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Looking to the future of oncology

Published on 09/04/18 at 11:10am

The oncology field moves so quickly that it can be hard to keep track of the latest innovations. Ben Hargreaves assesses some of the major movements and looks to the future of treatment

Pharmaceutical companies currently love the oncology space. It’s an area marked by high innovation and, more controversially, high prices. Both of these factors combined give pharma plenty of reasons to invest in the area and that’s exactly what’s happened; most big pharma players have pivoted to the space to drive growth, leading companies such as MSD (known as Merck in North America), AstraZeneca and Bristol-Myers Squibb to focus their respective pipelines in the area.

All three of these companies have one thing in common: a PD-1/L1 immunotherapy treatment in their portfolio. Since their development and first approval by the FDA in 2014, the therapies have changed the field of oncology permanently. Many patients who otherwise would have had no treatment options have had their lives extended or been sent into complete remission by the drugs. This form of treatment was welcomed as a huge breakthrough in the field and they have gone on to have serious successes in the intervening years, with an entirely new indication granted to MSD’s Keytruda for treating patients based on specific genetic features rather than a tumour’s location in the body – a first in cancer treatment.

The area continues to develop and more is expected as companies begin to explore combination treatments that will only make this wave of therapies more effective. However, the focus of this feature will not be on these types of immunotherapies – much has already been written on them – but on the next wave of treatments coming through, potential treatments of the future and of progress that still needs to be made in certain areas.

CAR T: Driving cancer treatment to new heights

PD-1/L1 treatments are still the darling of the industry, not least because the financial success that they have brought to their owners, but the latest science that has captured the imagination of the industry has moved on, and rapidly, to focus on CAR T treatments. Similar to PD-1/L1, the reason is due to how effective the treatments are for patients that would, only a few years prior, have had no hope for further treatment; now, those same patients are being treated with CAR T therapies and being sent into remission. This success is not in an isolated few patients that have reacted well to treatments – it has been seen in a large proportion of patients in trials.

Novartis’ Kymriah was the first to achieve approval, under authority of the FDA in the US, based on incredible data from a paediatric trial into the treatment being used to treat B-cell precursor acute lymphoblastic leukaemia that was refractory or in second or later relapse. The results of the Phase 2 trial revealed that 83% of patients receiving the treatment achieved complete remission within three months of infusion.

Paying the price for innovation

A one-time therapy in patients with no other treatment options achieving such a high-level of response is almost unheard of in the industry, with the closest, most recent parallel being Gilead’s hepatitis C treatment, Sovaldi. Much like Gilead’s treatment, there is one considerable controversy over CAR T: the price. When treatments have such a profound impact on patients, there’s usually a price tag attached to reflect this.

So it was the case with Novartis’ Kymriah, which has a cost of $475,000 per course of treatment. In order to offset the huge price tag, it positioned itself aggressively by promising that if patients did not see any benefit from the treatment within one month, it would not charge for the dose. Some would argue that this was a means of ensuring that the pharma company only charged when patients saw benefit; the cynics would argue that it’s a PR exercise designed to deflect from the price and also to position itself proactively against its closest rival, Gilead.

Gilead entered the CAR T area by using the massive profits it had gained from Sovaldi and its other hep C treatments to fund the $12 billion purchase of Kite Pharma, acquiring its ready-to-commercialise CAR T treatment, Yescarta. Gilead didn’t offer the pay-for-performance deal offered by Novartis because its patient pool for its first indication is too small to make this feasible. It led Gilead to offer its treatment at a price of $323,000, for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.

A developing field

Novartis and Gilead are the two big pharma behemoths dominating the CAR T scene, but they are not the only players in the market and definitely not the only ones looking to make an impact. One company that has received a good amount of press regarding its own work in the field is TC BioPharm. Unusually for a UK-based biotech, the biotech is based in Scotland, just outside Glasgow, but has attracted enough to attention to have recently signed a deal with NIPRO, a Japanese pharma company.

Speaking to Chief Executive Dr Michael Leek on the current position of TCB’s treatment, he revealed: “We’ve done a safety and dose-escalation study in late-stage cancer patients, who had not responded to any previous treatments, and were able to show that we could take gamma-delta T cells out of those patients, grow them up in large numbers and infuse them back with no safety issues. In addition, some patients with aggressive disease showed evidence of stabilisation. In all of those patients, we were able to get doses of 50-60 billion cells – so, very large cell numbers. We can use this backbone technology, the ability to expand gamma-delta T cells in very large numbers, and CAR them to attack various different cancer targets/antigens. This is the second part of the technology – the ability to take our platform, the expanded gamma-delta T cells, and then add a CAR.”

