Improved GVHD-free and relapse-free survival after ex vivo αβTCR and CD19 depleted allogeneic HSCT compared to T cell replete HSCT
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Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy
The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is effective in B cell malignancies. However, the persistence of cancer cells with low levels or complete absence of the target antigen, thereby evading detection by CAR T cells, leads to relapse. These evasion mechanisms highlight the need for receptors with enhanced sensitivity and multispecificity. We introduce a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity compared with CARS and previous hybrid TCR designs and is readily adapted for bispecific targeting. ChTCRs replicate the structure of natural TCRs, form classical immune synapses and demonstrate TCR-like signaling. T cells expressing bispecific ChTCRs (Bi-ChTCRs) are more effective than bispecific CAR T cells in eradicating tumors with heterogeneous antigen expression in vivo in female mice. The Bi-ChTCR architecture is resilient and can be designed to target pairs of B cell and multiple myeloma antigens. These findings provide a widely applicable strategy to combat tumor heterogeneity and prevent relapse.
Myeloablative conditioning in cord blood transplantation for acute myeloid leukemia patients is efficacious only until age 55
Umbilical cord blood transplantation (CBT) is accepted as an effective treatment for acute myeloid leukemia (AML), and reduced-intensity conditioning (RIC), rather than myeloablative conditioning (MAC) regimens allowed elderly patients to be treated safely. However, appropriate intensities of conditioning regimens are still unclear, especially for middle-aged patients. To compare outcomes after RIC and MAC regimens, we analyzed AML patients aged 16 years or older in the Japanese registry database, who underwent single cord unit CBT between 2010-2019. Median ages of the RIC group (n = 1353) and the MAC group (n = 2101) were 59 and 51 years (P < 0.001), respectively. 5-year overall survival (OS) after MAC was superior to that of RIC (38.3% vs 27.7%, P < 0.001) with lower incidence of relapse (33.9% vs 37.4%, P = 0.029) and better neutrophil engraftment (84.7% vs 75.9%, P < 0.001). Detailed subgroup analysis revealed that age at transplantation is the most important factor affecting 5-year OS in RIC and MAC. This analysis identified a threshold of 55 years, beyond which the superiority of MAC disappeared, irrespective of other factors such as disease status or performance status. In conclusion, RIC may be preferable for patients aged 56 or older in CBT for AML due to higher potential toxicities.
Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis and neuromyelitis optica spectrum disorder — recommendations from ECTRIMS and the EBMT
Autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option for relapsing forms of multiple sclerosis (MS) that are refractory to disease-modifying therapy (DMT). AHSCT after failure of high-efficacy DMT in aggressive forms of relapsing–remitting MS is a generally accepted indication, yet the optimal placement of this approach in the treatment sequence is not universally agreed upon. Uncertainties also remain with respect to other indications, such as in rapidly evolving, severe, treatment-naive MS, progressive MS, and neuromyelitis optica spectrum disorder (NMOSD). Furthermore, treatment and monitoring protocols, rehabilitation and other supportive care before and after AHSCT need to be optimized. To address these issues, we convened a European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop in partnership with the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party, in which evidence and key questions were presented and discussed by experts in these diseases and in AHSCT. Based on the workshop output and subsequent written interactions, this Consensus Statement provides practical guidance and recommendations on the use of AHSCT in MS and NMOSD. Recommendations are based on the available evidence, or on consensus when evidence was insufficient. We summarize the key evidence, report the final recommendations, and identify areas for further research.
Improved prognosis of advanced-stage extranodal NK/T-cell lymphoma: results of the NKEA-Next study
A retrospective study of extranodal natural killer/T-cell lymphoma (ENKL) patients diagnosed between 2014 and 2021 in Japan was conducted. Among 351 patients with sufficient data, 116 (33%) were in the advanced stage (5 in stage III and 111 in stage IV) at diagnosis, and were further analyzed. The median age was 60 years (range: 19–90), and 68 (59%) were male. Ninety-four (85%) of stage IV patients had two or more extranodal involvements. The most common first-line regimen was SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide; 52%). The 2-year overall survival (OS) for all patients was 38.5%, which was significantly improved after 2017 (25.2% for 2014–2017 vs. 50.7% for 2018–2021; P = 0.008). Patients treated with SMILE showed better OS than those treated with DeVIC or CHOP (2y-OS: 57.1%, 35.8%, and 0%, respectively; P < 0.001). The prognosis was significantly better in patients who received hematopoietic stem cell transplantation (HSCT) than in those who did not (2-year OS: 68.3% vs. 17.6%, P < 0.001). Multivariate analysis showed SMILE and HSCT were significant factors for OS. In conclusion, the prognosis of advanced-stage ENKL has improved in recent years. The L-asparaginase-containing chemotherapy and subsequent HSCT is considered the recommended strategy.
The 2023 EBMT report on hematopoietic cell transplantation and cellular therapies. Increased use of allogeneic HCT for myeloid malignancies and of CAR-T at the expense of autologous HCT
In 2023, 47,731 HCT (20,485 (42.9%) allogeneic and 27,246 (57.1%) autologous) in 43,902 patients were reported by 696 European centers. 6042 patients received advanced cellular therapies, 4888 of which were CAR-T. Compared to the previous year there was an increase in CAR-T (+52.5%), in allogeneic HCT (+7.8%) but none in autologous HCT (+0.4%). Main indications for allogeneic HCT were myeloid (11,748; 60.7%), lymphoid malignancies (4,850; 25.0%), and non-malignant disorders (2558; 13.2%). Use of allogeneic HCT increased for AML (+12.1%) and for NHL (+11.0%), particularly in T-NHL (+25.6%). Main indications for autologous HCT were lymphomas (7890; 32.2%), PCD (14,271; 58.2%), and solid tumors (1608; 6.6%) with recovering numbers for autoimmune diseases. In patients with allogeneic HCT, the use of sibling donors increased by +1.0%, haploidentical donors by +11.7%, and unrelated donors by +11.1%. Cord blood HCT decreased again by −5.4%. Pediatric HCT activity increased slightly (5455; +0.1%) with differences between allogeneic (4111; −0.5%) and autologous HCT (1344: +1.7%). Use of CAR-T increased to a cumulative total of 13,927 patients including patients treated for autoimmune diseases. Overall, numbers show a complete recovery from the pandemic dip with increased cellular therapy at the expense of autologous HCT. Allogeneic HCT activity focuses on myeloid malignancies.
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