In just a couple of decades, immuno-oncology has taken center stage in the biotechnology industry. We discuss the evolution of the field with experts who have been in it from the very beginning.\r\n\r\nWhile immuno-oncology is one of the hottest areas of medicine at the moment, that wasn’t the case 20 years ago. The idea of harnessing the immune system to fight against cancer just wasn't heard of. \r\n\r\nBack in the year 2000, Harpreet Singh was completing a PhD in immunology. Together with two colleagues, he co-founded Immatics, a company in Germany that develops cancer immunotherapies. \r\n\r\n“Immuno-oncology didn’t really exist then. Actually, I don’t think the word immuno-oncology existed at that point,” said Singh. “I remember meeting with a pharma company and they said our T-cell technology was homeopathy, that ‘this will never work, it’s just too weak.’”\r\n\r\nIt was not the best time to start a pioneering company. “When we finally had a business plan in 2002, enthusiasm in the biotech industry had just collapsed in Europe,” Singh explained. “This was a complete disaster for biotechnology. Lots of companies died, no one was around to invest.”\r\n\r\nStill, the team persevered and managed to find their first investor two years later. This was no mean feat back when most investors did not trust the promise of immuno-oncology. \r\n\r\n“When I joined the industry in 2001 as an investor at Atlas Venture, there had just been too many failed trials over the years,” explained Karl Nägler, now Managing Partner at life sciences investment firm Wellington Partners. \r\n\r\nHe recalls a company in the portfolio of Atlas Venture, called IDM Pharma, which aimed to direct the immune system against tumor antigens. “It sounds quite modern today. At that time, it sounded like science fiction.”\r\n\r\nWhile companies like IDM Pharma and Micromet ended up being very successful pioneers in the field of immuno-oncology, that was not so apparent 20 years ago. \r\n\r\n“The issue was that many of those ideas were based on concepts from the ‘80s and there was just not enough knowledge about the immunology of cancer to make such drugs work. We didn’t know how to study those drugs,” Nägler said.\r\n\r\nIn the beginning, many considered that immuno-oncology was not just too complicated, but even dangerous. In 2006, a cancer immunotherapy developed by German company TeGenero caused systemic organ failure in its first clinical trial on healthy volunteers, raising concerns about the safety of cancer immunotherapies.\r\n\r\nBut just a few years later the situation started to change. Nägler believes there was an inflection point in 2011, when ipilimumab, the first checkpoint inhibitor drug, received FDA approval. That same year, Amgen acquired British immuno-oncology company Biovex for $1B.\r\n\r\nNowadays, it’s evident the tables have turned. The field of immuno-oncology has moved from being considered science fiction to creating huge expectations. Not all of them have been met. \r\n\r\n“There was the expectation that it would be quite straightforward to use combinations to bring up the response rates from 20% to maybe 60% to 80%,” said Nägler. “It worked in a few situations, but it's not yet the magic bullet for all cancer entities. We have also seen many disappointments of other checkpoint inhibitors and targets that have not delivered. On the other hand, we have seen exceptional responses in cell therapy.”\r\n\r\n“When somebody says there is hype in the field, that makes me nervous because it means there is a premature perception or assessment,” added Singh. “Hypes are, I think, irrelevant. What matters are things that work in patients, not things that are perceived nicely, although that may affect the stock price for a shareholder that’s just interested in short-term benefit.”\r\nThe next frontier in immuno-oncology\r\nWhile immuno-oncology has clearly grown and evolved over the past 20 years, it still has a long way to go. The main challenge in the field at the moment is to target solid tumors.\r\n\r\n“Checkpoint inhibitors work in certain populations, CAR-T works in certain populations, mostly hematological tumors,” said Singh. “What we really need now is to unlock solid cancers.” \r\n\r\nImmatics aims to do that by targeting molecules inside rather than on the surface of the tumor cells. “If you look at CAR T-cell therapy or antibodies, which work wonderfully in blood cancers, they just recognize extracellular targets. That’s just 20-25% of the cancer proteome,” Singh explained. “We can dive below the tip of the iceberg. Particularly in solid cancers, most of the relevant targets are sitting inside the cell, not on the surface.”\r\n\r\nBut as new technologies are starting to show promise in solid tumors, their pricing is starting to become a challenge. In recent years, CAR T-cell therapies have been at the center of this controversy, as they can reach a price of well over $400,000 per patient in the US. \r\n\r\n“Any technology in immuno-oncology or other areas always has pros and cons,” said Singh. “Cell therapies are very potent but also very complex, particularly autologous cell therapies generated from the own T cells of the patients.”\r\n\r\nSingh is adamant that with advances in manufacturing technology and the development of off-the-shelf cell therapies that are obtained from donors, part of the problem will be addressed. Still, in the future, he believes different technologies might be right for different patient populations. \r\n\r\n“Companies typically make the choice, for a very good reason, to go for one therapeutic modality. We have not taken that choice,” explained Singh, noting that Immatics is simultaneously developing cell therapies and bispecific antibodies. \r\n\r\n“This allows us to actually go to populations where, because of price points, cell therapies may have restricted entry. Larger markets, earlier cancer populations, combination treatments, where the complex applications of cell therapies may be prohibitive.”\r\n\r\n“We actually think cell therapy and bispecifics could exist side by side in different patient populations – late-stage disease with big, bulky tumors where cell therapies are extremely potent, and then bispecifics can go into earlier stage populations, or late populations with lower disease burden and be marketed as a simpler, cost-effective treatment.”\r\n\r\nAs the field keeps growing and developing, a wide range of technologies may provide different solutions to different needs. Nägler sees potential in emerging technologies such as checkpoint inhibitor targets, macrophage CARs, gamma delta T cells, and treatments that target the innate immune system. \r\n\r\nFor most players, the challenge now is to stand out among the growing numbers of companies in the immuno-oncology field. When looking at investment opportunities, Nägler says that it’s essential a company has a high level of differentiation. “That's getting more and more complicated in this field now because the largest part of biotech is oncology, and the largest part of oncology is immuno-oncology.”\r\n\r\nThe quality of the science, the expertise of the team, and an investment-focused strategy are other critical factors to make a company stand out. \r\n\r\n“Think about the end from the beginning,” Nägler advised. “It's not just about the novelty of the target. How can we, very early on, show that this is relevant in a particular patient setting? How is that differentiated from other approaches that could target the same patient setting?” \r\n\r\nAnother challenge for companies in the immuno-oncology field today is that it’s becoming very capital intensive, according to Nägler. While regular cancer drugs might already see some indication of efficacy in phase I trials, that is not the case in immuno-oncology. “It just takes a long time. Therefore, you need to be able to explain early on why this is very important for particular patient settings.”\r\n\r\nAll in all, the field is developing rapidly, and much like immuno-oncology didn’t even exist 20 years ago, a lot will have changed 20 years from now. It might take a while to see the next breakthroughs in immuno-oncology, but Singh believes it’s important to take the time needed to do things right. That is generally a particular strength of European culture. \r\n\r\n“We allow ourselves more time in Europe and we’re not ashamed of it. We’re not the usual fly-by immuno-oncology company that’s been just built and may die in a short time,” said Singh. “Deep and long history translates into quality.”\r\n\r\n\r\n \r\n\r\n\r\n\r\nCover illustration by Elena Resko. This article was originally published on 20/07/2020 and has since been updated.