Michael Hudecek ^1* Ulrike Koehl ² WASEEM QASIM ³

• ¹ University Hospital Würzburg, Würzburg, Germany
• ² Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Lower Saxony, Germany
• ³ University College London, London, England, United Kingdom

As we witness the early stages of CAR-T cell therapy, the initial feedback underscores both its transformative potential and its current limitations. This novel therapy, which has the ability to induce long-lasting remission (Odak et al.) or even cure with just a single application, represents a significant leap forward in cancer treatment. By potentially replacing traditional therapies that require frequent and ongoing administration, CAR-T therapy could dramatically improve patient well-being, reduce the physical and psychological burdens of treatment, and relieve families and caregivers from the demands of standard cancer care. However, as with any groundbreaking medical innovation, the journey of CAR-T therapy is marked by challenges that must be addressed. Despite its promise, the therapy is still in its infancy, and much remains to be learned about the complex mechanisms it triggers within the immune system. While CAR-T cells have shown remarkable success in hematologic cancers, their limitations-such as relapses, adverse side effects, and the narrow scope of antigen targeting-are becoming increasingly apparent. Expanding CAR-T therapy beyond its current niche will require overcoming these hurdles (Svec et al.).Ongoing research is questioning established treatment regimens and manufacturing methods for CAR-T cell therapy, seeking to accelerate the development of CAR-T products at every level. Current manufacturing processes, often centralized and timeconsuming, are being scrutinized, with efforts underway to create faster, more efficient production methods (Colina et al., Hood et al.). This includes new point-of-care manufacturing models that offer the potential for real-time, localized production of CAR-T cells, minimizing delays between cell extraction, modification, and reintroduction (Aleksandrova et al.).Recent innovations are reshaping the field. The development of novel transduction methods (Kapitza et al.), such as those highlighted in the recent study on nanofibrils (Rauch-Wirth et al.), could significantly streamline the gene-editing process by improving the delivery of genetic material into T cells. Additionally, artificial intelligence is being applied to better understand CAR-T cell actions, enhance their maturation, and identify optimal targets for therapy. AI's ability to analyze vast datasets is helping researchers refine CAR-T design, enabling them to create therapies that are more precise and effective (Wang et al., Bäckel et al.). Genetic modifications are another key area of exploration, with scientists striving to improve CAR-T cell functionality and develop allogeneic CAR-T products, which could be produced from healthy donors and used across multiple patients (Calvino et al.). This would greatly reduce the cost and time involved in creating individualized treatments, expanding access to CAR-T therapy for more patients. Meanwhile, researchers are investigating previously understudied areas that influence CAR-T efficacy, such as the role of the microbiome. Emerging evidence suggests that gut microbiota may play a critical role in modulating the immune system's response to CAR-T therapy, opening new avenues for improving outcomes through complementary treatments (Staudt et al.).The field of cellular immunotherapy is evolving rapidly, with new entrants like NK cells and alternative therapeutic approaches challenging the status quo (Ciulean et al.). These innovations signal the beginning of a wave-like transformation in cancer treatment, with CAR-T therapy at the frontiers of cellular immunotherapy. As the field moves forward, continued research and collaboration will be essential to unlocking the full potential of CAR-T therapy, ensuring its safety, efficacy, and accessibility for patients across the world (Garcia-Calderon et al., Karsten et al., Ammar et al.).In closing, we extend our deepest gratitude to the authors who have contributed their outstanding scientific work to this special issue. Their innovative research and insights have been invaluable in advancing the field of cellular immunotherapy. We would also like to thank our project partners from the EU IMI Innovative Medicines Initiative, T2EVOLVE, and imSAVAR, as well as the Collaborative Research Center Transregio 338 LETSimmun, for their cooperation and support. The publications curated here were made possible through their dedication and shared vision in pushing the boundaries of immunotherapy research.