The 8th CAR-TCR Summit returned to Boston from 29 August to 1 September 2023, bringing together key updates on CARs, TCRs and a variety of cell types. DDW’s Megan Thomas heard from attendees about their key takeaways from the event.
Dr Mindy Miller, Lead Research Scientist, Terumo Blood And Cell Technologies
Conversations and data shared at the CAR-TCR 8th Annual Summit highlighted the importance of optimising the science behind the therapies to broaden patient access. We now appreciate that CAR-T therapy is an effective treatment for hematologic malignancies with great strides toward solid tumours and potentially autoimmune targets. While there is immense progress on developing even better CAR constructs and identifying novel antigens and receptors, the theme that I felt strongest at this annual summit was that of increasing the availability of these therapies to patients—whether that is through ensuring equitable distribution, decreasing the burden of insurance payment, or shortening the time to infusion.
This hit home for TerumoBCT, as we strive to create products to enhance the availability of therapies to patients through automated fully closed platforms. We were able share new data that describes an expansion process in Quantum Flex that produced high quality Tscm cells in a relatively short period. With fully closed and automated devices, therapy manufacturing will hopefully be able to break the next barrier in patient access to generate safe products in record time.
Lee Buckler, Senior VP of Advanced Therapies, Blood Centers of America
What struck me about the content and tone of this year’s CAR-TCR conference was that it was as much about improving every single aspect of our current therapies and the underlying infrastructure supporting them, as it was about already thinking about how to completely disrupt them even before this occurs. For example, while we were talking in one session about how to optimise existing manufacturing to lower time and cost of production, in another session we were talking about completely disrupting the entire manufacturing model. While on the one hand we were excited about new data coming out from CAR-TCR therapies in the pipeline, we were already talking about how to evolve beyond ex vivo production of CAR-TCRs by moving everything we do to in vivo manipulation.
What is clear to me is that the pace of innovation is so exciting but fundamentally disruptive that organisations like ours supporting the industry must ensure we have a clear line of sight into the evolving ways we can contribute value without getting stuck in a particular business model that the industry pivots away from without us seeing it coming. BCA Advanced Therapies Network, for example, has a national footprint of hyper-local facilities with a well-established BioServices supply relationship to hospitals throughout the country. While today our highest value might be the supply of blood-based starting material for further manufacture of CAR-T therapies, tomorrow it might be about leveraging that footprint for decentralised manufacturing and supply of final therapies for infusion.
Becky Cap, Senior Vice President, Biobridge Global
On the six-year anniversary of the launch of Kymriah, the Advanced Therapies industry is starting to earnestly engage on the substantive issues that will directly affect access and adoption of these therapies. Scientific and clinical data presented at the conference clearly builds on decades of research and insight gained in HSCT experience. Cell and biomarker subtypes were shown this year to have critical importance to patient outcomes. As we begin to sketch in the structure of this picture of a new way of clinical practice, we’re getting some specific areas detailed finely. We are hearing about the challenges and opportunities for new populations and different starting materials to come into play, and in that discussion, we heard the echoes of the evolution of HSCT – allo, auto, matched, mismatch, haplo-, liquid tumour, solid tumour, inpatient isolation, inpatient, hospital-adjacent, financial viability, and tremendous variability in access by location and infrastructure challenge.
This year’s programme at CAR-TCR took on some of those challenges with their tracks focused on logistics and supply chain, CMC and analytics, and commercialisation. Several of the programmes this year, tackled key questions of logistical access – shortened manufacturing and release testing times for autologous therapies, the best starting materials for allogeneic therapies, and the infrastructure and control issues tied to the question of centralised vs decentralised manufacturing. On this last point, it was refreshing to see this young field emerging into the clinical and commercial arena, beginning to look to an experienced, stable network of community blood centres to help support and extend their reach to geographies and patients that might not otherwise be supportable. These access issues are important to consider alongside the more traditional economic – pricing and coverage – access issues, and it was energising to see these topics being explored and solutions being offered at this year’s conference.
It takes a special kind of determination and thinking to build in a new space – to be a pioneer. As the fields’ pioneers are proven out, two worrisome concepts emerged in the conference. We heard presentations from developers who, two decades or more ago, looked to establish proof of concept and clinical feasibility. In that context, the draw of the late-line, rare and ultra-rare disease was strong. The rationale for demonstrating benefit in the sickest patients and small populations made sense. Even so, the licensing approvals over the past six years have relied on development visions established 20 years ago. The commercial reality of these therapies and the challenges of widespread adoption and clinical delivery now become as critical an issue to solve as mapping the biochemical and signaling pathways that enable the therapies. We need to rethink comparability models and the clinical development models that would enable a therapy to move into earlier lines of treatment. I heard leaders in the field map out models that echoed “the way we’ve always done it” moving cytotoxic therapies into earlier lines of treatment. It made me wonder – what do we need to unlearn and relearn ways to move Advanced Therapies forward in this new phase of implementation.
