus).

Almost all the healthy cells in your body display their protein contents on their surface via MHC proteins (red blood cells are an exception). Simplistically, one can think of this as an ‘inventory’ of the cell’s contents. These MHC receptors interact with the immune system (T-cells and antibodies) and alert it to the presence of foreign tissue (likely an infectious agent) so that the infected cells can be destroyed.

This process is going on continually and is known as immuno-surveillance. It is much more complex in reality than the simple summary described here and it also requires several cytokine molecules to be present to generate an effective immune response. As such, the local environment around a cancer cell (commonly referred to as the ‘tumour micro-environment’) plays a role, and this ties into the immune cloaking effects described in last month’s missive that allow some tumours to escape the immune system’s attention. We will come back to this point later.

As described last month, cancer arises when cells begin to divide in an uncontrolled manner. At the molecular level, one or more gene mutations result in the over-production (over expression) of a normal signal or receptor that induces uncontrolled proliferation by drowning out other signals, or some other protein product is produced in a mutated form that prevents regulatory processes from controlling division. In either case, a cell will be over-expressing a protein or it will be expressing a protein that is mutated (often both are true; cancer typically involves the processes going wrong in multiple ways as there are numerous checks and balances in the regulatory systems).

What this means in practical terms is that the ‘inventory’ presented to the immune system on those MHC receptors will look abnormal and the immune system can identify these cells as containing foreign material and destroy them, or detect that they are over-active and counter these signals in a process known as equilibrium. This is how the immune system is able to keep a lid on uncontrolled cellular proliferation most of the time.

In terms of the combination of mutations that drive uncontrolled cellular proliferation, everybody’s cancer will be unique to them. However, certain tissue types show common over-expression of certain receptors or proteins and, in this way, we can link certain cancers to certain patterns of over-expression. This is the basis of many of the early stage cancer detection (‘next generation sequencing’) tests that are now on the market. In addition to their value as a diagnostic sign-post, it is easy to understand how these proteins that are commonly over-expressed could become a basis for therapeutic intervention.

With the basic science covered, let us come back to vaccination as a cancer treatment. Thus far there have been four distinct approaches to anti-tumour vaccination:

• 1. Induction of an immune response through vaccination using an antigen linked to an over-expressed protein or a common functionally mutated protein.
• 2. Treatment with modified dendritic cells forced to express a common tumour antigen and thus initiate a sustained immune response.
• 3. Treatment with an oncolytic virus that will preferentially replicate in tumour cells using a virus already likely to induce a meaningful response.
• 4. Creation of a bespoke vaccination through identification of epitopes unique to a person’s tumour burden via the proteomic sequencing of a biopsy sample.

The first approach is the one that is most similar to traditional vaccination against an infectious agent and has been widely evaluated, thus far to little avail. Two projects made it into later-stage larger trials: Tecemotide (aka Stimuvax, BLP-25) was a synthetic antigen that mimicked a glycoprotein called MUC-1 that is widely over-expressed in a number of different cancers and was evaluated in several clinical trials from 2001 to around 2014. Whilst none of the trials were successful, they generated positive signals that encouraged the developers to continue plugging away. Eventually though, they gave up.

Melanoma-associated antigen 3 (MAGE-A3) is another antigen associated with several types of cancer and is also a negative prognostic indicator (i.e. cancers that over-express MAGE-A3 are more difficult to treat). Around the same time as Tecemotide was being evaluated, GlaxoSmithKline developed a vaccine consisting of recombinant MAGE-A3 protein (GSK-2132231) and an already proven adjuvant (a compound added to vaccines to increase the intensity of immune response) and tested it in two large-scale phase 3 trials for both melanoma and lung cancer. Neither showed any activity and the programme was ended.

We have used these two examples because they were the ones that progressed into large-scale (1000+ patient) studies. However, we are aware of a further 14 tumour-specific antigens where vaccine trials have taken place since the mid-1990s. The bottom line here is that there is no classical single antigen therapeutic cancer vaccine on the market.

Why didn’t they work? Was the antigen itself too weak to illicit an immune response, or is the immune response that is generated too weak on its own to overcome the tumours cloaking propensities?Could the solution be to use multiple antigens in the hope that you get a polyclonal response to the tumour?, or combine with a checkpoint inhibitor to enhance immune presentation by the tumour cells. We will return to these questions in due course.

