Unraveling Vulnerabilities and Pathways Responsible for AITL Malignancy to Improve Patients' Treatment

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma characterized by poor clinical outcomes following conventional CHOP-based chemotherapy and the lack of effective disease-specific therapeutic options. The disease finds its origin in CD4 follicular helper T (Tfh) cells and is driven by recurrent genetic alterations, including mutations in TET2, RHOA, DNMT3A, and IDH2. Despite the rarity of AITL, preclinical models have been fundamental in elucidating disease pathogenesis, identifying key molecular vulnerabilities and providing platforms for the evaluation of novel therapeutic strategies. These studies have highlighted multiple targetable pathways, including aberrant mTOR, T-cell receptor and NF-κB signaling. Additionally, widespread epigenetic alterations in the neoplastic T-cells were uncovered due to mutations in epigenetic modifiers in AITL. More recently, metabolic reprogramming has emerged as an additional therapeutic vulnerability, revealing a strong dependence of AITL cells on mitochondrial respiration and lipid metabolism, particularly the choline metabolic pathway. Advances in the understanding of AITL biology have also accelerated the development of immunotherapeutic strategies. Monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown encouraging preclinical and early clinical activity. Of note, the first preclinical results on an in vivo CAR-T-cell approach for AITL are reported. Here we provide a broad overview of AITL, discussing its biological features, pathogenesis, preclinical models, current treatment landscape, and recent advances in therapeutic approaches.