Ulrich Blache, Fraunhofer IZI, Leipzig
Adoptive immunotherapy using T cells genetically equipped with chimeric antigen receptors (CAR) against CD19 has led to impressive remission rates in cancer patients and six autologous CAR T cell products are market approved for late stage therapy of hematological malignancies. Furthermore, CAR T cell treatment is on its way to also become a second-line and maybe even first-line care option 1. In addition, hundreds of clinical studies2 are ongoing with CAR-T cells, mainly with application in cancer treatment but also non-malignant indications including autoimmune and fibrotic disease are becoming targets for CAR immunotherapy3,4. These great developments in the area of translational medicine leaves us with an unanswered, but under-researched, question: How to produce sufficient numbers of CAR cell products to treat the growing group of patients?5Aside from biological challenges related to tumour-specific efficacy, the mainly manual production of autologous CAR T cells ex vivo severely limits their large-scale application.
Currently only a few products can be reliably fabricated at sufficient scale, and then only at very high cost. Indeed, while the molecular engineering of new CAR T cells has made great progress, developing the required technologies to produce enough CAR cell products is lagging far behind. Consequently, adequate clinical availability of CAR T cell products may become a bottleneck in cancer immunotherapy and urgently needs to be addressed. Therefore, new biological concepts and manufacturing technologies are needed to further drive the wave of success adoptive immunotherapy is currently on. Three options with high potential to generate many more CAR products are 1) alternative cell sources enabling allogenic off-the-shelf batches, 2) automation of CAR cell manufacturing and 3) in vivo CAR cell generation directly in patients.
References
1. Westin, J. & Sehn, L. H. CAR T cells as a second-line therapy for large B-cell lymphoma: a paradigm shift? Blood 139, 2737–2746; 10.1182/blood.2022015789 (2022).
2. Saez-Ibañez, A. R. et al. Landscape of cancer cell therapies: trends and real-world data. Nat Rev Drug Discov 21, 631–632; 10.1038/d41573-022-00095-1 (2022).
3. Mackensen, A. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28, 2124–2132; 10.1038/s41591-022-02017-5 (2022).
4. Rurik, J. G. et al. CAR T cells produced in vivo to treat cardiac injury. Science (New York, N.Y.) 375, 91–96; 10.1126/science.abm0594 (2022).
5. Blache, U., Popp, G., Dünkel, A., Koehl, U. & Fricke, S. Potential solutions for manufacture of CAR T cells in cancer immunotherapy. Nature communications 13, 5225; 10.1038/s41467-022-32866-0 (2022).
