On December 20, 2023 CellOrigin Biotechnology reported that a CAR-macrophage therapy product (CAR-M) SY001 was dosed to the first patient in a hospital in China (Press release, CellOrigin Biotech, DEC 20, 2023, View Source [SID1234638734]).
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"A single center, single-arm, dose-escalation, exploratory clinical trial to examine the safety, tolerability, pharmacokinetics and preliminary efficacy of SY001 from CellOrigin Biotechnology in patients with advanced solid tumors" is the first investigator-initiated clinical study of CAR-M cell therapy product in China. The successful completion of the first patient dosing of SY001 demonstrates the advanced technology of the company’s R&D platform and the maturity of the CMC platform. Currently, the clinical study is actively recruiting patients.
SY001 was well tolerated and no dose-limiting toxicity (DLT) was observed (n=2). Only 2 grade 3 adverse events occurred; Common grade 1 – 2 adverse events included fever, elevated C-reactive protein, etc. No cytokine release syndrome or neurotoxicity related to cell infusion occurred in any patients.
The clinical data of CAR-M products up to now suggest the excellent safety and certain clinical benefits of macrophage immunotherapy. CellOrigin expects that this innovative product will prove its safety and effectiveness in clinical trials, bringing new hope for the treatment of solid tumors, thereby improving patients’ quality of life and prolonging their life span.
Besides, in November 2023, CellOrigin collaborated with Zhejiang University to publish a paper entitled "A second generation M1-polarized CAR macrophage with antitumor efficacy" in Nature immunology, designing an exclusive CAR with antigen-dependent polarization and activation of macrophage function (TIR-CAR or M-CAR) by introducing the TIR signal transduction domain. Based on M-CAR, a functionally enhanced second generation CAR-iMAC has been developed to enhance the effectiveness of the therapy for solid tumors. The mechanism of antigen-dependent activation and polarization of the second generation CAR-iMAC and the mechanisms of solid tumor cell killing were also revealed.
In November 2020, the team published a paper in J Hematol Oncol entitled "Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions." It opens the door for human iPSC-derived CAR-macrophage (CAR-iMAC) and its applications in targeted anti-tumor research. The first generation CAR-iMAC was designed, and was capable of carrying out the antigen-dependent killing of tumor cells.
On September 11, 2023, the team collaborated with Dr. Wang Ben’s Research Group of Zhejiang University to publish a paper entitled "Targeted glycan degradation potentials cellular immunotherapy for solid tumors" in Proceedings of the National Academy of Sciences (PNAS). The collaboration found that simultaneous deletion of sialidase-binding immune checkpoints Siglec-5 and Siglec-10 (DKO-CAR-iMac) on macrophages significantly enhanced CAR-iMAC’s anti-solid tumor function.
Almost the same time, the team published another paper entitled "Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophases in solid tumors" in Nature communications. A CRISPR Screen method was used to find the key metabolic genes related to CAR-iMAC polarization in tumor microenvironment. It was discovered that knockout of ACOD1 (or IRG1) could improve macrophage proinflammatory polarization, phagocytic capacity and tumor-killing activity. Furthermore, the study also found that the anti-tumor effect of ACOD1-/- MSLN-CAR-iMAC can be further enhanced by combining immune checkpoint inhibitors. These findings offer fresh concepts for remodeling macrophages based on metabolic reprogramming or editing the immune checkpoints.
Based on these research results, CellOrigin is conducting a series of pre-clinical and clinical studies of CAR-macrophage therapies for solid tumors in an effort to provide patients with safe and effective treatment choices as soon as possible.