ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.
A chimeric mouse-human Fab protein that binds specifically to the human carcinoma cell line C3347 has been expressed and secreted from Escherichia coli. This molecule, which contains functionally assembled kappa and Fd proteins, binds as effectively to sites on the surface of C3347 cells as Fab fragments prepared proteolytically from whole chimeric or mouse antibody. The production in Escherichia coli of foreign heterodimeric protein reagents, such as Fab, should prove useful in the management of human disease.
Multiple sclerosis is an autoimmune disease in which T lymphocytes reactive to myelin basic protein (BP) could play a central role. T cells specific for BP were cloned from the blood of multiple sclerosis patients and normal individuals, and expression of T-cel receptor variable region genes was analyzed. A remarkable bias for use of f-chain variable region (VP) 5.2 and, to a lesser extent, Vj36.1 was seen among BP-specific clones from patients but not from controls. Multiple sclerosis (MS) is an immune-mediated disease characterized by central nervous system mononuclear cell infiltration and demyelination. Although the pathogenesis of MS is unknown, both genetic and environmental factors have been implicated in the disease process. Major elements ofthe genetic predisposition include an association of disease with particular class II major histocompatibility complex (MHC) haplotypes, in particular HLA-DR2 and -DQwl (1-5), as well as with certain polymorphisms within the T-cell receptor (TCR) a-chain and (3-chain gene complexes (6-9). These studies suggest that the disease involves CD4+ T cells bearing af3 TCR. In support of this idea, CD4+ T cells represent a major component of mononuclear cells in the brains of active patients (10), and limited sets of a-chain TCRs are present within central nervous system tissue of MS patients but not controls (11).T lymphocytes that recognize myelin basic protein (BP) have been shown to have potent demyelinating and encephalitogenic activity in animals (12-18). Accumulating evidence also suggests that BP-specific T cells may contribute to the pathogenesis ofMS. Thus, cells selected from MS patients on the basis of in vivo activation have specificity for BP (19). In addition, the frequencies of BP-reactive T cells are increased Monoclonal antibodies directed to these regions or synthetic peptides with sequences common to these TCR V regions can both protect and treat animals with clinical signs of experimental autoimmune encephalomyelitis (21,22,(25)(26)(27). For a similar approach to be applied to MS patients, it is critical to know if potentially pathogenic T cells also preferentially use a limited set of V region genes. In this manuscript, we analyze the TCR Va and Vf3 genes expressed in BP-specific T cells selected from the blood of MS patients and normal individuals.
MATERIALS AND METHODSPatients. Blood samples were obtained from seven patients being followed at the Oregon Health Sciences University MS clinic. All patients had clinically and laboratory-supported definite MS with an average ambulation index of 3.2 + 1.7 (range 2-6) and an average Kurtzke disability status score of 3.8 + 2.0 (range 2-6). Four patients had relapsing/remitting disease, and three patients had chronic progressive disease. The normal individuals were from the Veterans Affairs Medical Center, selected on the basis of a positive proliferative response of peripheral blood mononuclear cells (PBMC) to human BP in culture (20). All subjects were HLA-typed by standard serological methods at the...
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