A Comparison Between Two CAR-T Approaches As mentioned, the challenges of CAR-T therapy are well-documented: foremost among them is the personalized nature of its manufacturing process, which keeps treatment costs prohibitively high. To recap, the process of allogeneic CAR-T therapy involves:
1. Collecting peripheral blood mononuclear cells (PBMCs) from the patient or a healthy donor.
2. Centrifuging to remove red blood cells and platelets, yielding a leukocyte separation solution.
3. Isolating T cells (e.g., using magnetic bead positive selection with anti-CD4/CD8 or anti-CD3 antibody-conjugated beads).
5. Genetically transducing the T cells-typically using viral vectors to introduce CAR genes, transforming them into CAR-T cells.
6. Culturing and expanding the CAR-T cells.
7. Infusing the expanded CAR-T cells back into the patient.
Source: CAR-T cell manufacturing: Major process parameters and next-generation strategies
The production cost for a single patient's CAR-T therapy is approximately $80,000 such as culture media, plasmids, nucleases, and viral vectors-used in culturing and transducing CAR-T cells-account for roughly half of these costs, totaling around $50,000 per dose. Due to the personalized nature of the therapy, economies of scale cannot be achieved to reduce costs. Notably, GMP production of viral vectors alone constitutes about 30% of total costs, a figure that could be easily reduced with scaled-up production. Beyond cost, traditional CAR-T has other limitations: the interval from blood collection to CAR-T infusion can take weeks, during which patients' conditions may deteriorate. A drug that could take effect within days would be far more ideal.
In Vivo CAR-T: Addressing These Shortcomings In vivo CAR-T technology is designed to tackle these flaws: it delivers CAR-gene-carrying vectors directly into the body, where lentiviral vectors integrate the CAR gene into the genome. This enables CAR proteins to be expressed on the surface of T cells, converting them into CAR-T cells in situ. This approach eliminates the need for personalized treatment, enabling off-the-shelf therapy and drastically reducing costs. As is well-known, CARVYKTI is priced at $465,000, while CAR-T therapies in China typically range from ¥1 million to ¥1.2 million. According to predictions from *Arterial Network*, if in vivo CAR-T technology is commercialized, its price could drop to one-tenth or even lower than that of traditional CAR-T therapies. In addition to significant cost reductions, in vivo CAR-T eliminates the need for ex vivo T cell isolation, activation, transfection, expansion, and reinfusion. Instead, it directly delivers the transgene, accelerating the onset of efficacy to just a few days.
Early Clinical Data
So, how advanced is this technology, and what clinical data is available? EsoBiotec SA, a relatively unknown biotech, has pioneered IIT (Investigator-Initiated Trial) data, with results published in *The Lancet*. The pipeline in question, ESO-T01, targets BCMA-a well-known antigen in hematologic malignancies. Key modifications to ESO-T01 include: - Mutations in critical residues of the vesicular stomatitis virus glycoprotein G to avoid broad viral attack on human cells. - Engineering of the viral membrane to overexpress CD47, inhibiting macrophage phagocytosis. - Incorporation of TCR antibodies for T cell targeting. - Knockout of MHC-I to reduce immunogenicity.
Source: Appendix to In-vivo B-cell maturation antigen CAR T-cell therapy for relapsed or refractory multiple myeloma
Efficacy results (as of April 1, 2025):
- All patients completed 2 months of follow-up; the first two completed 3 months.
- Patient 2 achieved sCR by day 28, with complete lesion regression.
- Patients 3 and 4 achieved partial remission (PR), with tumor reduction by day 28.
- Overall response rate (ORR) was 100% (2 CR, 2 PR).
Safety, however, lags behind traditional CAR-T: 3 patients developed grade 3 cytokine release syndrome (CRS), and 1 had grade 1 CRS-whereas traditional CAR-T typically causes grade 1-2 CRS, with grade 3 being rare. In vivo metrics showed: - Peripheral blood CAR-T cells were first detected on days 4-8, peaking on days 10-17. - CAR-T cells were also detected in bone marrow, tumor tissue, pleural effusion, and cerebrospinal fluid.
Source: Appendix to In-vivo B-cell maturation antigen CAR T-cell therapy for relapsed or refractory multiple myeloma.
Notably, the starting dose of ESO-T01 was set at one-tenth the human equivalent dose (calculated from effective murine doses). Even so, its maximum concentration and area under the curve (AUC) from day 0 to 28 were comparable to idecabtagene vicleucel and ciltacabtagene autoleucel. This suggests ESO-T01 can achieve strong therapeutic effects at lower doses, potentially further reducing costs.
Current Landscape of In Vivo CAR-T Major pharmaceutical companies worldwide are betting on in vivo CAR-T therapy:
Internationally, AbbVie's recent $2.1 billion acquisition of Capstan is notable. Capstan's in vivo CAR-T uses LNP (lipid nanoparticle) delivery instead of viral vectors, requiring more frequent dosing but allowing real-time dosage adjustments to enhance efficacy and reduce toxicity. Additionally, short-term CAR expression may limit CAR-T cell exhaustion-a key mechanism of treatment failure. Its lead pipeline targets autoimmune diseases and is in Phase I trials in healthy subjects.
Domestically, CStone Pharmaceuticals is leading in in vivo CAR-T development, also using LNP delivery.
Conclusion
CAR-T therapy is long overdue for a revolution. Its current exorbitant cost puts it out of reach for ordinary patients. The true goal of innovative drug research is to develop treatments accessible to the majority of those in need. Reference sources:
1. CAR-T cell manufacturing: Major process parameters and next-generation strategies
2. Cost-effective strategies for CAR-T cell therapy manufacturing
3. "Why is CAR-T Therapy So Expensive? A Breakdown of Manufacturing Processes and Costs," Sina Pharma
4. "CGT 'New Favorite': In Vivo CAR-T," Arterial New Medicine
5. In-vivo B-cell maturation antigen CAR T-cell therapy for relapsed or refractory multiple myeloma