War on cancer – is the end in sight?

More than four years have passed since Global University Venturing last detailed some of the university venturing trends in cancer treatment, but that is little more than an instant in humanity’s long fight with the disease.
Billed as a comprehensive “biography” of cancer, Siddhartha Mukherjee’s Emperor of all Maladies charts humanity’s understanding of a condition that ruthlessly hijacks, replicates and fortifies human DNA, to the cost of countless lives.
Cancer has been targeted for thousands of years. In times less medically sophisticated, society opted for the best tools available, often resorting to rudimentary surgical cleavages or resigning itself to superstition, stigma and palliative care.
Mukherjee’s book tells the fascinating story of some of the 20th century’s eminent oncologists and their advocates. Faced with human tragedy, the likes of Sidney Farber and Mary Lasker sought to convince the government, public and the medical profession that a “war” on cancer could be won, with sufficient will and funding.
Their efforts were not without error.  Breakthroughs descended into despair as patients relapsed. And yet our understanding of cancer has gradually improved, alongside advances in radiation therapy, surgery and cytotoxic drugs.

Immunotherapy

Oncology today is a profession emboldened, after decades of targeted government funding and as pivotal insights into genetics and immunotherapy begin making their mark.
Paul Ashley, the head of licensing and ventures for life sciences at University of Oxford’s tech transfer office, Oxford University Innovation (OUI), said: “We have an early-stage drug discovery initiative called Lab282, which looks at new drug discovery projects from the university. Around a third of our applications have been oncology projects.
“There are a good number of early-stage ideas, potential new targets and new insights into the biology of disease states that are exciting, but these can be some way off development into products or treatments. The university also has great examples of innovations and discoveries that are at the cutting edge of immuno-oncology and some of the more developed approaches to treating cancer.
“I am in tech transfer, so I am an inherent optimist. Immuno-oncology is an incredibly busy field with many clinical trials going on at the moment. People are looking very innovatively at how to make these new types of treatment more bespoke, more personalised and combine them with some understanding of the disease to create the best chance of success.
“Collectively, this does represent a pretty big step change [for cancer treatment]. Also, with a better understanding of genomics and the ability to have many subsets or cohorts of patients, it means one can only hope this is an approach that is going to have some success.”
Immunotherapy, in particular, appears on the threshold of a stunning success, as the idea of equipping immune system blood cells with enough firepower to thwart what is known as cancer’s immunosuppressive environment gains traction.
Last month, the UK’s National Health Service pledged to expand its range of next-generation medicines, building on the provision of Roche’s Herceptin for HER2-positive breast cancer, which includes an immunotherapeutic element, in 2017.
Also in 2017, US regulator the Food and Drug Administration approved pharmaceutical firm Novartis’s first chimeric antigen receptor engineered T-cell therapy (Car-T), Kymriah, for treating of patients up to 25 years old with refractory or relapsed precursor acute lymphoblastic leukaemia.
Car-T is one of immuno-oncology’s most promising advances. The technique involves showing tumour antigens to a patient’s guardian white blood cells – known as T-cells – so they can recognise and attack the same antigens on the surface of cancerous cells.
Work in the same area has led to the emergence of what is termed genetically-modified T-cell receptor (TCR) therapy, which differs in that it aims to remove the tumour’s protection against T-cells through gene modification, rendering them vulnerable to attack by antibodies or small molecule drugs. Both approaches have generated considerable excitement, and, looking back over GUV’s case studies from 2014, immunotherapy spinouts appear to have progressed furthest.
Oxford immunotherapy spinout Adaptimmune went public the following year for $191.3m, surpassing its $175.7m target. The company’s approach, dubbed NY-ESO TCR, utilises genetically modified TCRs trained to confront the tumour-specific antigen NY-ESO.
Adaptimmune has a strong business development relationship with drug maker GlaxoSmithKline, which activated an exclusive option on the spinout’s NY-ESO TCR therapy for indications including synovial sarcoma in 2018, after it had proved effective in treating solid tumours in what GSK claimed was a first for cell therapies. Adaptimmune has now turned its attention to its other TCR candidates, including treatments for hepatocellular carcinoma – a form of liver cancer – bladder melanoma and non-small cell lung cancer.