The second approach offers an alternative solution to the induction of a powerful response. Sipuleucel-T (marketed as Provenge by Dendreon, which is now privately owned) is a therapeutic cancer vaccine (of sorts) that was approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) in 2010.

The therapy involves the collection and isolation of immune cells called dendritic cells. These cells are antigen presenting cells and their function is to process antigen material (the stuff presented on those MHC proteins mentioned previously) and act as an intermediary to other types of immune cells to co-ordinate a broad response against that antigen.

The harvested dendritic cells are then exposed in vitro to an antigen called prostatic acid phosphatase (PAP), which is commonly expressed on prostate cancer cells. The cells are then matured with cytokines and re-infused into the patient, where they induce a sustained immune response. Why is this a “vaccine”? The therapy induces an immune response against the cancer cells and is thus technically a vaccine (the WHO definition of a vaccine is “something that trains your body to create antibodies”).

Provenge did not live up to initial commercial hopes and Dendreon went bankrupt in 2014; its assets were later acquired and the company has changed hands several times since. The main drawback initially was the time it took to harvest, process and mature the cells, although this is now down to about three days.

Although the treatment modestly extends survival, it is not curative. As the company has been private since 2015, it is difficult to ascertain commercial sales, but revenues were self-reported to be around$300m in 2017, well below the last audited figure in 2014 and the company has not launched any further products based on the same approach and looks to have pivoted to being a cell therapy contract manufacturing company.

The third approach is the use of an oncolytic virus. Talimogene laherparepvec (aka T-VEC, marketed by Amgen since 2015 as Imlygic for the treatment of melanoma) is a modified herpes simplex virus and the approach echoes Coley’s toxin (cf. last month’s musings), whereby an immunogenic pathogen is injected directly into a tumour to induce an immune response.

Where this 130 year-old idea has been updated is that the modified virus is lacking a key part of its genome so that it will not reproduce in a healthy cell as it cannot successfully ‘hijack’ the replication machinery of the cell (cells have evolved innate responses to viral attack and these must be overcome if the virus is to reproduce). In contrast, most melanoma cells contain mutations that make them vulnerable to such viral attack and thus the T-VEC will reproduce in them and thus attract the immune system’s attention.

This approach is well suited to melanoma as the skin tumours are easily accessible for direct injection. However, melanoma is a very well served market already and so the drug has met with limited commercial success (revenues are not disclosed by Amgen but look to be somewhere in the $50-100m per annum range after seven years on the market). Amgen has no other oncolytic virus products in its R&D pipeline.

In conclusion then, there have been many attempts to develop therapeutic cancer vaccine products over the past 30 years but these have ended in either utter failure or been a commercial flop due to a combination of limited efficacy, high complexity or cost. The idea is sound in principle, but clearly more challenging in reality than one might imagine.

That having been said, the reasons for failure from the first approach can only really fall into two buckets, since we know well that the epitopes being targeted are valid: the failure to induce a strong enough immune response or the tumour micro-environment supporting the response leading to an attack on the tumour.

The next generation of prospective therapeutic cancer vaccines cover the first and fourth approaches. Technology has moved on and we better understand now why the immune system cannot always ‘see’ a tumour, even when we know the targeted epitope is being over-expressed and further we know that this issue can be addressed in some patients via the use of a checkpoint inhibitor drug targeting that PD-1/PD-L1 pathway.

Let us deal with the first approach. As noted previously, single antigen vaccines as monotherapy have not proven to be effective, but that does not mean that the idea is without merit. We know that a polyclonal (more than one antibody) immune response is better than a monoclonal one, and that the best way to illicit a polyclonal response is to vaccinate with multiple antigens, to promote the immune response if possible and to maximise visibility via utilisation of a checkpoint inhibitor.

The German mRNA vaccine company BioNTECH is exploiting both these ideas in a programme called FixVac, which thus far has initiated trials with five cancer-specific vaccines. Each vaccine consists of four mRNA sequences, each coding for a non-mutated (i.e. over-expressed) antigen associated with a specific tumour type and each sequence is encapsulated in a liposome that is designed to integrate it into dendritic cells, which are critical with ‘training’ and maintaining an immune response (cf. Provenge mentioned previously).

