单纯输注抗BCMA与抗BCMA输注联合抗CD19嵌合抗原受体T细胞治疗复发/难治性多发性骨髓瘤免疫重建的对比

OBJECTIVE: We observed and compared the differences in immune reconstruction between single-infusion anti-B-cell maturation antigen（BCMA）, chimeric antigen receptor T cells（CAR-T）, and combined infusion of anti-CD19 CAR-T cells in the treatment of recurrent/refractory multiple myeloma（RRMM）. METHODS: Sixty-one patients with RRMM who underwent CAR-T cell therapy in our hospital from June 2017 to December 2020 were selected. Among them, 26 patients received anti-BCMA target, and 35 patients received anti-BCMA combined with anti-CD19 target. Using flow cytometry, we determined T cell subsets（CD3(+), CD4(+), CD8(+), CD4(+)/CD8(+)）, B cells（CD19(+)）, and NK cells（CD16(+) CD56(+)）at different time points before and after CAR-T treatment, and detected immunoglobulin IgG, IgA and IgM levels by immunoturbidimetry. We compared the reconstruction rules of lymphocyte subsets and immunoglobulins in the two groups. RESULTS: CD8 (+) T lymphocytes recovered most rapidly after the infusion of CAR-T cells, returning to pre-infusion levels at 3 months and 1 month after infusion, respectively［BCMA: 695（357, 1264）/µl vs 424（280, 646）/µl; BCMA+CD19: 546（279, 1672）/µl vs 314 （214, 466）/µl］. NK cells returned to normal levels at 3 months after infusion in both groups［BCMA: 171 （120, 244）/µl, BCMA+CD19: 153（101, 218）/µl（Normal reference range 150–1100 /µl）］; however, the NK cells were not maintained at stable levels in the BCMA CAR-T cells group. The recovery of CD4(+) T lymphocytes in both groups was slow and remained persistently low within 12 months after infusion, and no recovery was observed in most patients. The reversal of the ratio of CD4(+)/CD8(+) lasted for more than a year. The levels of CD19(+) B cells in both groups returned to baseline 3 months after infusion［BCMA: 62（10, 72）/µl vs 57（24, 78）/µl; BCMA+CD19: 40（4, 94）/µl vs 29（14, 46）/µl］. IgG returned to the pre-infusion level 12 months after infusion in the group with anti-BCMA cells alone, but not in the group with combined infusion of CD19 CAR T cells［7.82（6.03, 9.64）g/L vs 6.92（4.62, 12.76）g/L］. IgA returned to pre-infusion levels at 9 and 12 months after infusion, respectively［BCMA: 0.46（0.07, 0.51）g/L vs 0.22 （0.12, 4.01）g/L; BCMA+ CD19: 0.46（0.22, 0.98）g/L vs 0.27（0.10, 0.53）g/L］. IgM in both groups returned to pre-infusion levels 6 months after infusion［BCMA: 0.43（0.06, 0.60）g/L vs 0.20（0.13, 0.37）g/L; BCMA+CD19: 0.53（0.10, 0.80）g/L vs 0.16（0.11, 0.28）g/L］. There was no significant difference in the indexes of lymphocyte subpopulation reconstruction and immunoglobulin recovery between the two groups at each time point. CONCLUSION: This study showed that in patients with RRMM treated with CAR-T cells, the appropriate target antigen can be selected without considering the difference of immune reconstruction between anti-BCMA CAR-T and combined anti-CD19 CAR-T therapy.