Miguel Forte, MD, PhD
ISCT President
mC4Tx
Belgium
Forty years ago, Steve Jobs made a visionary speech about the use of computers. People would be using computers all day long! He added that “people would be going to ask themselves, several years down the road, “if this was not always like this”. And he was not even mentioning, or anticipating, the correlated mobile phone use.
For me cell and gene therapy will be like that down the road in the near future!
He also said that he, and those around him at the time, were at the right place at the right time to give something back to society overall. Absolutely true for cell and gene therapy today addressing unmet medical needs with a long-term benefit and curative potential! We are privileged to be launching this value of Cell and Gene Therapy for patients with unmet medical needs with a curative potential!
Nevertheless, we need to manage expectations on the deployment of that value. Innovation is always overestimated in the short term but underestimated in the long term. And the time frame for development of these products is long and still costly.
In 2017, with the approval of the first meaningful gene engineered cell therapy, Kymriah (tisagenlecleucel), as a consequence of the Novartis licensing from University of Pennsylvania, the world woke up to the enormous value of these therapies for patients, personified by the well known Emily Whitehead, but also for the expected great business opportunity.
Several products have followed with currently 6 CAR-T cell products approved by FDA for several haemato-oncological indications. These products are delivering to patients increased rates of remission and survival together with reduction of the need for additional therapies. The value of these cell therapy products is well established, and we are seeing increased patient global access, also with alternative regional production and access approaches, validating the business opportunities.
At the same time, gene therapy, while currently delivering enormous value to very severe and costly diseases is still lagging on patient access. The value, patient benefit and cost avoidance is clear, so we will see increasing patient numbers seeking access, and with well executed clinical product launches.
A signal of the growth and healthiness of the field has been the recent expansion of CAR-T therapies to other areas beyond the initial field of oncology. For B cell based autoimmune diseases, B-cell targeting CAR-T approaches have delivered amazing results as described in the main recent publication in the NEJM (1) in February earlier this year. One could say that we are now at the cell and gene therapy age of autoimmunity, clearly in cell and gene therapy development, but also in the context of biotech in general!
A recent couple of publications, from the same group that made the initial publication (2,3) have reviewed and expanded knowledge on this B cell targeting approach in autoimmunity. The review paper (1) outlines the current status with a few key messages to consider for the continued development of these products and subsequent commercialization.
The key one is the choice of the right disease and the right target patient population, in terms of pathology but also in terms of stage and progression of the disease! Related to this is the choice of the best and more adapted CAR target. CD19 is potentially better than CD20 but BCMA may be even better. Also, one could consider bispecific CD19-BCMA CAR T that might be preferential in some settings although it may come with an “immunological cost”. Regarding the customary use of lymphodepletion, it remains recommended, potentially with dose reduction but this will have to be considered carefully, but aggressively, going forward in my view.
It goes practically without saying that the monitoring of these patients and their treatment is of paramount relevance, primarily for the safety monitoring and management but also for the expansion of our experience and efficacy assessment with these therapies for the future broadening of their use!
We are still at the entry door of the use of these treatments in autoimmunity, but the potential is real for B-cell immune system resetting, with deep tissue depletion of B cells, as shown in the second paper (2), leading to a promise of induction of long-term drug-free remission and immunological resetting in these severe autoimmune pathologies.
Current CAR-T cell treatments target B cells and consequently address auto-antibody-mediated diseases such SLE. Other autoimmune diseases, more T cell dependent, like IBD and Psoriasis would not be suitable for this approach. These are still waiting for Treg centered approaches with wide, ideally off-the-shelf, application. Several academic research groups and companies are targeting Treg dependent autoimmune diseases, but the Treg direct approaches still require an autologous or HLA matched approach. At the same time, some indirect approaches, modulating Treg function up or down, are being actively explored. These include small molecules, antibodies and gene engineered cell therapies. In addition, attempts of Tcell depletions are also being pursued! These will for sure in the near future expand the opportunities for the treatment of additional autoimmune diseases.
Overall, this expansion to autoimmunity has been welcomed by the majority of stakeholders further endorsing the value of cell and gene therapy. Nevertheless, we see market reactions to the stock of autoimmune representative companies, like Cabaletta Bio or Kyverna Therapeutics, translating some apparent reservations from the investment market. The stock of these companies over the last months has shown a slow downwards trend since a high expectant value, with some singular reactions, namely when Cabaletta announced safety results on their Lupus study (4) when, probably a bit of a knee-jerk reaction, the stock presented a dip.
It is important to manage expectations, for all stakeholders, and in particular for investors in the face of the development of products for these indications. As we learn, and experience expands, more and earlier stage patients will be included and treated, broadening the use beyond the initial patients with very severe disease, completing the safety profile picture, while we become more experienced in managing the safety. This will at same time expand the opportunity use and will enable further return on investment, while, and very importantly, help a larger number of patients.
The key message to take home is to expect an increase on the translation and use of cell and gene therapy products, with a consequent return on the investments, scientific, clinical and financial, as the use of cell engineered products expands into additional indications and disease areas and patient numbers globally.
Then for sure, we will be asking: “was it not always like this?….”
References:
- Muller, F. et al . CD19 CAR T-Cell Therapy in Autoimmune Disease – A case series with Follow-up; NEJM 390-8, 687-700 (February 2024)
- Schett, G et al. Advancements and challenges in CAR T cell therapy in autoimmune diseases; Nature Reviews 20, 531-544 (September 2024)
- Tur, C. et al. CD 19-CAR T-cell therapy induces deep tissue depletion of B cells; Ann Rheum Dis 0, 1-8 (August 2024)
- Ayisha Sharma, Autoimmune CAR-Ts are under the microscope after Cabaletta’s safety issues in lupus; Endpoint News, 9 August 2024
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