Axicabtagene ciloleucel (KTE-C19), an anti-CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin’s lymphoma

Abstract

Adoptive T-cell immunotherapy is a rapidly growing field and is shifting the paradigm of clinical cancer treatment. Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell therapy that was initially developed at the National Cancer Institute and has recently been commercially approved by the US Food and Drug Administration for relapsed or refractory aggressive non-Hodgkin’s lymphomas including diffuse large B-cell lymphoma and its variants. The ZUMA-1 Phase I and II clinical trials formed the basis of the US Food and Drug Administration approval of this product, and we discuss the particulars of the clinical trials and the pharmacology of axi-cel. In addition, we review the CD19 chimeric antigen receptor T-specific toxicities of cytokine release syndrome and neurotoxicity, which remain the challenges to the safe delivery of this important therapy for aggressive B-cell lymphomas with poor prognosis.

Chimeric antigen receptor modified T cell therapy in B cell non‐Hodgkin lymphomas

“…However, two of these constructs (liso‐cel and CTL019) contain an internal 4‐1BB costimulatory domain with CD3ζ, while axi‐cel contains a CD28 combined with CD3ζ. Preclinical and clinical data suggest that 4‐1BB CD3ζ CAR‐T cells have longer persistence than CD28 CD3ζ CAR‐T cells, while the latter have increased short‐term expansion which may lead to more tumoricidal activity . These difference in CAR‐T kinetics between CD28 and 4‐1BB constructs likely explain the difference in median time to onset of CRS (2 days for axi‐cel vs 5 days for liso‐cel) .…”

CAR-T Therapy for Solid Tumors: Development of New Strategies

“…The success of CD19-targetted CAR-T cells against hematological cancers is aided by the ability to recognize and bind to cancer cells readily upon CAR-T infusion [18,12] . In solid cancers, particularly in bulky tumors, there are multiple factors that complicate efficient targeting of cancer cells, including penetrability of the tumor and specificity of scFv to antigens present in the cancer but not, or much less, in normal cells [25] .…”

“…Due to the remarkable positive clinical outcome brought by immunotherapy, it is now becoming as the first line of treatment in some cancer types [10] . The technology involves transfusions with (autologous or allogeneic) T cells that are engineered to recognize cancer cells (Figure 1a), known as chimeric antigen receptor T (CAR-T) cell therapy [11,12] . CAR-Ts are engineered T cells expressing scFv (single chain variable fragment) domain of antigen-specific antibody linked to a TCR (T cell receptor)-associated intracellular signaling domain such as CD3 zeta [13] (Figure 1b).…”

Standard- oder Therapieverändernde Erkenntnisse in der Hämatologie

“…Sicherheit und Verträglichkeit von Pembrolizumab bei Patienten mit rezidivierten/refraktären primär mediastinalen B-Zell-Lymphomen [19] Behandlungsmöglichkeiten für Patienten mit rezidivierten/refraktären primären mediastinalen diffus großzelligen B-Zell-Lymphomen (rrPMCL) sind begrenzt und die Axicabtagene Ciloleucel CAR T-Zell-Therapie bei Patienten mit refraktären/rezidivierten B-Zell-Non-Hodgkin-Lymphomen [22] Axicabtagene Ciloleucel (Axi-cel) ist eine anti-CD19-Therapie mit CAR-T-Zellen, die ursprünglich am National Cancer Institute entwickelt wurde und von der Food and Drug Administration (FDA) für rezidivierte oder refraktäre aggressive Non-Hodgkin-Lymphome zugelassen wurde. Die klinischen Studien ZUMA-1-Phase-I und -II bildeten die Grundlage für die Zulassung dieses Produkts durch die FDA [23]:…”