Anbalcabtagene autoleucel (anbal-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy incorporating dual PD-1 and TIGIT knockdown to enhance antitumor function and durability. We report results from a phase 1 and 2 study in patients with relapsed or refractory large B-cell lymphoma. In phase 2, 79 patients received anbal-cel, and its efficacy was evaluated in 73 patients. The complete response (CR) and partial response rates were 67.1% and 8.2%, respectively. Median progression-free survival (PFS) was 6.04 months (95% confidence interval, 4.34-16.46), and the 6-, 12-, and 18-month PFS rates were 50.9%, 41.1%, and 35.2%, respectively. Median overall survival (OS) was not reached, with 12-and 18-month OS rates of 66.6% and 57.3%, respectively. CAR T-cell expansion (Cmax) was significantly greater in responders than in non-responders (median Cmax, 20 403 vs 8580 copies per mu g). Patients were categorized into long-term response (LR) group or non-LR group based on sustained CR at 6 months. Reduced PD-1 and TIGIT expression on CAR + T cells was observed in the LR group. Most patients (97.5%) experienced grade >= 3 adverse events, most commonly neutropenia (93.7%), followed by thrombocytopenia (41.8%) and anemia (30.4%). Cytokine release syndrome (CRS) and neurological events occurred in 57.0% and 13.9% of patients, respectively. Grade 3 CRS occurred in 8.9% of patients, with no grade 4 events reported, and grade >= 3 neurological events occurred in 3.8% of patients. Serious infections occurred in 25.3% of patients, including grade 5 infection reported in 3 patients. This trial was registered at www.clinicaltrials.gov as #NCT04836507.
Antiphospholipid syndrome (APS) is an immunothrombotic disorder, frequently attributed to autoantibodies that bind 2-glycoprotein I (2GPI). A study showed that the platelet-specific chemokine, platelet factor 4 (PF4), binds to 2GPI, enhancing recognition of 2GPI by APS antibodies. APS antibodies induce the release of neutrophil extracellular traps (NETs), webs of decondensed chromatin that bind both PF4 and 2GPI. We propose that PF4 bridges 2GPI to NETs (and other PF4-targeted polyanions), leading to the formation of prothrombotic PF4:2GPI:NET immunotargets in APS. Dynamic light-scattering studies of isolated immunoglobulin G from 4 patients with triple-positive APS show formation of PF4:2GPI:NET complexes that bind APS antibodies. NETs released in a microfluidic system bound 2GPI, but only in the presence of PF4, forming a multimolecular APS antigenic target. Whole blood infused through a photochemically injured, endothelium-lined microfluidic channel formed platelet-, fibrin-, and complement-rich thrombi that bound APS antibodies only in the presence of PF4. Thrombi were reduced in size if either ADAMTS13 or DNase I was infused. In a murine APS model, wild-type and transgenic mice expressing human PF4 (hPF4) +/- FcyRIIA developed more intense neutrophil rolling along veins and more extensive thrombus formation after laser injury to cremaster arterioles and venules, whereas mice lacking PF4 did not. Three antigenically distinct anti-hPF4 monoclonal antibodies blocked thrombosis in vitro and neutrophil rolling and thrombosis in vivo. Our studies provide new insights into the basis of APS that has mechanistic parallels to other known PF4 immunothrombotic disorders and offer potential diagnostic and nonanticoagulant therapeutic strategies for clinical management.
Glanzmann thrombasthenia (GT) is characterized by absent platelet aggregation in response to all agonists except ristocetin and is caused by recessive inactivating variants in ITGA2B or ITGB3. Although patients with GT typically are described as having normal platelet counts, autosomal dominant activating variants in ITGA2B or ITGB3 cause macrothrombocytopenia. Interestingly, in our cohort of 16 patients with GT, 8 consistently exhibited platelet counts at the lower end of the normal range. We studied the role of integrin a IIb R 3 in platelet formation using megakaryocytes (MKs) derived from genetically modified immortalized MK cell lines (imMKCLs), focusing on 2 modifications of ITGB3: ITGB3 -/- (inactivating) and ITGB3 WT/D673_E713del (activating). In static differentiation culbut reduced proplatelet formation. Platelet production was also impaired in a 3-dimensional silk-based bone marrow system and in shaking cultures, confirming a quantitative role for ITGB3 in platelet production independent of the type of variant. Although thrombin receptor activating protein-activated, in vitro-generated platelets lacking a IIb R 3 failed to bind the activation-dependent PAC-1 antibody, ITGB3 WT/D673_E713del platelets bound PAC-1 before activation, mimicking the patient's phenotype. Transcriptome profiling and metabolomic analyses of integrin a IIb R 3 -deficient MKs revealed impaired serine metabolism and downregulation of SLC3A2 (CD98hc), an amino acid transporter chaperon known to interact with the R 3 subunit. Flow cytometry confirmed decreased CD98hc in mutant MKs, whereas reexpression of wild-type ITGB3 in ITGB3 -/- MKs restored a IIb R 3 and CD98hc expression, normalized proplatelet formation, and enhanced serine uptake. These results uncover a previously unrecognized role of integrin a IIb R 3 in coupling serine metabolism to platelet biogenesis.
Host-versus-graft reaction (HVGR) is a major challenge in allogeneic chimeric antigen receptor (CAR) T-cell therapy. To counter host natural killer (NK) cell attacks, we armored allogeneic, HLA-I-deficient, B-cell maturation antigen (BCMA)-targeting CAR T cells with an NKG2A CAR. In vitro and animal studies demonstrated that allogeneic CAR-NKG2A T cells effectively resisted host NK cell-mediated killing. BCMA and NKG2A dual-targeting allogeneic CAR T cells (CT0590) resisted killing by NK cells and showed robust antitumor activity in preclinical in vivo models. On the basis of these data, a first-in-human study enrolled 5 patients (4 with relapsed and refractory multiple myeloma [RRMM] and 1 with primary plasma cell leukemia [pPCL]). CT0590 was well tolerated and caused no doselimiting toxicities, treatment-related death, or graft-versus-host disease. Three patients achieved confirmed responses, including 2 with stringent complete response (sCR). Notably, sCR in the patient with RRMM was still ongoing (duration of response >23 months) at the time of data cutoff, and sCR in the patient with pPCL lasted for 20 months. Both patients showed robust expansion of universal CAR T cells (maximum concentration of >280 000 copies per mu g genomic DNA) and higher baseline NKG2A expression on NK cells than nonresponders. These results suggest that CAR-NKG2A technology may overcome HVGR, especially in patients with elevated NKG2A expression on NK cells. Further studies of CT0590 in RRMM and pPCL are warranted. This trial was registered at www.clinicaltrials.gov as NCT05066022.