GUV’s 2013 investment of the year, cellular therapy developer Kite Pharma, was snapped up by Gilead Sciences for $12bn in August 2017, months before its Yescarta T-cell product became the second FDA-approved gene therapy, targeting certain forms of non-Hodgkin lymphoma.
Kite now operates as a wholly-owned Gilead subsidiary, adding its expertise to Gilead’s core offering, which had historically focused on HIV and Aids. And to complete the circle, Kite now invests in spinouts, having acquired University of California San Francisco cellular medicine company Cell Design Labs in December 2017 and bought shares in University Medical Centre Utrecht-founded TCR drug developer Gadeta in July last year.
Acclaimed for GUV’s Deal of the Year in 2014, Car-T spinout Juno Therapeutics had amassed $310m of external funding within the space of 10 months before it was sold to drug major Celgene for an eye-watering $9bn the following year. However, the company suffered a major setback in late 2016, when five patients died from brain swelling during clinical trials of its JCar015 Car-T candidate.  It was tragic proof that the spectre of failure is never far from the surface for pharmaceutical developers.
Juno’s current lead drug, JCar017 for B-cell non-Hodgkin lymphoma, is currently recruiting patients for phase 1 clinical testing. The company’s platform extends research from Fred Hutchinson Cancer Research Centre, Seattle Children’s Research Institute and Memorial Sloan-Kettering Cancer Centre.
Away from T-cells, oncologists are targeting other immune system responses that could combat cancer in patients unresponsive to first-line immunotherapies. With only around 25% of cancer patients responding to immunotherapies at present, according to Ashley, alternative techniques that demonstrate therapeutic credibility are likely to draw significant investor interest.
One alternative, crowned GUV’s 2018 Technology of the Year, is being advanced by Dundee and Stanford-linked Palleon Pharmaceuticals, which believes it has identified another route to stimulating the immune system’s ability to fight tumours.
Palleon’s thesis focuses on sugar molecules called glycans on cancer cells, which are known to deceive the body’s glycol-immune checkpoints as to cancer’s presence. Given that more immune cell subtypes present glycol-immune checkpoints than just T-cells, Palleon hopes the concept will help patients who have already failed T-cell treatment.
The concept has struck a chord with big pharma, which was well represented in Palleon’s $46.7m series A round. Four pharmaceuticals corporate venturing units – GlaxoSmithKline’s SR One, Pfizer Ventures, Takeda Ventures and AbbVie Ventures – committed funding, as did Singaporean government-backed VC fund Vertex Healthcare.
Stifling immunosuppression is also the motivation for a fresh group of projects targeting the immune system mechanism responsible for converting nutrients into energy, known by biologists as the immuno-metabolism.
Cancer stunts the immuno-metabolism by commandeering its nutrients, forcing immune cells to operate at a metabolic disadvantage. Immuno-metabolic drugs could therefore work alongside existing immunotherapies to improve their effectiveness. Spinouts pursuing immuno-metabolism research include Johns Hopkins University’s Dracen Pharmaceuticals, which closed a $40m series A round backed by Osage University Partners, Deerfield Management and I&I Prague in March 2018.
Dracen is developing both standalone and combination treatments centred on a class of glutamine antagonist. Coincidentally, the company is an example of academic cooperation across borders, advancing research from both Johns Hopkins University and the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences in Prague.
Also making headway in the immuno-oncology space are vaccines such as those conceived by Oxford’s Vaccitech, whose pipeline includes a candidate for metastatic prostate cancer. Vaccitech is one of a number of vaccine developers looking to exploit a biological vector ordinarily used by the adeno-associated virus to deliver an antigen that will drive an immune response.
For all the promise of immunotherapy, however, we are still to reach the point where its drugs satisfy the needs of most cancer patients. Engineering patient-derived T-cells is a complex approach unlikely to fit the circumstances of many, restricting the scope of their utility, according to Bobby Soni, a life sciences-focused partner at UK-based commercialisation firm IP Group.
