CAR-T cell therapy clinical trials: global progress, challenges, and future directions from ClinicalTrials.gov insights

1 Introduction

Chimeric antigen receptor T (CAR-T) cell therapy is a groundbreaking immunotherapy that confers target-specific recognition capacity to autologous or allogeneic T cells through genetic engineering. The canonical CAR architecture consists of three essential components: an extracellular antigen-binding single-chain variable fragment (scFv), a transmembrane domain, and intracellular activation/co-stimulatory signaling domains (e.g., CD28, 4-1BB). This unique design enables direct binding to target antigens via a major histocompatibility complex (MHC)-independent mechanism, triggering T cell cytotoxic activity and thus representing one of the most promising therapeutic strategies in modern medicine, especially in oncology (1). CAR-T therapy has achieved remarkable success in hematologic malignancies, with anti-CD19 products revolutionizing B-cell malignancy management and constituting >50% of investigational or commercialized cell therapies (2, 3). Emerging applications now extend to solid tumors, autoimmune disorders, and infectious diseases (4-6). However, critical scientific and translational barriers hinder its broader clinical translation. In hematological contexts, the long-term efficacy is still limited by insufficient expansion and poor CAR-T cell persistence (7). Solid tumors present amplified challenges: the immunosuppressive tumor microenvironment (TME) impedes therapeutic success through physical barriers, metabolic competition, and immune checkpoint overexpression, collectively suppressing T cell infiltration, survival, and effector functions while promoting exhaustion (8). Antigen escape mechanisms - notably target loss (e.g., CD19-negative relapse in 30-50% of B-ALL cases) or downregulation - further drive therapeutic resistance (9, 10). In addition, the development of optimally effective CAR-T cell therapies necessitates a balanced integration of potency and safety, particularly addressing the two most critical toxicities: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These toxicities are mechanistically intertwined with CAR-T cell activation kinetics and tumor burden, necessitating risk-adapted designs (8). Additional accessibility barriers arise from complex manufacturing processes and exorbitant costs (>$500,000 per treatment course), compounded by developmental attrition rates where only 35% of initiated trials progress beyond Phase 2 (11).

ClinicalTrials.gov, the largest publicly accessible online database, reveals a rapidly evolving landscape (11). This review synthesizes global trends from 1,580 CAR-T trials registered on ClinicalTrials.gov (2003-2024), to map the global trajectory of CAR-T development, dissect unresolved challenges, and propose actionable strategies to accelerate clinical translation. Based on the publicly available contact information, we surveyed the CAR-T researchers to identify barriers to research advancement and result dissemination, and to propose collaborative strategies.