Multi-Targeting CAR-T Cell Strategies to Overcome Immune Evasion in Lymphoid and Myeloid Malignancies

Background: Chimeric antigen receptor (CAR)-T cell therapy has become a groundbreaking treatment for hematological malignancies, particularly lymphomas and multiple myeloma, with high remission rates in refractory and relapsed patients. However, most CAR-T therapies target a single antigen, such as CD19, which can result in immune evasion through antigen escape. This mechanism describes the downregulation or complete loss of the targeted antigen by the tumor cells, eventually leading to relapse. To address this issue, multi-targeting strategies like logic-gated CARs, adapter CARs, or combination therapies can increase the potency of CAR-T cells. These approaches aim to minimize immune evasion by targeting multiple antigens simultaneously, thereby increasing treatment durability. Additionally, advanced tools such as next-generation sequencing (NGS), direct stochastic optical reconstruction microscopy (dSTORM), or multiparametric flow cytometry are helping to identify novel tumor-specific targets and improve therapy designs. Summary: This review explores the current landscape of CAR-T cell therapies in lymphoid and myeloid malignancies, highlights ongoing clinical trials, and discusses the future of these innovative multi-targeting approaches to improve patient outcome. Key Messages: Antigen escape limits CAR-T cell therapy success, but multi-targeting strategies like logic gates and adapter CARs offer solutions. Optimizing antigen selection and CAR design, along with larger clinical trials, is essential for improving patient outcomes. Personalization using advanced technologies like CRISPR screening and single-cell RNA sequencing can enhance durability and effectiveness of treatments for heavily pretreated patients.