He said: “I think there are some very large technical hurdles associated with what is out there. At the moment, Car-Ts are taken out of patients, modified and then put back in. That is doable but it is not a process for all patients. We need to reach the point where we have allogenic T-cell therapies you are able to take off the shelf and give to patients, much as you would with any other biological products, rather than the complicated manufacturing process of autologous therapies where the patient is the source. That is a large technical hurdle, but I think when we reach that point where Car-T is allogenic that will be a huge leap for patients.”
Projects claiming an allogenic breakthrough are likely to make an impression. The aptly-named Allogene Therapeutics is a case in point, having filed for a $100m IPO in September 2018 mere months after launching with $300m of series A funding from backers including University of California’s office of the chief investment officer of the regents and pharmaceutical firm Pfizer.

Diagnostics

With immunotherapy making the headlines, other fields of cancer research run the risk of being eclipsed. Cancer diagnostics, for example, has not produced the number of exits immunotherapy has, despite promising research.
Diagnostic stars in 2014 included Oxford Enhanced Medical, the developer of a handheld breast and liver tumour detection device powered by electromagnetic and acoustic waves. The device was aimed at communities with poor access to ultrasound facilities. The company received $1.6m of seed funding in 2015 but appears to have announced little since then.
Durham University-founded molecular testing business FScan has produced no equity update since its $163,000 seed round in 2009, though it did license its prostate cancer test to pharmaceutical development company Glide Pharma in 2014 for an undisclosed sum. FScan’s handheld test applies luminescent chemicals – elements emitting non-heat derived light – to gauge how many citrate compounds are present within a fluid sample, with sub-normal citrate levels a strong indicator of prostate cancer.
Diagnostics companies often generate lower investments than therapeutic medicines, but that is likely to be a function of the soaring costs associated with drug development. Also, given cancer treatment becomes less propitious as the disease develops, it follows that improved diagnostics are fundamental to the discovery of successful therapies.
Elsewhere, Johns Hopkins Kimmel Cancer Centre’s CancerSeek liquid biopsy project has won much publicity in recent years. CancerSeek screens eight cancer subtypes from a single blood test and can pinpoint where the disease is located. It does this by looking for genetic biomarkers denoting the presence of a specific cancer type; combinations of tumour-derived molecules floating through the patient’s bloodstream known as mutated circulating tumour DNA.
Jeanine Pennington, portfolio director at Johns Hopkins Technology Ventures, the tech transfer office of Johns Hopkins University, said: “I would say these new tests that have been evolving for the detection of disease, specifically these liquid biopsies, are quite frankly amazing.”
The direction of travel points towards diagnostics that can stratify cancer patients better, resulting in medical engagement earlier and more often. Other university-born companies focusing on expedited cancer diagnosis include University of Nottingham’s Oncimmune.
Rather than focusing on cancerous DNA, Oncimmune profiles the body’s natural immune response to cancer, autoantibodies reacting to tumour-associated antigens, which it claims emerge during the disease’s nascent stages. It is thought Oncimmune could detect cancer up to four years earlier than conventional tests.
Oncimmune floated on London’s Aim stock exchange in 2016, generating IPO proceeds of $14.5m to invest in further development of its platform. Asked whether cancer’s complex nature meant the diagnostics side of oncology was ripe for further commercialisation, OUI’s Ashley said: “I think it does, and I think we see that in the increased demand for companion diagnostics and being able to predict which patients will respond to a treatment or will avoid the side-effects of a treatment.
“A lot of what clinicians want to do is identify who is the best patient to receive all these types of drugs or combinations of treatments. You have increasing segmentation of different types of cancer, so understanding you have a patient with a certain type of cancer – and how the individual is likely to respond to a specific treatment – will then inform what you prescribe.”

Precision medicine

Many of these diagnostic advances would be impossible without precision medicine – the idea of targeting genetic malfunctions specific to a given disease. Oncologists have long studied carcinogenic triggers linked to our environment, lifestyle and genetic inheritance. However, the advent of computational tools such as genome sequencing means they have more precise information on cancer’s origins. Pennington said: “Next-generation sequencing and other developments in that area are very critical.
