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Cell free DNA analysis reveals determinants of failure of CAR-T cell therapy for LBCL

Ash Alizadeh, Ludwig Cancer Research
Ash Alizadeh
Brian Sworder, Ludwig Cancer Research
Brian Sworder

Researchers led by Ludwig Stanford’s Ash Alizadeh and Brian Sworder profiled over 700 longitudinal specimens from two independent cohorts of relapsed/refractory large B cell lymphoma (r/rLBCL) patients treated with CAR-T cells targeting CD-19 to identify determinants of resistance to this therapy. Relapse is seen in roughly half of such patients. The researchers developed a method called STEP to simultaneously profile tumor DNA, CAR-T cell effectors and receptor rearrangements of ordinary T cells in the blood and integrated these profiles to assess treatment failure. They also constructed a multivariate model incorporating these features and used it to predict outcomes. Ash, Brian and colleagues reported in a January paper in Cancer Cell that alterations in multiple classes of genes are associated with treatment resistance, including those affecting B cell identity (PAX5 and IRF8), immune checkpoints (CD274) and the microenvironment (TMEM30A). Somatic tumor alterations influence the efficacy of anti-CD19 CAR-T therapy at multiple levels, including CAR-T cell expansion and persistence and conditions of the tumor microenvironment. They found that the genotype and phenotype of tumors influence the expansion of CAR-T cells, which can in turn shape those characteristics of tumors. The researchers suggest their findings could inform the development of improved and personalized CAR-T cell therapies for LBCL.

Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas
Cancer Cell, 2023 January 9

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