SALV
Red Hot Biotech Alert:
Dear Reader,
In the late 1990s researchers working for the Japanese pharmaceutical company Kirin extracted a chemical from a marine deep sea sponge which, they found, activated certain cells. This is the origin of a new approach to cancer therapy that could propel our latest Breakthrough Biotech portfolio pick to stardom.
As I described in BBA #223 (August 8th) SALVARX (AIM: SALV) is intent upon taking the most promising research in the field of cancer immunotherapy and turning then into commercial winners. So far it has invested in just two programs, one from the USA’s Intensity Therapeutics and the other, from my home city of Oxford, from iOx Therapeutics. To get the latest news on the latter I cycled up the Weatherall Institute of Molecular Medicine to meet iOx’s founding father Professor Vincenzo Cerundolo, the man who has spotted the potential of this sea sponge compound.
Professor Cerundolo is bullish for cancer immunotherapy and as he is a scientist this enthusiasm is of course based on observable facts. ‘The field of tumour immunology is on very solid, both conceptual and technical, footing,’ he has said. ‘We are benefiting from the basic knowledge derived from the last thrity years of research and we are applying those concepts to the clinic, to cancer patients right now.’
http://www.imm.ox.ac.uk/vincenzo-cerundolo
‘By far the most exciting development in the field,’ he continues, ‘is the use of antibodies that can block inhibiting signals in T cells, lowering the threshold of activation of T cells.’
This is the basis of today’s key cancer immunotherapy drugs, such as Bristol Myers’ nivolumab, Merck’s pembrolizumab, and Roche’s recently approved atezolizumab. The ‘-ab’ suffix denotes antibody and each of these acts to prevent the cancer cell from fending off the killer T cell. This makes them all ‘checkpoint inhibitors’, a class of drugs that ‘relieves the brakes’ on the immune response whereas other drugs aim to ‘press the accelerator’ by giving the immune response a boost.
As I said in BBA #223, these checkpoint inhibitors have proved effective and in a minority of cases cleared up the patient’s cancer. The thrust now is to understand why they do not always work, and improve therapy by delivering other drugs in conjunction – pressing the accelerator and lifting the break at the same time, perhaps. I hope that you know this much already and also that Professor Cerundolo’s drug candidate, IMM60, is likely to be tested on patients in combination with a checkpoint inhibitor – more on this in a moment. But I wanted to understand exactly how IMM60 works. This is not easy to explain, but here goes.
I have often referred lazily to T-cells as if they are the only cells of the immune system, roaming the body and killing anything that should not be there. But rather than a single player the immune system is an orchestra with several players including B-cells, thymocytes, granulocytes, macrophages and more. One cell type is the invariant Natural Killer T-cell (‘iNKT’s). In a 2013 paper in Nature Magazine these cells were described as existing ‘in a poised effector state, which enables them to rapidly produce cytokines (the weapons that destroy cancer and other foreign cells) following activation. They recognize…..antigens in a conserved manner, but their activation can catalyse a spectrum of polarized immune responses’.
In the case of cancer this means that the iNKTs both act directly upon the tumour cells, but also set off a chain of events that further boosts the immune response.
Specifically the chain of events goes like this. The iNKT cell binds to dendritic cells, stimulating the latter to produce Interleukin12 proteins. In turn these cause white blood cells called T lymphocytes to express a surface marker called CD8. This new abundance of CD8 helps the T lymphocytes to find, and then destroy, cancer cells.
This is what biotechnologists refer to as a ‘pathway’ that starts with activation of the iNKT cells and finishes with destruction of the cancer cells. So the key question is – how do we set off the iNKT cells? This leads me back to the marine deep sea sponge. Remember that a chemical extracted from this was able to activate cells? Well, synthetic forms of this chemical activate iNKT cells by providing a link between them and the dendritic cells. This enables iNKT cells to hook up to dendritic cells and kicks off the process I have described.
IMM60 is the name of the link designed by Professor Cerundolo and his team, and is the basis of a new drug that has been successfully trialled agaisnt mice. Now we shall see if it works in humans. The first human trials in humans are planned and if, as seems possible, the trials are offered to patients whose metastatic (i.e. spreading) melanoma has failed to respond to any other treatment then volunteers are likely to sign up fast. In any event the trial will be very much an Oxford affair. As Professor Cerundolo explained IMM60 was discovered in Oxford, it has been developed to this point in Oxford and the trial will be run in Oxford by the leading oncologist Professor Mark Middleton. So this is a chance for the city to demonstrate that academic research is integrated into the wider medical community and it would love to be able to advertise a success.
The plan is to enrol sixty patients. Twenty would be given a checkpoint inhibitor drug (anti PD-1) on its own; twenty more would be given only IMM60; and the remaining twenty would be given both. Although the sample size is quite small this should be enough to see whether IMM60 is efficacious. If so it will attract the attention of the big pharmaceutical companies that desperately want to participate in cancer immunotherapy, but in particular it should appeal to the checkpoint inhibitor providers.
All being well the trial will get under way next year and results one advantage of trials for this sort of therapy is that results become evident quite quickly – within a matter of months the cancer either recedes or it does not. The result of this trial will be critical to the immediate future of iOx and success would persuade investors that SalvaRx has the ability to spot winners in what is a crowded space. I will of course keep you right up to date as this story unfolds, but before wrapping up I must mention two other things. First that iOx is already working on a ‘second generation’ version of IMM60, called IMM65. I will not atttempt to explain its mechanism of action, but suffice to say that this is a nanoparticle that delivers the IMM60 ‘link’ as well as an antigenic protein, and this could make it more powerful than IMM60 alone.
The other important thing that I got from my meeting with Professor Cerundolo was his appreciation for the backing of SalvaRx. Academics and business folk do not always mix easily but the Professor enthused about the progress that has been made since SalvaRx got involved, for example in arranging clinical trials. This is all most encouraging and with SalvaRx intent upon making more investments into cancer immunotherapy the story is exciting. But remember – it is very high risk. So don’t bet the ranch. My buy limit is 30p. BUY UP TO 30p.