“When we look at detecting cancer, there is maybe less than a percent of [cancerous material] in a liquid biopsy sample – to detect cancer in a blood test where there is not a whole lot of the cancer DNA circulating around in the blood, we really need to have methodologies that are high-sensitivity and high-specifity. There is a lot of development going on the side of algorithms and machine learning to help figure out new ways of detecting that one DNA strand in a sea of thousands or millions that harbours the critical mutation that could lead to cancer.”
The importance of sequencing to oncology is confirmed by the substantive sums raised by the likes of University of California San Francisco’s Mission Bio, which has captured at least $80m in total for its high-throughput DNA processing platform Tapestri, from investors including Stanford-StartX Fund, scientific diagnostics firm Agilent Technologies, and Lam Research Capital, a corporate venturing arm of semiconductor manufacturing equipment supplier Lam Research.
Tapestri can perform DNA analysis on thousands of cells while distinguishing each one individually such that genomic variability within and across cell populations is detected. Initially, Tapestri will target blood cancer research. However, its underlying technology has also been designed with solid tumours and gene editing applications in mind.
Also from University of California, Mekonos uses microchip technology to access a cell’s DNA, paving the way for new drug programs including chemotherapies. It is hoped that, in providing a cheaper and safer means of delivering individual cancer treatments using technology rather than expensive vectors, oncological medicine will become more accessible for patients.
Genetic medicine’s coming-of-age seems particularly critical for cancer treatment because treatment traditionally favoured aggression over precision. In Mukherjee’s words, drug development was a matter of forming “large-scale chemotherapeutic attacks” with “death-defying” series of compounds. Thanks to genomics, oncology has moved beyond this hit-and-hope blitz to identify the genetic processes culpable.
Christine Gulbranson, senior vice-president and chief innovation officer at University of California, said: “Advancements in genomic sequencing have literally been fundamental to chemotherapy drug development. We are talking about accessing the DNA level of cells and being able to alter single-cell biology. When you can do that, you can accurately target and tackle cancer to remove it from the body.”
University spinouts targeting cancer-actioning genetic mechanisms include Cambridge’s Storm Therapeutics, which has built a discovery platform for small molecule drugs that inhibit RNA-altering enzymes to stop tumour growth.
While less well known than DNA, RNA is essential to the coding, decoding and regulation of genes. Previously, it has been of interest mainly for messenger RNA strands whose code outputs biological proteins, instructions that have been observed to transform alongside cancerous mutations. However, Storm has set its sights further, with plans to identify enzymes that modify a multitude of RNA subtypes to open up new avenues for treatment.
Keith Blundy, CEO of Storm Therapeutics, said: “What we are trying to do has a successful paradigm before it [in DNA research]. As with DNA and histone proteins previously, we are producing inhibitor drugs that block the modifications on many types of RNA, whether they code proteins or not, whether they are structural or not or whether they are things like micro-RNAs which regulate other genes.
“The world of understanding RNA modifications and their role in disease is still very new and is only just emerging, and one of the strongest cases for a drug target is one which methylates particular messenger RNAs. Our three main programs target three types of RNA. We were the first people trying to do this anywhere in the world – it is genuinely novel science from Cambridge University.”
Storm Therapeutics’ founding research was conducted by Tony Kouzarides, a professor of cancer biology at Cambridge’s Gurdon Institute, and one of his colleagues, Eric Miska, the Herchel Smith professor of molecular genetics.
Cambridge Innovation Capital, a patient capital fund affiliated with the university, along with Touchstone Innovations, now part of IP Group, and Taiho Ventures, the investment arm of drug manufacturer Taiho Pharmaceutical, all participated in the spinout’s series A round, which raised $21.4m across two tranches in June 2016 and January last year.
Merck Ventures and Pfizer Venture Investments, respective strategic investment divisions of Taiho’s peers Merck and Pfizer, also equipped Storm with series A funding, and the company is now raising series B funding to help push its first candidates into the clinic, with an announcement anticipated towards the middle of this year.
