Challenges and Clinical Strategies of CAR T-Cell Therapy for Acute Lymphoblastic Leukemia: Overview and Developments

Abstract

Chimeric antigen receptor (CAR) T-cell therapy exhibits desirable and robust efficacy in patients with acute lymphoblastic leukemia (ALL). Stimulated by the revolutionized progress in the use of FDA-approved CD19 CAR T cells, novel agents with CAR designs and targets are being produced in pursuit of superior performance. However, on the path from bench to bedside, new challenges emerge. Accessibility is considered the initial barrier to the transformation of this patient-specific product into a commercially available product. To ensure infusion safety, profound comprehension of adverse events and proactive intervention are required. Additionally, resistance and relapse are the most critical and intractable issues in CAR T-cell therapy for ALL, thus precluding its further development. Understanding the limitations through up-to-date insights and characterizing multiple strategies will be critical to leverage CAR T-cell therapy flexibly for use in clinical situations. Herein, we provide an overview of the application of CAR T-cell therapy in ALL, emphasizing the main challenges and potential clinical strategies in an effort to promote a standardized set of treatment paradigms for ALL.

Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion

“…However, durable remission following CAR T cell therapy is not guaranteed, as demonstrated by relapse occurring in up to 75% of patients treated with CD19 or CD22 CAR T cells for hematological malignancies. 9 , 10 , 11 Most commonly, CAR T cell therapy failure is attributed to antigen escape, wherein selection pressure under CAR T surveillance leads to the emergence of antigen-negative tumors. 12 However, relapse also occurs with antigen-positive disease, suggesting that CAR T cell-intrinsic factors can contribute to poor anti-tumor response.…”

Strengthening the CAR‐T cell therapeutic application using CRISPR/Cas9 technology

“…Meanwhile, there are other problems associated with CAR‐T cell therapy, including antigen escape, poor trafficking and tumor infiltration, low persistence, inhibition and resistance of T cells, and CAR‐T associate clinical toxicities (Sterner & Sterner, 2021). Importantly, obstacles such as cost of treatment, gap between leukapheresis and manufacturing, and specific inclusion and exclusion criteria set by clinical trial restrict patients from getting the treatment (Xu et al, 2020). Furthermore, CAR‐T therapy has also been used against solid tumors and showed promising therapeutic approaches; however, up to now FDA approved no CAR‐T products for solid tumors.…”

Pro-Apoptotic Potential of Pseudevernia furfuracea (L.) Zopf Extract and Isolated Physodic Acid in Acute Lymphoblastic Leukemia Model In Vitro

“…However, the use of vincristine is associated with side effects, including neurotoxicity [7]. Therefore, the identification of novel natural or synthetic substances with reduced toxicity and anti-cancer activity for ALL treatment is a major challenge in this research area [8][9][10][11][12][13].…”