A 5-Year Follow-up Clinical Study of the B-cell Maturation Antigen Chimeric Antigen Receptor T-cell Therapy HDS269B in Patients with Relapsed or Refractory Multiple Myeloma

Article

Author: Sun, Xuedong ; Du, Juan ; Chen, Zhi ; Qiang, Wanting ; Xiang, Fang ; Chen, Dongjian ; He, Haiyan ; Jiang, Songfu ; Zhu, Yu

AbstractPurpose:This study aimed to report the 5-year clinical outcomes of anti–B-cell maturation antigen chimeric antigen receptor (CAR) T-cell (HDS269B) therapy in patients with relapsed/refractory multiple myeloma (RRMM), including those with poor performance status [Eastern Cooperative Oncology Group (ECOG) scores 3 to 4], and to identify factors influencing long-term outcomes.Patients and Methods:Forty-nine patients with RRMM enrolled from 2016 to 2020 received HDS269B (9 × 106 cells/kg) after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics.Results:With a median follow-up of 59.0 months, the overall response rate was 77.55%. The median progression-free survival (PFS) and overall survival (OS) were 9.5 months [95% confidence interval (CI), 5.01–13.99] and 20.0 months (95% CI, 11.26–28.74), respectively. The 5-year PFS and OS rates were 21.3% (95% CI, 12.3%–36.7%) and 34.1% (95% CI, 22.7%–51.3%), respectively. Patients with ECOG 0 to 2 had marked longer survival, with a median PFS of 11.0 months and a median OS of 41.8 months. Early minimal residual disease negativity, higher and persistent CAR T-cell expansion, and the absence of extramedullary disease were associated with better survival outcomes. No new CAR T-cell therapy–associated toxicities were observed. Importantly, ECOG scores 0 to 2, prior therapy lines <4, and CAR T-cell persistence at ≥6 months were independently associated with longer OS.Conclusions:HDS269B is effective and safe, especially for patients with ECOG scores 0 to 2. Early CAR T-cell intervention may improve prognosis in patients with RRMM.

01 Sep 2024·Transplantation and Cellular Therapy

Clonal Hematopoiesis is Associated With Severe Cytokine Release Syndrome in Patients Treated With Chimeric Antigen Receptor T-Cell (CART) Therapy

Article

Author: Wong, F Lennie ; Goldsmith, Scott R ; Mei, Matthew ; Rhee, June-Wha ; Armenian, Saro H ; Bosworth, Alysia ; Budde, L Elizabeth ; Htut, Myo ; Chen, Sitong ; Forman, Stephen J ; Iukuridze, Aleksi ; Pillai, Raju ; Shouse, Geoffrey ; Janakiram, Murali

Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR T therapy, inflammation pre- and post-CAR T infusion is implicated in the development of toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and likely contributes to prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells harboring somatic mutations, has been associated with inflammasome upregulation. Herein, we examined the prevalence of pre-CAR T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between the presence of CH mutations and CAR T-related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR T therapy from 2017 to 2022 at City of Hope and had available pre-CAR T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected <30d of CART infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH and absolute neutrophil count (ANC) recovery at day +30 and +60, maximum grade CRS and ICANS, grade <2 versus 2+, and OS and PFS at 1y. Covariates considered were age at CART, baseline ANC, sex, race, CAR-HEMATOTOX, LDH, bridging therapy (Y/N), and number of prior lines of therapy. Fifteen (24%) patients had at least one pathogenic CH mutation; 2 (13%) had ≥2 CH mutations concurrently. DMT3A mutations were the most common; 29% of mutations had VAFs >10%. Patients with CH were significantly more likely to develop grade ≥2 CRS (60% versus 28%, p = .03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p = .027). Accounting for baseline ANC (which was higher among the CH cohort and associated with delayed ANC recovery, p = .02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p = .17). There was no association between CH and ICANS, nor with 1y PFS or OS. CH was frequent (24%) in this cohort of CAR T recipients and was associated with a higher risk of development of grade ≥2 CRS after CAR T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis. Translational studies could aim to prove a direct relationship between CH-mutated myeloid cells and CRS.

10 May 2024·Science Immunology

Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity

Article

Author: Bu, Bi-Tao ; Huang, Liang ; Wang, Di ; Heming, Michael ; Qin, Chuan ; Dong, Ming-Hao ; Meyer Zu Hörste, Gerd ; Hao, Yi ; Cai, Song-Bai ; Li, Chun-Rui ; Dong, Chen ; Xiao, Jun ; Mou, Da-Peng ; Wang, Wen ; Zhang, Min ; Zhou, Luo-Qi ; Wu, Long-Jun ; Shang, Ke ; Wang, Wei ; You, Yun-Fan ; Tian, Dai-Shi

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti–B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8 + CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

100 Deals associated with Anti-BCMA CARNK-cell therapy (Takeda)

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Indication	Highest Phase	Country/Location	Organization	Date
Mature B-Cell Neoplasm	Preclinical	JP	Takeda Pharmaceutical Co., Ltd.	15 Nov 2022
Mature B-Cell Neoplasm	Preclinical	US	The University of Texas MD Anderson Cancer Center	15 Nov 2022
Multiple Myeloma	Preclinical	US	The University of Texas MD Anderson Cancer Center	15 Nov 2022
Neoplasms	Preclinical	US	Takeda Pharmaceutical Co., Ltd.	-
Neoplasms	Preclinical	US	Anderson University	-

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