I attended the CAR-TCR Summit Europe 2019 (http://cartcr-europe.com/) over February 26 and 27, where I got the chance to see a variety of fascinating talks on the burgeoning field of T-cell redirection for the treatment of cancer. It was also an opportunity to meet with scientists from pharma companies, biotechs and academic institutions; regulators; reimbursement specialists; and healthcare providers interested in the potential for CAR-Ts (Chimeric Antigen Receptor-T cell therapies) and TCRs (T-Cell Receptor therapies) to transform cancer therapy. With enough high science presented to make the head of this (as someone very aptly put it to me during the conference) reformed scientist spin, I will leave the summary of findings presented to those more research-inclined. Instead I want to pull together a few points that left a lasting impression to me and even extract some learnings for companies entering, or already navigating, this vibrant area.
Excitement, camaraderie and partnership
In our industry, we talk and write a lot about buzz. Every new merger, venture, molecule, biologic gets hyped. You could argue that this is the case with CAR-Ts and TCRs but it honestly felt different. Throughout the presentations, poster sessions and impromptu chats at the well-catered coffee breaks and drinks reception here was genuine excitement and goodwill among the different stakeholders. You could argue that this is due to the newness of it all and how close to the lab we still are but I think there is more to it than that. This collaborative spirit is also born out of necessity. This will be a common theme from our learnings – right now it feels like since there are no standards set yet, everyone involved in bringing Advanced Therapy Medicinal Products (ATMPs) to the market is trying to work together to find the most efficient way of operating to, ultimately, get products to patients. It was truly refreshing to hear drug developers freely discussing how the regulators and value assessors are “bending over backwards” to help them.
If you are or getting into the CAR-T or TCR space, be prepared to find yourself engaging partners, regulators, HTA assessors and healthcare providers much earlier than you would “normally” expect to. While this will give you an opportunity to collect early feedback and adjust your direction it will also mean that you need to be ready and flexible if you are to make the most of this early engagement.
If only there was a rule book to rewrite
CAR-Ts, and in particular autologous CAR-Ts like the ones currently commercially available, not only represent a new therapeutic approach for the treatment of leukaemia and lymphoma (and maybe soon of solid tumours), but also a completely new method in developing and delivering this treatment. Every other presentation in the CAR-TCR summit had diagrams (of varying complexity) explaining the stepwise process of apheresis, enrichment, gene modification, activation, ex vivo expansion, quality assessment, formulation, delivery back to the clinic and finally administration back to the patient. It quickly became apparent is that there is a daunting number of new processes and concepts for the ATMP manufacturers to content with - every step in the process described breaks down to smaller sub-steps, which are either designed from scratch or constantly optimised. This is a far cry from traditional and standardised small molecule pharmaceutical manufacturing, and even a stepwise change from one-size-fits-all biologic therapies.
From the practicalities of scalable cell culture, to managing the supply chain, to dealing with chain of custody and chain of identity, to the selection and training of specialist centres, to the handling of inpatients and outpatients (who may be outpatients in name only, since they may have to be kept in special observation units), to the poorly understood regulatory environment (that may have you dealing with untold numbers of local authorities to get a clinical trial authorisation in Germany, or trying to follow two different interpretations of the European legislation governing the transport of the activated cells), everything is being revised time and again and the industry standards typical of a mature process are conspicuous by their absence.
So what does this mean for you if you are trying to bring a CAR-T in the market? It means that you must get comfortable with uncertainty. Learn to form hypotheses and use them to drive decisions and learn to closely monitor the right metrics that may signal changes in conditions and the need to revisit processes. If there was one thing that everyone seemed to agree on it is that in this space, agility will win.
Innovation attracts innovation
The CART-TCR Summit brought together the novelty in every aspect of developing and commercialising an ATMP. And this innovative, cutting edge area of science will inevitably attract more innovation on all fronts, around the novel medicinal products themselves. There is a lot of white space surrounding CAR-Ts and TCRs and the temptation will be to fill it with out-of-the-box thinking. However, this search for innovation as a cure-all can end up being a distraction or delaying factor rather than an accelerator. New, larger culture vessels with semi-permeable membranes that will allow you to scale up your cell cultures seem a great idea, but does your company also really need blockchain to handle patient data?
In making decisions on when to apply further innovation you must be open but critical and pragmatic. Always keep in mind the challenge you are trying to overcome and the appropriate scale of the solution. Not everything will need to be re-designed for the sake of it – on the other hand, there is opportunity for those who present the right innovations at the right time and make them the new standard.
Engage early and often
We consultants constantly counsel our clients to seek advice as early as possible when dealing with new challenges or projects central to their brand or therapy area strategies. Early engagement may have become a cliché but it is not always done equally well – and it holds true especially in a dynamic, ever-shifting space such as ATMPs. When it comes to CAR-Ts and TCRs everybody is on the same steep learning curve. Understanding will evolve, opinions will change, new evidence will emerge – and early discussions with regulators, assessors and gatekeepers will allow companies to be a part of the learning conversation.
Engage early, form your hypotheses, plan for success, review and revise frequently. Start by identifying your unknowns, engage in scenario planning around them, lay out the roadmaps and trigger points that signify changing conditions, partner with regulatory authorities and other stakeholders early and keep these conversations alive.
CAR-Ts and TCRs have immense therapeutic potential and with it promise an exhilarating, thrill-filled journey from lab to patient. Here at Cello Health we are proud and excited to be part of that journey and help navigate our clients through this novel space.