Clinical Impact of LAG3 Single-Nucleotide Polymorphism in DLBCL Treated with CAR-T Cell Therapy

Lymphocyte-activation gene 3 (<i>LAG3</i>) is an immune checkpoint receptor and inhibitory regulator of T-cells. Here, we analyzed the prevalence of <i>LAG3</i> rs870849 in B-cell lymphoma patients and the treatment outcomes according to the <i>LAG3</i> genetic background and discovered that <i>LAG3</i> germline variants may affect the risk of developing lymphoma and also affect the treatment outcome of DLBCL patients in the current CD19 CAR-T cell therapies. The <i>LAG3</i> rs870849 was prevalent at high frequency in DLBCL patients. Significant differences in treatment outcomes to CAR-T cell therapy emerged in <i>LAG3</i> I455hom versus I455Thet and T455hom carriers. The overall and complete response rates to CAR-T cell therapy were lower in the I455hom genetic subgroup with median PFS in the I455hom of 2 versus 20 months in the T455hom and I455Thet subgroups (<i>p</i> = 0.025). Median OS was 6 months in the <i>LAG3</i> I455hom versus 41 months in the T455hom and I455Thet subgroups (<i>p</i> = 0.007). <i>LAG3</i> rs870849 may affect treatment outcome in CAR-T cell therapy, with favorable outcomes in T455 carriers. Specific combinations of <i>CTLA4</i> and <i>LAG3</i> germline variants may cooperate to affect the response to CAR-T cell therapy.