Autoimmune diseases are driven by dysregulated immune responses against self-antigens, resulting in chronic inflammation and progressive tissue damage. Chimeric antigen receptor (CAR) T cell therapy and T cell engagers, initially developed for the treatment of hematologic malignancies, have demonstrated that they can mediate profound and sustained depletion of pathogenic B cells, leading to long-term remissions in otherwise refractory diseases. In this review, we explore key insights gained from hematologic applications of CAR T cells and T cell engagers, and discuss how these lessons can guide the clinical use of these therapies in autoimmune diseases.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (B-ALL), with high remission rates across various CAR T-cell constructs. However, the durability of these responses remains a major challenge, with many patients experiencing relapse after an initial remission. This systematic review and meta-analysis aimed to compare the efficacy and safety of different CAR T-cell constructs across 40 clinical trials, including a total of 1540 R/R B-ALL patients. We assessed the impact of patient demographics, prior treatment exposure, and construct characteristics on treatment outcomes. The pooled complete remission rate (CRR) was 83.4% (I2 = 49%), with a minimal residual disease-negative complete remission (MRDneg-CR/CRi) rate of 92.7% (I2 = 48%). 4-1BB co-stimulatory domain constructs showed higher MRDneg-CR/CRi rates compared with CD28 (94.0% vs. 84.4%p = 0.048) and a lower incidence of immune effector cell-associated neurotoxicity syndrome. Additionally, CAR T-cell products targeting CD19 or CD19/CD22 patients presented higher MRDneg-CR/CRi rates than those targeting CD22 alone. In conclusion, our findings suggest that 4-1BB-based CAR T-cell therapy targeting CD19 offers the best efficacy and safety profile in R/R B-ALL.

Donor-derived cytogenetic abnormalities are a rare finding following allogeneic hematopoietic cell transplantation. Deletion of the long arm of chromosome 20 [del(20q)] is one of the more frequently observed structural abnormalities, but its significance in the post-transplant setting remains unclear. We describe a unique case of donor-derived del(20q) with 26 years of post-transplant follow-up, the longest reported to date. The recipient remains well with normal blood counts despite persistent del(20q) in both myeloid and lymphoid lineages and the presence of coexisting somatic mutations in DNMT3A and TP53. Retrospective analysis of the donor's marrow confirmed del(20q) and low-level DNMT3A and TP53 mutations at the time of transplant; the donor later developed therapy-related MDS after radiation therapy for thyroid cancer. To contextualize this case, we reviewed 20 published reports of donor-derived del(20q) post-transplant. The median time to detection was 16 months post-transplant, and 35% of cases progressed to donor-derived malignancy. Among those who progressed, the median time to malignancy diagnosis was 22 months post-transplant. Clinical outcomes across cases ranged from asymptomatic persistence and cytopenias to donor-derived myeloid malignancies, highlighting the need for long-term follow-up and potential use of molecular profiling to better define the neoplastic potential of donor-derived del(20q) after transplantation.

The gut microbiota has emerged as a critical factor influencing outcomes following allogeneic hematopoietic cell transplantation (alloHCT). Notably, disruptions to the intestinal microbiome-referred to as dysbiosis-have been strongly linked to the development of acute graft-versus-host disease (aGVHD). The gut microbiome interacts closely with the host immune system, influencing both immune reconstitution and alloHCT complications. As a result, microbiome-targeted strategies are being investigated to improve outcomes and include antibiotic stewardship, prebiotic and diet intervention, probiotics including fecal microbiota transfer (FMT) and postbiotics. These approaches are being investigated not only as a therapeutic intervention in particular for aGVHD, but also as preventive strategies.