CAR ‐T Therapies and Emerging Alternatives: Reassessing Cost‐Effectiveness and Future Directions in Modern Immunotherapy

Over the past decade, Chimeric Antigen Receptor T-cell (CAR-T) therapies have significantly impacted the landscape of hematologic oncology. By engineering autologous T cells to express receptors that recognize tumor-specific antigens, CAR-T enables targeted cytotoxicity against malignant cells 1. Since the first U. S. Food and Drug Administration (FDA) approval in 2017, the therapeutic class has expanded to seven licensed CAR-T products by 2025, primarily targeting refractory lymphoma and myeloma 2, 3. Beyond these hematologic indications, numerous clinical trials have been initiated to evaluate CAR-T therapy for solid tumors, signaling an expanding horizon 4. A brief overview of the key articles informing this discussion is summarized in Table 1. Allo-CAR research On LBCL Allo-CAR research On ALL BsAbs research On DLBCL BsAbs research On DLBCL Nevertheless, enthusiasm has been tempered by persistent challenges. The personalized nature of autologous CAR-T imposes high manufacturing costs and prolonged production timelines. Furthermore, potentially life-threatening complications, including cytokine release syndrome and neurotoxicity, complicate their use 1. Accordingly, CAR-T is primarily used in relapsed or refractory settings in current practice: clinically relapsed or refractory situations. Whether its use cannot be answered uniformly across indications, considering its cost, risks, and alternatives remains a pressing clinical and policy question. In this editorial, we appraise the cost-effectiveness of CAR-T, highlight recent advances, compare emerging alternatives, and consider whether CAR-T should remain a guarded intervention or evolve into a broader therapeutic standard. A central debate concerns whether the incremental benefits of CAR-T warrant its extraordinary costs. Zuber et al. 5 examined treatment patterns among adults with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Among DLBCL patients (the largest subgroup), 41% required subsequent therapy after CAR-T, including lenalidomide, ibrutinib, or other immunotherapies. Failures after CAR-T were associated with increased out-of-pocket expenditure, in some cases approaching a doubling of the already significant financial burden. Similarly, Thavorn et al. 6 conducted a systematic cost-effectiveness analysis and found that CAR-T was associated with QALY gains compared with standard therapies in modeled analyses. However, incremental cost-effectiveness ratios (ICERs) varied widely, from US 9424 to more than US 4 million per QALY gained, depending on cancer subtype, comparator, and model assumptions. Such heterogeneity underscores the uncertainty of current estimates, which are sensitive to trial design, disease subtype, comparator, modeled time horizon, willingness-to-pay threshold, health-system context, and local economic parameters. Collectively, these data illustrate a paradox. CAR-T has demonstrated selected relapsed or refractory settings compared with conventional options, yet its cost-effectiveness remains highly context-dependent. Current evidence does not support a uniform conclusion regarding its optimal placement across treatment lines. Methodological constraints, small sample sizes, and selection bias in existing studies further complicate interpretation 6. In 2024, the FDA approved obecabtagene autoleucel (obe-cel) for B-cell acute lymphoblastic leukemia (B-ALL) 3. Preliminary studies suggest a reduced toxicity profile compared with earlier products; however, long-term safety data are still needed. The extension of CAR-T into solid tumors represents another milestone. A phase 2 study of Claudin-18. 2–directed CAR-T reported encouraging efficacy in gastrointestinal malignancies, historically resistant to such approaches. Concurrently, early-phase trials have tested CAR-T in autoimmune diseases, including systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis. Initial reports suggest feasibility and safety, suggesting potential applications of CAR-T beyond oncology, though confirmatory trials are essential 7. Equally noteworthy is the exploration of off-the-shelf products. Allogeneic CAR-T (allo-CAR-T) and CAR-natural killer (CAR-NK) therapies, derived from healthy donors, bypass the logistical challenges of harvesting patient T cells 8. These strategies may shorten production times, reduce costs, and broaden eligibility, particularly for patients with lymphocyte depletion from prior therapy. Early-phase studies report promising safety and efficacy, with some studies suggesting comparable activity in early-phase settings 9. However, these data derive from small, heterogeneous, single-arm cohorts with limited follow-up, and direct comparisons with autologous CAR-T are not yet available; claims of equivalent efficacy would therefore be premature. Concerns regarding graft-versus-host disease (GVHD), durability of response, and long-term persistence must be carefully addressed before broader clinical adoption. An important therapeutic class alongside CAR-T has emerged in the form of bispecific antibodies (BsAbs). By simultaneously binding CD3 on T cells and tumor-associated antigens, BsAbs recruit endogenous T cells to mediate cytotoxicity without ex vivo manipulation 10, 11. Epcoritamab, a BsAb targeting CD20, has demonstrated clinically meaningful activity in DLBCL and is associated with reduced personnel time, outpatient administration, and lower upfront cost compared with axicabtagene ciloleucel (axi-cel). Unlike CAR-T, which requires specialized infrastructure, BsAbs are off-the-shelf agents with greater scalability. Although longer-term data are needed to establish durability, current estimates suggest that BsAbs may offer a potentially attractive option. Combined with their logistical simplicity, BsAbs represent promising alternatives, especially in healthcare systems with constrained resources. CAR-T therapies exemplify the duality of modern innovation: transformative efficacy coupled with prohibitive cost and complexity. Evidence supports their use for relapsed or refractory cases, but extension to earlier lines or to other disease settings requires careful, indication-specific evaluation. ICER estimates remain highly variable, shaped by methodological inconsistencies and limited follow-up. In this context, cost-effectiveness claims should be interpreted cautiously. Nonetheless, the trajectory of CAR-T innovation is encouraging. Next-generation constructs aim to reduce toxicity, broaden tumor targeting, and extend applications into solid tumors and autoimmune diseases. Allogeneic CAR-T and CAR-NK platforms may overcome limitations of autologous therapy, while BsAbs provide a practical, scalable alternative. To fully realize the potential of these therapies, standardized frameworks for economic evaluation and robust long-term survival data are urgently required. Only with such evidence can policymakers, clinicians, and patients weigh the true value of CAR-T against its alternatives. For now, CAR-T remains a guarded but indispensable option. The coming decade will determine whether it transitions from an extraordinary intervention to a standard pillar of modern immunotherapy. Y. -C. W. drafted the manuscript. C. -J. L. critically revised the manuscript. S. -B. Y. and P. -C. S. supervised the work and critically revised the manuscript. The authors declare no conflicts of interest. The authors have nothing to report.