Blundy said: “When we talk to investors and pharma biotech companies about our progress, they think we have had a very successful couple of years. We have some proprietary tools in our drug discovery toolkit that allow us to do things through mass spectrometry that no one else has – for instance measuring the amounts of particular modifications in cells in specific RNAs.
“We have set all the foundations and ground rules and know that finding inhibitor drugs is a doable proposition now, and people are quite impressed by that. We are still early with the individual lead programs – the most advanced of those is now progressing to in-vivo proof-of-efficacy experiments. But that is quite good progress from a standing start in just two years.”
IP Group’s Soni added: “I think there is huge potential here. There is lots of evidence now that RNA is modified all the time and that it changes its translation. We are just getting started – the three targets coming out of Tony’s and Eric’s lab, we think that is just the beginning. Right now, they are doing a lot of the bioinformatics and target validation work that will identify additional targets to move forward.”
Spun out from Ecole Polytechnique Fédérale de Lausanne (EPFL) in 2016, Cellestia Biotech’s clinical-stage small molecule program has taken aim at inappropriate activations of a pathway – known as Notch – responsible for more than 250,000 cancer diagnoses each year. It has raised a total of $28m of funding, most recently amassing $20m in a December 2018 series A financing led by FC Capital.
The company’s approach was pioneered in the lab of Freddy Radtke, a professor in the EPFL School of Life Sciences, who said: “We were able to take advantage of the technologies offered here at EPFL to set up the screen, to use robotics and chemical libraries. We could screen small molecule libraries and then develop them further up to the stage where we had the option of making a spinout. We started Cellestia with the goal of bringing the compound we identified to the clinic and to do clinical trials to the benefit of patients where this particular pathway is active.”
Radtke said that while precision medicine marked an advance for oncological therapy, some patients might require multiple small molecules based on precision medicine to overwhelm specific tumours.
“With small molecules in precision medicine, the idea is to identify patients in whom the growth of the tumour is driven by the same specific changes within the genome. Then you want to give only the drug that will inhibit this particular pathway and driving force for these cancers no matter what the type of cancer is.
“The problem is that you can have patient relapse in cases where the tumour was heterogenous and perhaps made up of multiple cell types harbouring diverse genetic alterations, some of which respond to the drug and are killed, while others that were irresponsive from the beginning take over growth of the cancer.
“Relapse can also result from Darwinian selection pressure, where small molecules hit their target pathway and cells either stop growing or are killed, but the genome continues to acquire changes in such a way that one or more tumour cells no longer respond to the drug because the three-dimensional structure of the binding pocket of the target protein may have slightly changed.
“The answer may be to attack the cancer from different angles, but we need to know the specific vulnerabilities of the tumour. What is happening more and more is that we are sequencing the tumour of cancer patients to obtain a better idea of what pathways are deregulated or what genes are causing malfunction.
“The idea is to treat patients with combinations of drugs that are specific for the activated targets or pathways of a tumour. With knowledge of the specific genetic alterations, the treatment of cancer patients can be personalised.”
As Radtke pointed out, it is misleading to draw a simplistic picture of chemotherapy as a campaign waged against a single homogenous disease. In fact, the term cancer itself is something of a misnomer, given the multitude of variants and subtypes it has come to represent.
Moreover, the likelihood of remission varies significantly between cancer subtypes. Cancer Research UK once estimated 14% of patients outlive malignant brain tumour diagnoses for at least 10 years, for instance, compared with 57% for bowel cancer patients.
Soni said: “This is a tough one because for me it is a question of why [the diseases] are tough to treat. If you think of something like pancreatic cancer, my understanding is there is almost a physical barrier around the cancer drugs getting there. So, we need other therapies that can address that.
“While you have great therapies for cell or blood-based cancers, those mechanisms may not apply to pancreatic cancer. But more broadly, I think we are in for a revolution with regards to precision medicine. You can think about for example, PARP inhibitors, and the way they target tumours, specifically due to the genetics of the tumour.
