PMC8326907_01
Pictures of the cervical region. (A) At D8, her cervical region was obviously swollen. (B) At D14, her cervical region returned to normal. With consent to publish from the patient.
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Her condition seemed to be improving, however, at 17:10 of the D8, she complained of foreign body sensation in the larynx, dyspnea and facial edema with neck circumference growing rapidly (shown by  Figure 1A ). At d11, the swollen neck almost subsided and corticosteroids were stopped ( Figure 1B ).
Clinical data of L-CRS. (A) The temperature profile. (B) levels of cytokine. (C) CAR-T copy number. (D) therapeutic process. FC, fludarabine and cyclophosphamide regimen; IL-6, interleukin-6; CRP, c reactive protein; PCR, polymerase chain reaction; FACS, fluorescence activated cell sorter; NSAIDs, non-steroidal anti-inflammatory drugs; Toc, tocilizumab; Tor, torasemide; Met, methylprednisolone; Dex, dexamethasone; FFP, fresh frozen plasma; BM, bone marrow.
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The temperature profile, CRS levels of cytokine, CAR-T copy number and therapeutic process of CRS are presented by  Figures 2A-D  respectively.
PMC8326907_02
The model of L-CRS for compartmental and systemic malignancies. (A) The model of L-CRS for compartmental malignancies. (1) Malignancy cells restricted; (2) First stage, CAR-T cell local expansion; (3) Second stage, CAR-T cell overflow and inflammatory cytokine surge; (4) Third stage, CAR-T cell redistribution and organ damage; (5) Fourth stage, recovery. (B) The model of L-CRS for systemic malignancies in our case. (1) Malignancy cells diffused. (2) First stage, S-CRS; (3) Second stage, CAR-T cell redistribution and organ damage, possible for L-CRS; (4) Third stage, CRS abatement and recovery, possible for a new cycle of S-CRS; (5) In most case, L-CRS does not happen or just too weak to be identified.
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As shown by  Figure 3B , our model comprises three stages, First stage, S-CRS stage [ Figure 3B-(2) ]: CAR-T cells expand, effect and release inflammatory cytokines; Second stage, CAR-T cell redistribution and organ damage stage, L-CRS may happen [ Figure 3B-(3) ]; Third stage, CRS abatement and recovery stage [ Figure 3B-(4) ]. Though in most cases L-CRS either does not happen or presents too mildly to be identified [ Figure 3B-(5) ], severe L-CRS may as well contribute to a new cycle of S-CRS if it does not just abate [ Figure 3B-(4) ]. In conclusion, we tentatively proposed a treatment algorithm for L-CRS of compartmental and systemic malignancies shown by  Figure 3 .
PMC8326907_03
The model of L-CRS for compartmental and systemic malignancies. (A) The model of L-CRS for compartmental malignancies. (1) Malignancy cells restricted; (2) First stage, CAR-T cell local expansion; (3) Second stage, CAR-T cell overflow and inflammatory cytokine surge; (4) Third stage, CAR-T cell redistribution and organ damage; (5) Fourth stage, recovery. (B) The model of L-CRS for systemic malignancies in our case. (1) Malignancy cells diffused. (2) First stage, S-CRS; (3) Second stage, CAR-T cell redistribution and organ damage, possible for L-CRS; (4) Third stage, CRS abatement and recovery, possible for a new cycle of S-CRS; (5) In most case, L-CRS does not happen or just too weak to be identified.
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As shown by  Figure 3B , our model comprises three stages, First stage, S-CRS stage [ Figure 3B-(2) ]: CAR-T cells expand, effect and release inflammatory cytokines; Second stage, CAR-T cell redistribution and organ damage stage, L-CRS may happen [ Figure 3B-(3) ]; Third stage, CRS abatement and recovery stage [ Figure 3B-(4) ]. Though in most cases L-CRS either does not happen or presents too mildly to be identified [ Figure 3B-(5) ], severe L-CRS may as well contribute to a new cycle of S-CRS if it does not just abate [ Figure 3B-(4) ]. In conclusion, we tentatively proposed a treatment algorithm for L-CRS of compartmental and systemic malignancies shown by  Figure 3 .