by ecancer reporter Clare Sansom

The One Nucleus networking organisation brings together professionals involved in research, development and commercialisation in the life science and healthcare industries throughout London and the East of England.

In 2011 it launched a series of day-long meetings known as the ‘Life Science Leadership Series’, each focusing on research, development and commercialisation in a novel technological or therapeutic field.

Several meetings in this series covering drug development in oncology have previously been featured on the ecancer site.

The latest of these, held early in 2013, was devoted not to oncology as such but to a topic that is very closely connected with cancer drug development: antibody therapeutics.

This is a fast-moving area, and significant progress in the last two years was reported at a similar meeting held at the Babraham Research Campus near Cambridge in February 2015.

The recent meeting, devoted solely to cancer immunotherapeutics, was divided into two main sections: the first was devoted to research and the second to commercialisation with a major focus on partnerships and investment mechanisms.

Following an introduction by Alain Rachon from Merck Millipore, one of the meeting’s major sponsors, Viia Valge-Archer from Medimmune and Tamara Wells from Merck Serono set the scene with a brief history of cancer immunotherapy.

A few years ago, the approach was considered to be a niche area within cancer drug discovery, but it has now entered the mainstream with a large number of drugs in clinical development.

The clinical developments that are causing such excitement today, however, developed out of decades of basic research.

Arguably, the field can be traced back to 1851 when William Coley read that some patients with tumours recovered following a boost to their immune systems after an infection and began injecting his own patients with bacteria.

Today, many of the promising immunotherapy drugs in clinical trials for oncology – and many of those in Medimmune’s clinical portfolio – are focused on modulating the T-cell response.

T-cells are the key cells involved in driving the immune response to tumours, but they only do so as part of a complex set of molecular and cellular mechanisms that can be driven in different ways by therapeutics.

Valge-Archer described three developments in cancer immunotherapeutics that she would like to see: firstly, understanding variability in the patient population and dividing patients into immunological subtypes; secondly, exploring ways to alter the tumour micro-environment to sidestep immune suppression; and, thirdly, multiple and combination therapies.

Wells introduced Merck Serono’s efforts in developing cancer immunotherapy, which are also focused on immune checkpoints inhibitors and combination therapies.

Merck Serono recently entered a strategic alliance with Pfizer to develop their anti-PDL-1 antibody Avelumab both as a single agent and in combinations with other anti-cancer agents.

Adrian Dawkes from the healthcare consultancy PharmaVentures then described some of the drivers behind this commercial focus on immunotherapy in oncology.

He looked back into recent drug development history, comparing immunotherapy to a recent brief fashion for investment in RNA interference (RNAi) based therapeutics.

Industrial interest in this technique burgeoned in 2005, seventeen years after it had first been demonstrated in C. elegans, and over $2.5 billion was invested in the area mainly over the next five years.

However, this enormous investment was not translated into profitable and useful therapeutics, with one of the few drugs to be licensed - Fomiversen for CMV retinitis – withdrawn in 2013.

Immunotherapy in cancer has a longer history but is now enjoying something of a similar boom.

One of the most important immunotherapy drugs to enter the clinic in recent years was ipilimumab, approved in 2011 for malignant melanoma and the first agent to show a significant survival benefit in advanced disease.

Four different companies over 13 years were involved in the development of this drug.

Dawkes ended by highlighting the strength of the pipeline in the area, contrasting immunotherapy with RNAi and predicting, optimistically, that ‘the best is yet to come’.

The second session comprised four speakers from biotherapeutic companies describing innovative methods of targeting tumours with immunotherapy.

Davidson Ateh, CEO of London-based BioMoti, was the first to speak.

Interestingly, his company was founded as NeuroMoti, targeting neurodegenerative diseases, and changed its name when it was re-focused on cancer.

Scientists at BioMoti are developing a technology to deliver chemotherapy drugs specifically to tumour cells by targeting proteins involved in their immune regulation.

A transmembrane protein known as FasL (“Fas ligand”) or alternatively as CD95L is expressed on the surface of many types of tumour cell; CD95L binding to its receptor, CD95, on the surface of an adjacent cell causes CD95 to form oligomers, triggering apoptosis.

This is one of the major mechanisms for inducing apoptosis.

High levels of CD95L expression on the surface of tumours and their vasculature is known to be correlated with a poor prognosis.

Cancer cells use CD95L to trigger the apoptosis of T-cells and thus avoid immune-surveillance.

The technology developed at BioMoti exploits this pathway against tumour cells by coating nano-particles containing anti-cancer drugs with CD95.

These particles will be selectively taken up by cancer cells expressing CD95L, where the drug can be released selectively and gradually into these cells, sparing neighbouring healthy tissue.

The technology, which is known as 'Oncojan', has been shown to have low toxicity and to be compatible with a wide range of small molecule and biological cancer therapeutics.

Furthermore, a fusion protein developed to block the interaction between CD95 and CD95L, APG101, has been shown in a phase II clinical trial to improve progression free survival in glioblastoma when combined with radiotherapy.

The next talk was given by Steve Arkinstall, CSO of Kymab Ltd.; this company, based on the Babraham Campus, was the first to be spun out of the Sanger Institute.

Researchers at Kymab have harnessed the deep knowledge of the mouse genome from that Institute to generate a range of transgenic mice engineered to produce the full repertoire of human antibodies.

Mice engineered through this 'Kymouse' platform have normal immune responses but can produce the same approximately 1014 antibodies as humans.

