PMC9096123_01
Hematoxylin and eosin (H&E) and immunohistochemistry staining of relapsed/refractory intravascular large B-cell lymphoma.
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Immunohistochemical staining revealed that the tumor cells were positive for CD20, CD34, and LCA and negative for CD3, CD30, CD68, MPO, CKpan, Syn, CgA, and CK8/18( Figure 1 ).
Head and liver imaging results of relapsed/refractory intravascular large B-cell lymphoma. Brain MRI images: (A) First time headache symptoms appeared at the initial diagnosis. (B)The intracranial infiltration was diagnosed. (C) 1 month after intrathecal chemotherapy. (D) 1 month after two courses of the adjusted treatment regimen MTX combined with Ara-C therapy. (E) 1 month before ASCT and CAR T-cell therapy. (F) 3 months after ASCT and CAR T-cell therapy. (G) 6 months after ASCT and CAR T-cell therapy. (H) 9 months after ASCT and CAR T-cell therapy. (I) 12 months after ASCT and CAR T-cell therapy. (J) 22 months after ASCT and CAR T-cell therapy. Abdominal images: (K) Abdominal CT at initial diagnosis. (L) PET-CT at initial diagnosis. (M) The most recent Abdominal CT after therapy. (N) The most recent PET/CT after therapy.
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Abdominal computed tomography (CT) ( Figure 2K ) revealed. multiple space-occupying lesions in the liver, the largest is about 3.7cm in diameter. Positron emission tomography-computed tomography (PET-CT) revealed multiple density shadows of abnormally high uptake of fluorodeoxyglucose (FDG) in the liver, the largest being about 3.7x2.9cm, the early maximum standard uptake value (SUV max) of the liver was 6.3, and the delayed SUV max was 8.2 ( Figure 2L ). Enhanced magnetic resonance imaging (MRI) ( Figure 2A ) of the head just revealed a few ischemic degeneration foci in the brain. Combined with the history of the disease, she was considered to have CNS progression, which was identified using head MRI ( Figure 2B ). Then she was administered CNS-directed chemotherapy including two courses of methotrexate (MTX)-based combination regimens (intrathecal injection MTX 10 mg, Ara-C 50 mg, dexamethasone 5 mg) and high-dose MTX therapy (rituximab 600 mg d0, MTX 5.4 g d1), but they did not work as re-examination of the head MRI ( Figure 2C ) after 1 month showed intracranial progress. Head MRI ( Figure 2D ) shows improvement compared with previous one. T-cell cocktail therapy treatment is shown in  Figure 2E . The patient was administered a standard dose of the BEAM (carmustine, etoposide, cytarabine, melphalan) regimen one week before ASCT. Twenty-two months after ASCT and CAR19/22 T-cell cocktail therapy, the patient was still disease-free, and the head MRI image is shown in  Figure 2J . The most recent FDG-PET/CT on November 17, 2021 was unable to detect any significant disease, and the infiltration of tumor cells into the liver continued to vanished ( Figure 2N ). Liver CT showed no new lesions ( Figure 2M ).
The protocol for the murine monoclonal anti-CD19 and anti-CD22 CAR T cell "cocktail" followed by ASCT and therapeutic response. (A) Schematic diagram of murine CAR19 and CAR22 CAR vectors. SP, signal peptide; VH, variable H chain; L, linker; VL, variable L chain. (B) Timeline of murine CAR22 and CAR19 transgene copy numbers. (C) Dynamic changes in IL-6 and ferritin after CAR T cell infusion. (D) Dynamic WBC numbers and lymphocyte numbers before and after CAR T cell therapy.
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T-cells (CAR22) (2.7x106 cells/kg) were infused on day +2, followed by CD19-targeted CAR T-cells (CAR19) (4.3x106 cells/kg) on day +3. The structure is as shown in  Figure 3A . Both CAR19 and CAR22 transgene copy numbers were determined by droplet digital polymerase chain reaction (ddPCR) ( Figure 3B ). After sequential infusion of anti-CD19 and anti-CD22 CAR T-cells, grade 1 cytokine release syndrome (CRS) was observed, and interleukin-6 and ferritin levels increased slightly and transiently ( Figure 3C ). The dynamic changes in white blood cells and lymphocytes after CAR T-cell therapy are depicted in  Figure 3D . The leukocytes were engrafted at 2 weeks, and bone marrow hematopoiesis recovered in about 20 days.
Timeline of disease status and corresponding treatment regimens.
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The timeline of the clinical treatment and disease status were shown in  Figure 4 .