Commenting on what sets TCB apart from the previously mentioned competitors in the field, he said: “The majority of CAR T treatments are predicated on alpha-beta T cells from the adaptive immune system and, in some cases, there have been toxicities linked to on-target-off-tumour effects where healthy cells have been targeted. We’re differentiated because our gamma-delta T cells are programmed only to become killer cells in the presence of IPP and healthy cells aren’t affected as they don’t produce IPP. We’re differentiated by virtue of the fact that gamma-delta CAR T cells will only be activated in the presence of IPP secreted by cancer cells.”

One major question that observers have on both Novartis’ and Gilead’s respective treatments are whether the success they’ve achieved in liquid tumours can be developed further to actually target solid tumours. The first treatment that could manage this would have a huge competitive edge, though it would obviously be dependent upon what results were shown.

Dr Leek sees this as a major advantage of the science behind TCB’s method of action. He explained: “If you look at the alpha-beta approach, while you may be able to treat haematological lesions, it may be difficult to treat solid tumours. Delivering billions of cells to attack a solid tumour antigen which is also expressed in large amounts on healthy tissues could be deleterious to the patient. With our products we are able to move from liquid, haematological tumours very quickly into solid tumours – for instance many different cancers express EGFR, as do many types of healthy cell. However, using our approach, the gamma-deltas would destroy the cancer cells, but specific binding to a healthy cell will not result in its death. That’s the market differentiator for our company – being able to rapidly progress treatment of solid tumours with large numbers of therapeutic cells.”

This adds up to a potentially promising future for the biotech and Dr Leek described how he had set up the company with a view to the long-term: “From the get-go, we’ve built a GMP manufacturing facility in Scotland so we could control our own destiny, and make our own product using our own quality systems. We also have a clinical team who run all our clinical trials in-house. We’re an integrated, small-cap pharma company that does everything ourselves, having grown to a 60-person team very quickly. That’s where our real strength lies because we have the bandwidth to treat patients without having to rely on third-party contract manufacturers. This allows us to move products into the clinic very quickly, through Phase 1 and 2 and eventually onto Phase 3. We don’t have a sales and marketing infrastructure however, so, our initial plan to get products into the market is to partner with companies like NIPRO and bluebird bio. I’m not ruling out TCB taking orphan indications to market ourselves, but for the moment our commercial approach is to partner with other companies that have existing sales and marketing skills.”

As mentioned previously, cost is a major talking point regarding any product within the oncology space and particularly within CAR T. Dr Leek was keen to position TCB away from some of the price tags that have been mentioned previously: “For both unmodified, gamma-delta products and CAR T variants, we’re looking at a cost of goods that should allow us to compete with products like the Novartis CAR T currently priced around the $500,000 mark. We believe it’s not just about showing efficacy – although that’s one of the most important endpoints – but we have an obligation to try to get the price down, providing greater access to cancer patients. Based on current estimates, we can make a significant reduction to those costs.”

Continuing innovation

If CAR T has been one of the most promising breakthroughs in the oncology space in recent years, it is only a sign of an area that is gathering huge momentum in research, funding and breakthroughs. One area that is now becoming increasingly spoken about is the potential of up or downregulating noncoding RNAs, which are known to play a role in the development of cancer, alongside autism and Alzheimer’s disease.

One scientist who is playing his part in extending the understanding of the role played by noncoding RNAs in the development of cancer is Dr Chandrasekhar Kanduri, who works out of the University of Gothenburg, Sweden. He described to Pharmafocus his recent proof-of-concept study looking into the relation between specific RNAs and cancer: “We selected the top differentially expressed and clinically-relevant lncRNAs and performed loss-of-function experiments using in vitro RNAi-based screening. The silencing of the selected lncRNAs in multiple cancer lines has significantly reduced the proliferative capacity of the cells and induced cell cycle arrest and apoptosis. Hence, we termed these lncRNAs as SCATs which stands for S-phase Cancer Associated Transcripts.

“We performed in depth studies on SCAT7 which is highly expressed in lung adenocarcinoma (LUAD) patients and acts as independent prognostic marker for patients’ survival in kidney clear cell renal carcinoma (KIRC),” he continued. “The silencing of SCAT7 in multiple cancer model systems reduced the proliferative capacity of the cells and restricted the invasion and migration capacity of LUAD and KIRC cell lines. Interestingly, we found that high levels of SCAT7 expression allow the cells to bypass senescence while lower levels promote oncogenic-induced senescence. Following that, we utilised high throughput sequencing to investigate the global effect of SCAT7 silencing on the transcriptional activities of HeLa cells (cervical cancer model), Caki-2 cells (KIRC model) and A549 cells (LUAD model). Surprisingly, SCAT7 silencing interfered with major pro-survival cancer signalling pathways such as FGF/FGFR and the downstream PI3K/AKT and Ras/MAPK pathways. We proposed a molecular model where SCAT7 interacts with hnRNPK/YBX1 complex to promote the transcriptional activity of different FGFR members and induce cell proliferation.”

