2026自主导航式CAR：体内CAR-T疗法在血液系统恶性肿瘤中的应用前景白皮书

Self-Driving CAR:The Promise ofIn Vivo CAR-T Therapyfor Hematologic Malignancies 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, IQVIACLAUDIA CHONG, APAC Marketing Associate, R&D Solutions, IQVIACAMERON TURTLE, CLEARbridge Chair in Cancer Immunotherapy, University of Sydney 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 areharvested from a patient and genetically engineeredin a laboratory to express the CAR. The patientreceives 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—governed by the qualities of a patient’s T cells andthe structural design of the CAR. These receptorscomprise four principal domains: an extracellularsegment responsible for antigen binding—typically asingle-chain variable fragment (scFv); a hinge region;a transmembrane domain facilitating membraneanchorage; and intracellular signaling modules thatmediate T-cell activation and target killing uponantigen engagement.8 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:acute lymphoblastic leukemia (ALL), non-Hodgkinlymphoma (NHL), and multiple myeloma (MM).Over recent decades, the global incidence of HMs hassteadily increased, while age-adjusted mortality rateshave declined, largely due to advances in treatment.1,2In 2019, an estimated 1.34 million new cases of HMswere 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 morecommon in children than in adults.1Diffuse large B-celllymphoma (DLBCL) is the most common NHL subtype,comprising approximately 30%–40% of NHL cases,with incidence rising with age.3The global incidenceof MM is also rising (155,690 cases in 2019),1particularlyin developed regions such as North America, whereincidence rates are about 4.7 per 100,000 comparedwith approximately 0.8 per 100,000 in West Africa.⁴Standard treatments differ between HMs but mayinclude chemotherapy, radiotherapy, therapeuticantibodies, small-molecule drugs, and cellulartherapies such as chimeric antigen receptor(CAR)-modified T cells (CAR-Ts) and autologous andallogeneic hematopoietic stem-cell transplantation(HSCT).5However, primary resistance, relapse,and adverse effects have led to treatment failurein many patients.5,6 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-stimulatorydomains in the CAR construct,13along with othermodifications to enhance efficacy and/or control ofthe CAR-Ts.13, 14Second-generation CARs thatincorporate a single CD28 or 4-1BB co-stimulatorydomain form the backbones of all currently approvedCAR-T products (Table 1).15-21 CAR-T therapies have demonstrated robust efficacyin subsets of relapsed/refractory (R/R) HMs (Table 1)in both global and Asia-Pacific (APAC) clinical trialsand real-world settings.22The first United StatesFood and Drug Administration (US FDA) approvalof a CAR-T product was granted in 2017. Since then,multiple products have been approved for a rangeof HMs (Table 1). Transformative impact of ex vivoautologous CAR-T therapies In response to the growing global burden of HMs,innovative therapies such as CAR-T treatments haveemerged. Ex vivo autologous CAR-T therapies haverevolutionized the treatment landscape for a subsetof HMs by establishing a targeted immune responseagainst tumor cells.7A CAR is a synthetically designedreceptor that—when introduced into a T cell—enablesthe engineered CAR-T to recognize the target antigen ALL, acute lymphoblastic leukemia; B-ALL, B-cell acute lymphoblastic leukemia; BCMA, B-cell maturation antigen; CD19 , cluster of differentiation 19;CLL, chronic lymphocytic leuk