Antibodies produced through this system have optimum biophysical properties and very high – up to picomolar – affinity for their target antigens, so they require little further optimisation.

It is also possible to use the technology to generate antibodies specific for the most challenging antigens, including highly glycosylated and membrane-bound proteins.

Oncology is one of the main therapeutic foci for antibodies developed through  Kymouse technology.

Tackling cancer with antibodies offers perhaps fewer complete cures than traditional chemotherapy or even targeted cancer drugs, but they are less toxic, and resistance develops less easily: it offers the chance of converting a lethal disease into a chronic and well-controlled one.

The company is exploring a number of targets for antibody-based cancer drugs, with an antibody targeted to a transmembrane protein, PD-L1 showing promise in late pre-clinical research.

Up-regulation of this protein is thought to enable tumours to evade the immune system, so inhibiting it will enhance the anti-tumour immune response.

Stephen Megit, Director of Business Development at Oxfordshire-based Immunocore, described a novel technology for re-directing T cells to kill tumour cells.

T-cell receptors have a generic advantage over antibodies as therapy in that they can be used to target intracellular as well as cell surface proteins.

Immunocore has developed a class of bi-specific, soluble proteins based on the T-cell receptor and known as ‘immune-mobilizing monoclonal TCRs against cancer’ or ImmTACs.

These consist of an affinity-enhanced T-cell receptor with picomolar affinity for its target HLA-peptide complex combined with an effector that binds T cells.

Recognition of an HLA-peptide complex on the surface of a tumour cell by an ImmTAC forms a complete immunological synapse, after which the T cell triggers apoptosis in the tumour cell.

As both parts of this construct are human-specific, toxicity tests in animal models are certain to be unreliable: pre-clinical safety testing has involved a panel of normal human cells and tissues and, interestingly, bioinformatics.

Immunocore’s lead molecule, IMCgp100, has its T-cell receptor optimised for an epitope of gp100, an antigen found on the surface of glioma and melanoma cells.

Phase I and IIa trials of this drug in advanced melanoma have shown that the drug promotes migration of T cells to the site of the tumour and induces apoptosis in the tumour cells.

Some patients on these small trials have seen durable responses of up to a year.

Megit concluded his talk by saying that there was a rich pipeline of validated tumour targets that could respond to this approach.

The final technology-based talk was given by Neill Mackenzie, CBO of Biotecnol Ltd.

Biotecnol is a specialist immuno-oncology company, located in Hertfordshire, which is engineering antibodies with multiple targets called KART-T that can engage T cells.

These “Tribodies” are Y-shaped molecules in which one arm comprises a standard Fab antibody fragment and the other two single-chain variable fragments (scFv); the molecule may be bivalent if one of the variable fragments has the same antigen specificity as the Fab region or trivalent if it does not.

There is an absolute requirement that these new generation “T-cell engaging molecules” such as these Tribodies and ImmTacs do not contain intact constant (Fc) regions, as these may trigger ‘cytokine storms’.

Biotecnol’s lead drug candidate is a bivalent tribody known as Tb535, which has two arms optimised to bind to an oncofoetal tumour antigen, 5T4, only expressed in tumour and placental tissue: the other arm is optimised to bind to CD3.

Both a chimeric and a fully human version of Tb535 have been engineered, and the fully human version is being taken into the clinic.

This molecule is being tested in mesothelioma, which generally expresses high levels of 5T4: it has shown to be effective in killing mesothelioma cell lines and reducing tumour burden in mouse models, and phase I / II clinical trials are due to start in 2016.

Biotecnol has a pipeline of Tribody products in development.

The afternoon sessions focused on strategies for finding development partners and attracting funding, and were therefore probably of less immediate interest to basic and clinical oncologists.

The topics covered included advice on selecting development partners and managing the partnership, and a checklist for maximising the chances that the crucial ‘first in man’ trial will be approved.

Richard Turner of Clinical Network Services, who gave the ‘first in man’ talk, stressed the changes that had been introduced into procedures for phase I clinical trials since the  TGN1412 trial in 2006.

Keith Bundy of Cancer Research Technology (CRT) and Ian Miscampbell of Sixth Element Capital described the CRT Pioneer Fund, which is investing £70 million in the discovery and development of new cancer drugs in the UK.

This fund aims to bridge the funding gap between basic discovery research in Cancer Research UK (CRUK) labs and clinical trials, reducing the time taken for a promising molecule to enter trials and keeping CRUK-generated intellectual property “in-house”.

Investments from the fund began in 2012 and the first molecule – a histone deacetylase inhibitor, CHR-2845 – has now entered phase I trials for hepatocellular carcinoma.

Most of the current drugs in the pipeline are small molecules, but there is no reason why immunotherapies should not benefit from this fund.

Finally, Hakan Goker of MS Ventures, the corporate venture arm of Merck Serono, presented details of their early stage company and project financing activities.

As one of the most prominent early stage investors in Europe and the USA, MS Ventures has created a large portfolio of companies most of which originate from leading academic labs covering fields such as RNA modulation, cancer metabolism, small and large molecule drug discovery platforms; they are investing from a 150-million Euro fund and have 22 current portfolio companies.

Summing up the day, Tony Jones of One Nucleus highlighted the advances that had been made since the last leadership seminar on this topic, and the pace of development is still accelerating: it is most unlikely that interest in cancer immunotherapies will fizzle out, as seems to have happened with RNAi.