In order to test how this worked in practice, Dr Kanduri moved the study into mouse models to determine potential therapeutic angles. He explained the findings: “Considering the functional role of SCAT7 in the regulation of cancer cell hallmarks, we explored the potential use of SCAT7 as a therapeutic target in cancer treatment. So, we separately engrafted immunocompromised mice with LUAD and KIRC cell lines deficient of SCAT7. In comparison to wild type cells, the silencing of SCAT7 has significantly reduced the tumour growth parameters. Moreover, we designed a treatment regimen where we locally injected locked nucleic acid (LNA) anti-sense oligonucleotides (ASOs) targeting SCAT7 into xenografts bearing lung metastatic patient-derived tumours (PDX). After five injections over 15 days, we observed 40-50% reduction in tumour growth compared to control. In conclusion, our study provides a comprehensive catalogue of lncRNA-based prognostic biomarkers and also demonstrates the potential use of lncRNAs in cancer therapy.”

The study is highly promising but the human applications, at least at the present moment, are limited. However, Dr Kanduri was keen to emphasise that the area, as a whole, could push forward cancer treatment exponentially: “Current cancer treatment methods based on protein coding genes offer only a 15-50% chance of cure, depending on the cancer. One explanation for this could be our poor understanding of how genome works during normal and cancer development. Given that nearly 98% of the transcriptional outputs represent noncoding RNA and a mere 2%, or less, constitute protein coding RNA, one can envisage a strong role for noncoding RNA in cancer development and maintenance. Consistent with this notion, accumulated evidence over the last decade implicate a strong role for noncoding RNAs in tumour development and progression. More importantly, to better anticipate the future of noncoding RNAs in cancer treatment, we need to have a better understanding of the complex regulatory network that governs the activities and functions of these RNAs in both normal and pathological conditions.”

Much still to be done

If Dr Kanduri’s research represents the future of where cancer research may be heading, there are still important questions in the short-term that need to be answered moving into the future. One of those tough questions is in the disparity of treatment outcomes within cancer. As Dr Kanduri mentions, treatment outcomes can vary widely and an area that has struggled hugely with effective treatment options, as well as ensuring individuals are diagnosed with sufficient time for treatment, is pancreatic cancer. Pancreatic Cancer UK recently revealed research showing that seven out of 10 pancreatic cancer patients will not receive any form of surgery, chemotherapy or radiotherapy.

Sarah Baird, Media Officer at the charity, explained why the organisation believes this dramatic headline is important: “We hope our headline will encourage researchers to further develop relationships they have with research funders and educate them about how tough pancreatic cancer is and how difficult it is to treat.

“A historic lack of research investment into the disease has meant that we have not seen the breakthroughs in the treatment of the disease, or the number of clinical trials available which we have for other cancers.

“Research funders must invest in pancreatic cancer to better understand how we can more effectively treat the disease, as existing treatment options are very few and not very effective. This should then lead to more clinical trials and then in the future, new treatment options. An advance in treatment that led to improvement in survival outcomes would be a monumental step forward.”

Calling on pharma

Advances in treatment often come from the pharma industry and Baird referenced how she hopes research initiatives will encourage companies to invest more in the treatment: “New research initiatives are being implemented in the UK that aim to increase pharmaceutical companies’ investment in pancreatic cancer clinical trials. Initiatives such as Precision Panc and the 100,000 Genomes Project provide the opportunity for deeper understanding of the biology of pancreatic cancer through molecular and genetic profiling, which could make personalised treatment selection for patients a reality. Being able to access state-of-the-art technology and world-leading expertise in this area provides a strong incentive for pharma companies to set up pancreatic cancer trials in the UK.”

In another statistic that was released through the same research, it was noted how 80% of those diagnosed with the cancer will not survive beyond a year. When asked how Pancreatic Cancer UK is aiming to change that stark statistic, Baird explained: “In the short-term, we are calling for national- and local-level commissioners to adopt the recommendations from the recently published NICE guidelines into their pathways for the treatment and care of pancreatic cancer, which should drive improvements in the treatment and care delivered and reduce variation.

“We are also leading the way towards change by sharing best practice examples in treatment and care as part of our new campaign, Promoting Innovative Practice. We want this best practice to be rolled out so more patients can benefit from it.

“Pancreatic cancer research isn't a short-term project. Over the next five years, our ambition is to double the UK survival rate for people with pancreatic cancer. We’re also calling for at least £25 million to be spent on research into pancreatic cancer by all funders in the UK every year by 2022.”

Reasons for optimism

Though it is always best to be mindful of the work still to be done to combat cancer, the advances that are being announced daily should temper any pessimism about how quickly the area is developing. Treatment is rapidly changing from even a decade ago, where even previously untreatable cancers are becoming targetable. Some of the research mentioned during the course of this piece also point towards a future where new innovations could open up new avenues of treatment previously thought impossible – hopefully this will soon include a new breakthrough in pancreatic cancer.

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