Matthew Lakelin, VP Scientific Affairs & Product Development, Co-Founder, TrakCel
The CAR-TCR conference is a bellwether for the advanced therapy industry. TrakCel has attended this event for many years and what is gratifying to see is that presentations have changed from the future tense to the present tense when discussing treating patients. Earlier iterations of this conference had many presentations by cell and gene therapy companies focusing on pre-clinical data.
However, this year’s event was notable because there has been a clear and distinct step change in the industry, with the emphasis on addressing ways in which supply of CAR-TCR therapies can be improved. Undoubtedly, the conference demonstrated the significant number of these therapies being administered to patients, emphasising the adolescent nature of CAR-TCR treatments.
More needs to be done for CAR-TCR treatments to mature. One sobering statistic presented at the conference detailed that only 20% of patients who qualified to receive a CAR-TCR obtained access to the lifesaving drug. The advanced therapy industry needs to collaborate to ensure all patients who can receive a CAR-TCR treatment can access these lifesaving treatments in a timely manner.
Karen Moniz, Technical Director, ICCBBA
This was my first experience at CAR-TCR. My work focuses on standards development in the areas of harmonised terminology and traceability which in turn supports biovigilance for medical products of human origin. I was delighted to find so many individuals from across the spectrum of attendees at the meeting who are interested in collaborating to work towards standardised solutions to better maintain the chain of custody. I had several open, engaging conversations with a variety of stakeholders that I would not have had the opportunity to meet if I had not attended.
Fabian Gerlinghaus, CEO and Co-founder, Cellares
My key takeaway from CAR-TCR is that the need for integrated and high-throughput cell therapy automation is greater than ever. The patient demand for cell therapies has been increasing rapidly and highlights the importance of Cellarers’ quest to meet the total patient demand for cell therapies globally.
Greg Deener, CEO, iCell Gene Therapeutics
A plenary discussion highlighted that universal/allogenic CARs are making progress but cannot yet match the efficacy derived from one’s own T cells. The anticipated breakthrough has not yet occurred. Moreover, solid tumours are making progress slowly with barriers higher than believed. CAR may have more of a short-term role in ensuring all cancer cells and micro metastases are eliminated after a successful treatment.
The biggest change from the 2023 CAR-TCR was the enthusiasm surrounding the hope for the “Holy Grail” of autoimmunity, a well-tolerated immune reset leading to long-term remission. The workshop with the highest attendance at the 2023 CAR-TCR was the autoimmune workshop. This enthusiasm is based upon early but promising lupus data from both Georg Schett in Germany (CD19) and iCell in China (BCMA CD19 combination CAR). The data to date, though exciting, is in a few patients (<30) and additional studies are needed to confirm the buzz of enthusiasm. Early findings include:
1. CARs are well-tolerated in autoimmune and preliminary data suggests better tolerated than in oncology:
- No CRS >1 (cytokine storm risk appears to be more related to the tumour burden than the CAR),
- No concern for infections: immunosuppression medications are discontinued prior to the CAR. Thus, innate & T cell immunity quickly recovers and appears to offset any issues related to short-term B cell or plasma cell depletion.
- B cells rapidly recover: B cells recover in ~3 months (which appears to be faster than with rituximab) and with the CD19 BCMA cCAR IgM recovers within 5 months and IgG & IgA within 6-8 months.
2. CARs can deliver an immune reset with the promise of long-term medication-free remission.
- The reason autoimmune diseases are so difficult to treat is antibody memory, your body makes antibodies to attack your healthy innate cells (like antibodies from vaccines which remember diseases, in autoimmune diseases the antibodies remember to attack your healthy tissue).
- B cells and Plasma cells have distinct memory (different antibody secreting cells). CD19 can eliminate B cell memory and BCMA can eliminate long-lived plasma cell memory. Eliminating B and plasma cells with CD19 & BMCA leads to an “immune reset” where your body no longer remembers to create antibodies to attack healthy cells. Like removing the memory on a computer with a virus and then when restarting it the virus is gone.
- The early data supports an immune reset led to long-term medication-free remission. The first iCell patient is now 4 years, no meds and no symptoms. Again, early results are promising, and more data is needed.
3. Cell therapy manufacturing is improving, autologous CARs have now been shown to be made in a few days and automation is quickly being adopted. This should lead to an increase in the number of patients treated.
- CARs are complicated and time consuming to make. The demand for CARs outweighs the current supply with only ~30,000 CARs made globally since 2018 (though ~15,000 in the past year).
- There has been significant investment to improve manufacturing for autologous in addition to the universal/allogenic or in vivo approaches. This investment appears to be paying off with much progress.
- If the early data showing autologous can be made in a few days with automation, this will improve the supply and importantly reduce the time cancer patients need to wait for this lifesaving therapy.
4. There was not enough focus on the IP risks for many cell therapy companies and this will be increasingly important over the next few years.
- Thousands of CAR patents have been filed in the past 10 years (chart below) with hundreds filed 2014 to 2016.
- It takes ~10 years for a patent to be granted, many of the patents filed in 2014 and 2015 are just now being granted.
