Disrupting the global CAR T paradigm from the Middle East: Ultra-fast swift CAR T and scalable point-of-care manufacturing of autologous CAR T cells for hematologic malignancies

Abstract

Abstract Background and Aims: CAR T-cell therapy has revolutionized treatment for CD19+ blood cancers, but conventional manufacturing is costly, complex, and slow, limiting global access. Point-of-care (POC) and ultra-fast platforms offer faster, more affordable production while preserving potency and regulatory standards. These advances improve CAR T-cell quality by enriching stem-like memory cells and optimizing expansion, marking a shift toward localized, efficient, and scalable cell manufacturing. Saudi Arabia faces a rising burden of aggressive blood cancers in a young population, and cancer cases expected to double by 2030, where delays in CAR-T therapy can mean loss of eligibility. Approved CAR-Ts are costly ($400K-$600K/dose) and logistically slow, making them unsustainable for widespread use. With strong local GMP infrastructure on horizon, SFDA support, and Vision 2030's push for biotech independence, we hypothesized POC, ultras-fast, low-cost CAR-T platform is essential. It enables timely access, reduces costs, improves survival, and ensures national readiness. Unlike rigid commercial models, it also allows adaptation to local disease patterns, positioning Saudi Arabia as a regional leader in CAR T therapy. Methods: We developed academic CAR pipeline (for CD19+, AML & MM indications) and SWIFT CAR T platform, an ultra-fast, cost-effective ~30 hrs CAR-T manufacturing process that eliminates the need for ex-vivo expansion, allowing to produce functional CAR-T cells, reducing brain-to-vein, vein-to-vein time, cost, and expensive equipment needs. This simplified process enables scalable, decentralized CAR-T production suitable for regional deployment, including in resource-limited settings. The high proportion of naïve and early memory T cells in SWIFT CAR-T platform is anticipated to improve the safety profile by promoting slower tumor-killing kinetics. Furthermore, to advance our clinical capabilities, we set-up a fully GMP-compliant, hospital-based CAR T-cell manufacturing unit at King Faisal Specialist Hospital & Research Centre (KFSHRC). Using the CliniMACS Prodigy and a second-generation CD19 CAR vector (CD19-4-1BB-TNFRSF19tm), we produced academic autologous CAR T cells for a Phase I clinical trial. The full process, from leukapheresis to T-cell activation, gene transfer, expansion, freezing, and quality release, was completed in under two weeks. We performed thorough in-process and final product testing, including viability, sterility, CAR expression, potency, VCN, and RCL testing, to ensure product safety and functionality. Results: We successfully developed academic CAR constructs for clinical applications and established a 30-hour SWIFT CAR T platform designed to preserve T memory stem cells and enhanced potency. This platform was used to generate CAR T cells targeting CD19+ malignancies and AML, achieving up to 69% transduction. Functionality was confirmed through co-culture with CD19+ (Raji, Daudi) and AML (U937) cell lines, showing strong cytotoxicity and high IFN-γ and TNF-α secretion. Intracellular staining further corroborated specific activation of CAR T cells upon encountering targets, demonstrating that the CAR-T cells are functional and specific for tumor antigens, capable of recognizing and killing their intended targets. Using the Miltenyi CAR vector, we established a GMP-compliant POC CAR T-cell manufacturing system with a complete in-house quality control and release testing framework. As part of the SFDA-approved Phase I clinical trial, we produced 4 Large-scale, clinical-grade CAR T-cell batches from healthy donors during validation runs, along with one patient-specific batch. These efforts supported regulatory approval for our first patient infusion. All products met/exceeded predefined release criteria, confirming the robustness and readiness of our POC CAR T manufacturing ecosystem. Conclusions: This study marks the first dual-platform, hospital-based CAR T-cell manufacturing program in the kingdom, successfully developing both conventional and ultra-fast autologous therapies at KFSHRC. By integrating point-of-care production, novel target design, and rapid turnaround, we determined to establish Saudi Arabia's first-in-human In-house manufacturing CAR T trials. Our SWIFT CAR-T platform demonstrates that advanced, affordable, and personalized immunotherapies can be developed and delivered locally, bringing new hope to patients through timely, flexible, and regionally scalable solutions.