Immune-related Adverse Events Associated With Checkpoint Inhibition in the Setting of CAR T Cell Therapy: A Case Series.

Abstract

Abstract Background Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy leads to high overall response rates of ∼80% even in heavily pre-treated diffuse large B-cell lymphoma (DLBCL), though relapse-free survival drops to ∼40% within the first 12 months. There are early data suggesting that inhibiting the programmed cell death protein 1: programmed cell death ligand 1 (PD-1: PD-L1) checkpoint axis may decrease T cell exhaustion and improve CAR T-cell function. However, there is limited data regarding the toxicity of sequencing these two modalities. This case series of three patients with relapsed/refractory DLBCL treated sequentially with CAR T and checkpoint inhibitor explores the immune-related adverse events (irAEs) with this approach. Case Presentation Case 1 is a 47-year-old male with refractory T-cell/Histiocyte-Rich Large B-Cell Lymphoma who was treated initially with pembrolizumab followed by CAR T-cell therapy and developed autoimmune thyroiditis. Case 2 is a 67-year-old male with refractory DLBCL who was treated with CAR T and subsequently pembrolizumab and developed pneumonitis and respiratory failure. Case 3 is a 22-year-old female with primary refractory mediastinal DLBCL who was treated with pembrolizumab following CAR T therapy and subsequently developed a T-cell mediated autoimmune skin reaction. Conclusions T cell exhaustion has been suspected to contribute to poor persistence of CAR T-cells and clinical relapse, which may be overcome by checkpoint inhibition. While the synergy between CAR T-cell therapy and checkpoint inhibition is promising, the interaction may also lead to off-target irAEs. Prospective trials exploring the safety and efficacy of this combination in relapsed/refractory DLBCL are under way.