Novel T Follicular Helper-like T-Cell Lymphoma Therapies: From Preclinical Evaluation to Clinical Reality

SIMPLE SUMMARY: This work reviews the multiple efforts that have been and are being invested by researchers as well as clinicians to improve the treatment of a specific T-cell lymphoma called follicular helper peripheral T-cell lymphoma. Still, though treatments for B-cell lymphomas have improved, this particular T-cell lymphoma has little to no new therapeutic options that show marked improvements in the survival of the patients compared to treatment with chemotherapy. We report here the evaluation of targeted new therapies for this T-cell lymphoma in new preclinical models for this cancer or in clinical trials with the objective to offer better (combination) treatment options. ABSTRACT: The classification of peripheral T-cell lymphomas (PTCL) is constantly changing and contains multiple subtypes. Here, we focus on Tfh-like PTCL, to which angioimmunoblastic T-cell lymphoma (AITL) belongs, according to the last WHO classification. The first-line treatment of these malignancies still relies on chemotherapy but gives very unsatisfying results for these patients. Enormous progress in the last decade in terms of understanding the implicated genetic mutations leading to signaling and epigenetic pathway deregulation in Tfh PTCL allowed the research community to propose new therapeutic approaches. These findings point towards new biomarkers and new therapies, including hypomethylating agents, such as azacytidine, and inhibitors of the TCR-hyperactivating molecules in Tfh PTCL. Additionally, metabolic interference, inhibitors of the NF-κB and PI3K-mTOR pathways and possibly novel immunotherapies, such as antibodies and chimeric antigen receptors (CAR) directed against Tfh malignant T-cell surface markers, are discussed in this review among other new treatment options.