Autonomous driving CAR: Prospects for CAR-T therapy for hematological malignancies in the body

Self-Driving CAR:The Promise of EDWIN GUMAFELIX, Medical Director, APAC Cell and Gene Therapy Center of Excellence, IQVIALARA KRISTINA DONATO, Medical Director, APAC Medical Science and Strategy, IQVIAMARIA ROSELLE LUCAS, Senior Medical Director, APAC Medical Science and Strategy, IQVIAMANFRED SEOW, Director, APAC Cell and Gene Therapy Center of Excellence, IQVIA Table of contents Introduction1Global burden of hematologic malignanciesTransformative impact of ex vivo autologous CAR-T therapiesCAR-T landscape in APAC countriesLimitations of conventional ex vivo CAR-T approachesIntroduction to in vivo CAR-T therapy6In vivo CAR-T paradigm8Clinical advances and trialsChallenges and considerations12Safety concerns and deliveryRegulatory considerationsFuture directions13Conclusion14What next?14References15About the authors20Acknowledgment21 Introduction Global burden of hematologic malignancies of the CAR.8In autologous CAR-T therapy, T cells are Hematologic malignancies (HMs) represent asignificant portion of the global cancer burden.This white paper focuses on in vivo-engineered T-celltherapy for three major HM subtypes of the B lineage: harvested from a patient and genetically engineeredin a laboratory to express the CAR. The patient receives the CAR-Ts shortly after completion of a shortcourse of lymphodepletion chemotherapy, which isadministered to promote CAR-T engraftment.9Thetherapeutic efficacy of CAR-T therapy is—in part— acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM).Over recent decades, the global incidence of HMs hassteadily increased, while age-adjusted mortality rates have declined, largely due to advances in treatment.1,2 In 2019, an estimated 1.34 million new cases of HMs were diagnosed worldwide1. Among these, leukemiahad the highest global incidence, with around 643,580cases reported. ALL accounts for a fraction of leukemiacases (~153,320 new cases in 2019) and is more common in children than in adults.1Diffuse large B-cell CAR-T therapy is the result of decades ofimmunological and bioengineering research(Figure 1). The design of the first generation of CARs,published in 1993 by Zelig Eshhar, combined an scFvfrom a monoclonal antibody with the CD3ζ signalingchain.10-12Subsequent generations added one (second-generation) or more (third-generation) co-stimulatory CAR-T therapies have demonstrated robust efficacyin subsets of relapsed/refractory (R/R) HMs (Table 1)in both global and Asia-Pacific (APAC) clinical trials Transformative impact of ex vivoautologous CAR-T therapies and real-world settings.22The first United StatesFood and Drug Administration (US FDA) approval In response to the growing global burden of HMs,innovative therapies such as CAR-T treatments have emerged. Ex vivo autologous CAR-T therapies haverevolutionized the treatment landscape for a subset Limitations of conventional CAR-T landscape in APAC countries The CAR-T landscape in APAC is evolving rapidly,driven by an expanding portfolio of therapies anddiverse country-level approaches to market access Ex vivo CAR-T therapies, although rapidly evolving, facemultifaceted challenges that hinder their widespread and funding. Approved CAR-T therapies in the regioninclude Kymriah, Yescarta, Breyanzi, Abecma, andCarvykti43, 44(Table 2). To better understand regional adoption. High manufacturing costs significantlycontribute to the high price of pharmaceuticalCAR-T products, which serves as a major barrier to Autologous CAR-T production is labor-intensive andprone to variability due to patient-specific factors.45 Manufacturing failures occur relatively infrequently,but can increase the complexity of delivery of cellularimmunotherapies.8, 46Manufacturing time presents asignificant bottleneck. Conventional ex vivo autologousCAR-T production can take several weeks, with cellexpansion alone requiring 1–2 weeks, and sterility Off-the-shelf approaches, including allogeneic CAR-Ttherapy derived from healthy donors or inducedpluripotent stem cells (iPSCs), and direct in vivo Allogeneic CAR-T therapy can reduce costs andmanufacturing time through centralized production and economies of scale, although the responseand survival rates and risks associated with adverse The patient journey — from referral and apheresisto cell reprogramming, infusion, and long-term monitoring — is inherently intricate, requiringcomplex logistical coordination that further amplifies The entire process is labor-intensive, costly, and time-consuming.13In contrast, in vivo CAR-T generation(Figure 2) bypasses these steps by delivering CARconstructs directly into the patient’s body usingviral vectors or nanocarriers, allowing T cells to bereprogrammed in situ.47This approach eliminates the Introduction to in vivo Conventional CAR-T cells are generated ex vivo foreach patient, requiring leukapheresis, T-cell activation,genetic modification, and culture in a suitably The transition from ex vivo to