“This just opens up a mechanism where you could have very safe and very efficacious treatments that are based on the genetics of the tumour itself. These are just wonderful tools that certainly will give better treatment for all cancers, because you will have safer more specifically targeted and efficacious drugs. But whether or not these specifically address the mechanisms by which hard-to-treat tumours are [resistant] to treatment is still to be determined.”
Duke University-founded Cereius is researching metastatic brain cancer, a later stage of the disease where metastatic lesions have sprouted far beyond the tumour site, making successful treatment less likely. Cereius hopes to combine targeted therapies with next-generation radiotherapeutic techniques to bypass the blood-brain barrier and carry enough force to penetrate shells surrounding metastatic tumours.
Also focusing on metastatic cancer is University of California’s AlloOnc, whose MesenkillerTM platform aims to solve the problem of toxicity in conventional radiation and chemotherapies by introducing an element which activates only once it has engaged directly with cancer cells. AlloOnc’s approach is evidence further improvement in cancer therapeutics could yet emerge by using technologies that improve the impact of existing drugs.

Ultrasound

Another example is the use of ultrasound, collections of sonic vibrations of a frequency typically used for medical imaging purposes, to assist penetration of drugs into a tumour. In July 2018, clinical research published by a multidisciplinary team at University of Oxford showed how the use of nanoparticles and ultrasound could assist cancer drugs penetrate a tumour.
Constantin Coussios, director of the Oxford Institute of Biomedical Engineering, led the research having co-founded spinout Oxsonics in 2013 to commercialise the design. Oxsonics raised a total of $15.9m across its series A and B rounds, supported by the university and an assortment of institutional and private investors.
OUI’s Ashley said: “Oxsonics is looking at an approach to aid the delivery of cancer drugs to the right location. The technology helps push existing therapies deeper into the tumour and so they are looking at their technology being used alongside existing and novel cancer drugs such as checkpoint inhibitors or small molecule cancer therapies.
“They have a nanoparticle that holds a small microbubble and if you pulse that with ultrasound it creates a mechanical force – cavitation – which pushes the cancer drug deeper into the tumour. Obviously one of the issues with the tumour microenvironment is that it is very hard to get these drugs into the centre of the tumour.”
Oncologists are also experimenting with ultrasound as a tool in cancer surgery, in many cases the most appropriate course of treatment for early-stage tumours yet to migrate. One spinout focused on ultrasound cancer surgery is University of Michigan’s HistoSonics, which had amassed about $42m of equity and debt funding as of July 2018, the year after its device, Rast, completed a set of preclinical trials.
Ultrasound waves pulsed from Rast can target tumours at a variety of locations in the body. Capable of ablating tissues at both cellular and sub-cellular levels, HistoSonics hopes the concept will end the need for deep surgical incisions.
Despite the potential of ultrasound, surgery more generally has spurred less oncological activity at universities compared with immuno-oncology and small molecule drugs. Of the 216 oncology spinouts and university-linked businesses tracked by GUV since 2016, only nine have been set up explicitly to commercialise surgical oncological projects.
It may be that the prospect of a step-change in oncological surgery has not grabbed inventors and investors to the same degree as advances in other areas. It is possible other innovations will make the need for surgical removal of tumours less frequent, Pennington suggested.
She said: “I know if I talked to our investigators here, and they are especially strong in the diagnostic space, the view is if you can detect the cancer before it needs to be operated on, the chances of survival go up orders of magnitude. If we can really find cancer early, we can treat it before something shows up in the scan and we may not need surgical intervention.”
However, another explanation may be that the tech transfer paradigm for surgical devices differs substantially from that of pharmaceutical products. Ashley said: “Typically surgical procedures are less easy to transfer and less easy to expose, commoditise or define because they are often in the hands of one individual.
“We have seen that technologies, like certain medical devices and surgical aids, are sometimes best licensed to existing companies that already have the wherewithal or the infrastructure to commercialise the products, rather than form a spinout company around those. For example, a surgical instruments company may be the best home for what may be a fairly niche surgical instrument for a particular disease area.”