DISTINCT PATTERNS OF LYMPHOID IMMUNE RECONSTITUTION AFTER BCMA-DIRECTED CAR-T THERAPY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA

@article{gusmao2026distinct,
  title = {{DISTINCT PATTERNS OF LYMPHOID IMMUNE RECONSTITUTION AFTER BCMA-DIRECTED CAR-T THERAPY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA}},
  author = {Arianne Fagotti GUSMAO and Raquel Garcia DA SILVA and Vanessa Dos Anjos BOVOLENTA and Bianca Batista CAL and Ana Costa CORDEIRO and Daniela DELECHIAVE and Sabrina Pinho Costa MENDES and Lais Lie Senda DE ABRANTES and Alexandre Silva CHAVES and Ana Luiza Sionti PACHECO and Larissa Souza CAMPOS and Mariana Soares GOMES and Gabriel Andrade DE PAULA and Filipe Freires DOS SANTOS and Marina De Matos NASCIMENTO and Mariela Pires Cabral PICCIN and Marta Maria Moreira LEMOS and Jayr Schmidt FILHO and Martin BONAMINO and Marjorie Vieira BATISTA},
  journal = {Hematology, Transfusion and Cell Therapy},
  year = {2026},
  month = oct,
  doi = {10.1016/j.htct.2026.107863},
  url = {https://doi.org/10.1016/j.htct.2026.107863},
  note = {CC BY},
}

TY  - JOUR
TI  - DISTINCT PATTERNS OF LYMPHOID IMMUNE RECONSTITUTION AFTER BCMA-DIRECTED CAR-T THERAPY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA
AU  - Arianne Fagotti GUSMAO
AU  - Raquel Garcia DA SILVA
AU  - Vanessa Dos Anjos BOVOLENTA
AU  - Bianca Batista CAL
AU  - Ana Costa CORDEIRO
AU  - Daniela DELECHIAVE
AU  - Sabrina Pinho Costa MENDES
AU  - Lais Lie Senda DE ABRANTES
AU  - Alexandre Silva CHAVES
AU  - Ana Luiza Sionti PACHECO
AU  - Larissa Souza CAMPOS
AU  - Mariana Soares GOMES
AU  - Gabriel Andrade DE PAULA
AU  - Filipe Freires DOS SANTOS
AU  - Marina De Matos NASCIMENTO
AU  - Mariela Pires Cabral PICCIN
AU  - Marta Maria Moreira LEMOS
AU  - Jayr Schmidt FILHO
AU  - Martin BONAMINO
AU  - Marjorie Vieira BATISTA
PY  - 2026
DA  - 2026/10/23
JO  - Hematology, Transfusion and Cell Therapy
DO  - 10.1016/j.htct.2026.107863
UR  - https://doi.org/10.1016/j.htct.2026.107863
AB  - Background: BCMA-directed CAR-T therapy has improved outcomes in relapsed/refractory multiple myeloma (RR-MM). However, responses remain heterogeneou, suggesting that immune recovery extends beyond CAR-T expansion alone. Although most studies focus on the infused cellular product, remodeling of CAR-positive T cells, endogenous CAR-negative T cells, and natural killer (NK) cells during early immune reconstitution remains poorly understood. Aim: To characterize early lymphoid immune remodeling after BCMA-directed CAR-T therapy by integrating CAR-positive and CAR-negative T-cell compartments, CD4/CD8 balance, memory differentiation, immune checkpoints, and NK-cell subsets. Methodology: Patients with RR-MM treated with BCMA-directed CAR-T cells were prospectively enrolled (CAAE: 65750722.3.0000.5432). Blood samples were collected before infusion and 30 days after treatment. PBMC were analyzed by multiparametric flow cytometry to assess CAR-positive and CAR-negative CD4⁺ and CD8⁺ T-cell subsets, memory differentiation, checkpoint expression, and conventional and non-conventional NK-cell phenotypes. Paired changes between baseline and day 30 were evaluated. Results: Paired analyses of three patients revealed marked interindividual heterogeneity in early lymphoid reconstitution. Circulating CAR-T frequencies ranged from robust expansion to minimal detectable expansion at D30. Total CD4⁺ and CD8⁺ T-cell compartments followed distinct trajectories, producing divergent CD4/CD8 architectures. The responding patient exhibited a more balanced CD4/CD8 ratio, whereas the two non-responders developed CD4- or CD8-dominant profiles. Corresponding alterations in CD4/CD8 balance were also observed within the CAR-negative compartment, indicating that remodeling extended beyond the infused product. Effector-memory enrichment was observed across CAR-positive and CAR-negative T-cell compartments, accompanied by sustained PD-1 and reduced LAG-3 expression, particularly among CD8⁺ T cells. All patients also showed expansion of non-conventional NK cells, with relative contraction of canonical NK subsets and reduced LAG-3 expression. These findings demonstrate multi-compartment lymphoid remodeling during early immune reconstitution. Discussion: The concomitant changes observed in CAR-positive T cells, endogenous CAR-negative T cells, and NK cells suggest that early immune recovery after BCMA-directed CAR-T therapy reflects systemic lymphoid reorganization rather than expansion of the infused product alone. The expansion of non-conventional NK phenotypes across patients with markedly different CAR-T frequencies may represent a shared feature of post-lymphodepletion immune recovery. The observation that the responding patient maintained a more balanced CD4/CD8 architecture, whereas non-responders developed opposite forms of imbalance, is hypothesis-generating and suggests that the organization of immune reconstitution may be biologically relevant. However, the limited cohort precludes conclusions regarding association with clinical response. Conclusion: BCMA-directed CAR-T therapy was followed by distinct patterns of early lymphoid reconstitution involving CAR-positive T cells, endogenous CAR-negative T cells, and non-conventional NK cells. These findings support further investigation of integrated lymphoid architecture, including CD4/CD8 balance, as a potential marker of immune recovery and treatment outcome in larger longitudinal cohorts.
SN  - 2531-1379
SN  - 2531-1387
ER  -