- It was not clear which patents for CARs would be granted 10 years ago and many companies began development of CARs in an uncertain IP environment. The number of companies able to go public in 2019 and 2020 with preclinical data facilitated beginning clinical studies without fully understanding the IP risk.
- While there are no IP limitations on conducting clinical studies, potentially violating another company’s patent, may impact filing or commercialisation. This will make it even more difficult for some companies to raise capital.
- One example of a potential issue, iCell has been granted the TARGET patent for CD7 in most global geographies and many companies are developing their own CD7 CAR but would need access to iCell’s target patent to file or commercialise.
Pamela Garzone, Chief Development Officer, Anixa Biosciences
The TCR CAR T Summit 2023 was well attended with a diverse agenda and presentations covering cell-based therapies from discovery through commercialisation. There are over 500 companies globally that are developing cell-based therapies- this is impressive and explains why science is advancing so rapidly.
I took away three main themes from this meeting from the sessions I attended. First, multiple speakers addressed the challenges of cell therapy in the treatment of solid tumours. There were presentations on how these challenges are being addressed, for example, the use of dual antigen CAR Ts is a strategy for antigen escape. TCRs and CARs are being armoured- engineered to excrete proteins such as cytokines or to express the cytokine receptors- to modify the immunosuppressive TME. Preconditioning regimens or combination with checkpoint inhibitors are being used to enhance tumour infiltration and persistence.
The second theme was that all types of cells are being engineered besides T Cells such as NK cells, monocytes and macrophages and that the use of cell-based therapy has moved beyond cancer- treatments are being evaluated in GVHD, type 1 diabetes and kidney transplantation as examples
The third take-away was the advances in cell manufacturing where automation is being used to reduce vein to vein time and where improvements in processing are relieving the bottleneck in manufacturing – U Penn has developed a process whereby CAR T cells can be made in one day and they demonstrated that the quality of the cells that did not have extensive ex-vivo expansion of cells was superior to those that had been extensively expanded.
Elizabeth Harris, Brand Director, Hanson Wade
One of the key takeaways from the 8th CAR-TCR Summit in Boston, US, was general agreement amongst all those attending that the cell and gene therapy sector needs to strive to deliver therapies for early line treatments, rather than late-stage therapies. One major and achievable challenge to delivering early-stage therapies is that manufacturing and QC timelines need to considerably reduce. Board members and investors will only be sold on the long-term dream if the wider sector works collaboratively to reduce timeframes. There was also general consensus at the CAR-TCR Summit that despite significant efforts, solid tumour solutions remain elusive. Current efforts focus on combination therapies, and we all to need to agree the right combinations to get the right duration of response. Delegates are also starting to look beyond combinations for other solid tumour approaches. There was also a focus on the tumour microenvironment. Agreement was reached that it is important to strive for synergy of the immune system and this can be achieved by the absence of lymphodepletion. Finally, 2023 is really the time where CAR-Ts and TCRs are demonstrating their potential beyond oncology to other indications, especially autoimmune diseases. It will be very interesting to see how this shift in focus from the sector applies to delivering therapies to patients.
Jonathan Wofford, Senior Director of Solution Architecture, Biotherapies Wellsky
While CAR-TCR 2023 was filled with many exciting updates, my key takeaway from the conference is the increasing need for collaboration and partnership between organisations across the continuum of therapy development. This includes clinical programs, donor centres, manufacturing organisations, logistics companies, device manufacturers, and information technology providers.
By way of example, one of the key areas for partnership development is the production of “off-the-shelf” therapies. As the push continues for allogeneic therapies, so does the demand for cell therapy donors. The development and management of donor programmes comes with several challenges including establishing methods for donor recruitment, eligibility determination, testing, cell or material collection, and ongoing donor engagement and retention. Manufacturing organisations and starting material providers can benefit from partnering with established donor programs, such as blood centres, to drive donor recruitment, testing, collection, and retention processes. By leveraging the existing infrastructure of these donor centres, manufacturers can focus on therapy development. Donor programmes can expand their business models through contracting with manufacturing organisations to support advanced therapies, creating new revenue streams. Information technology providers can then play a critical role in connecting manufacturing organisations and donor centres to streamline services and enhance process visibility and data sharing. Electronic data management systems can bring automation and process optimisation to donor services by streamlining recruitment and scheduling functions, allow for the configuration of program specific donor forms and eligibility requirements – automating the eligibility determination for donors specific to program or study requirements, promote systems interoperability, and drive strategies for donor engagement and retention through modern technologies.
Further, electronic data capture and centralisation across donor, collection, and manufacturing areas creates an environment to drive data analytics and to provide insights into effective donor populations and therapy development. A centralised platform can create the opportunity to help standardise practices while leveraging the already existing infrastructure, product inventories, and expertise that blood centres can provide, especially those already operating in a GMP setting. As organisations increase efforts around collaboration to drive therapy development, we will be able to accelerate the delivery of these life-saving treatments to the patients and families that are desperately waiting.