The first of these, BNT-111 (melanoma) and BNT-113 (HPV+ve squamous head and neck) are currently in phase 2 trials. BNT-112 (prostate), BNT-115 (ovarian) and BNT-116 (non-small cell lung cancer) are in phase 1. In each case, the vaccine is co-administered with Regeneron’s PD-1 inhibitor cemiplimab. BNT-111 has received Fast Track designation from the FDA following promising early results from the phase 1 where a mix of partial responses and stable disease were seen, including one complete response. Various secondary assessments of immunological activity suggested a strong response against the targeted antigens was achieved. Final results from the BNT-111 phase 2 study will be available in 2024/25, but we would expect to see interim results before then. Meanwhile, we view the phase 1 results as interesting rather than compelling.

The fourth approach has been made more practical by the huge improvements in gene sequencing technology and the now relatively low cost of producing custom sequences of genetic material. Without wishing to diminish the scientific complexity of the process itself, it is not really very complicated or expensive anymore to get a full genetic workup on a tumour biopsy (various commercial labs can do this to order, or a hospital or academic research team could buy the equipment to do it themselves if they were well funded), identify unique epitopes via comparison to various public databases such as OpexVax and then create vaccines (adjuvanted-protein or mRNA-based) from this data to create a truly unique and personalised approach to cancer treatment.

Positive studies using this approach have been reported by teams at Dana Faber Cancer Institute (for aggressive brain tumours) and the Broad Institute (Melanoma). These results include some complete responses, akin to functional cures.

Both BioNTECH and US-based Moderna, the other major player in mRNA vaccines are looking at this approach with their iNeST (autogene cevumeran) and MRNA-4157 programmes respectively. In each case, a tumour biopsy will be compared to healthy cells from a blood sample to identify unique cancer-specific epitopes and a cocktail for 20-odd custom mRNA sequences will be created as a vaccine. Moderna’s construct is co-administered with Merck’s PD-1 drug pembrolizumab. Early results from the Moderna programme look very interesting, with some complete responses without detectable disease and results from a 150-patient phase 2 study could be available at the end of this year and we are genuinely excited to see what the results look like.

Let us come back to the original question – why aren’t we keen on investing in cancer if we think there is a possibility that personalised cancer vaccines, when used in combination with a checkpoint inhibitor, may potentially be curative for some patients?

Firstly, let us imagine this stuff does work really well. Happy days all around, unless of course you make your money from selling some other type of very expensive cancer treatment. If you think a revolution is around the corner, the best thing to do is leave town for a bit. That way you may keep your head. Everyone else can stick around and eat cake, that’s fine with us.

Secondly, let us put down the Kool-Aid for a moment and take some deep breaths. We have been here before, more than once; optimism is one of humanity’s greatest traits. However, we are talking about positive results in a few patients. The results are amazing for them, no doubt. But let us see how far this goes in terms of cancer types and patient types with a bit more data before we start betting the farm.

Thirdly, we must consider the IP situation here. From what we can tell, Moderna and BioNTECH are planning to do exactly the same thing. Others have done it before with off the shelf kit. How easy is it to build a protected franchise in this stuff? Can others follow? If you wish to commercialise such a product at scale, you need to convince regulators, doctors and patients that you can deliver the product to them in an acceptable timeframe (cf. Dendreon). In this respect, you may be better with some artisan product from a cancer lab at a major hospital than with big pharma. Based on what the research-led initiatives have said, this is going to be expensive and the economies of scale are not that huge, given it’s a bespoke product for each patient.

Finally, let us assume that we can get comfortable with points 2&3. There is then the question of whether or not the assets in question represent a good investment opportunity. In the case of BioNTECH and Moderna, this question is currently clouded by the wider COVID vaccine situation.

Interesting times indeed and we are very much looking forward to seeing how things unfold… from the sidelines.

We always appreciate the opportunity to interact with our investors directly and you can submit questions regarding the Trust at any time via:

shareholder_questions@bellevuehealthcaretrust.com

As ever, we will endeavour to respond in a timely fashion and we thank you for your continued support during these volatile months.

Paul Major and Brett Darke