Adoptive Cell Therapy for Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia

Abstract

Refractory and relapsed acute myeloid leukemia (AML) and T-lineage leukemia (T-ALL) have poor prognosis and limited therapeutic options. Adoptive cellular immunotherapies are emerging as an effective treatment for patients with chemotherapy refractory hematological malignancies. Indeed the use of unselected donor lymphocyte infusions (DLIs) have demonstrated successes in treating patients with AML and TALL post-allogeneic The development of ex vivo manipulation techniques such as genetic modification or selection and expansion of individual cellular components has permitted the clinical translation of a wide range of promising cellular therapies for AML and TALL. Here, we will review clinical studies to date using adoptive cell therapy approaches and outline the major challenges limiting the development of safe and effective cell therapies for both types of acute leukemia.

Emerging Challenges to Cellular Therapy of Cancer

“…Banks of allogeneic NK cells genetically modified to express cytokines and CARs have now been tested in cancer patients. 19 In a clinical trial of 11 patients with CD19+ lymphomas, infusions of allogeneic CD19-CAR expressing cord blood derived NK cells induced CRs in 7 patients without causing GVHD or other T-cell associated toxicities (such as cytokine release syndrome [CRS] or neurotoxicity), although persistence has yet to be documented long-term. 16 These promising clinical data have encouraged multiple additional academic (NCT03415100, NCT04245722 etc.)…”

“…This property has led to several HSCT donor-derived and OTS allogeneic NK cell trials for a variety of malignancies. Banks of allogeneic NK cells genetically modified to express cytokines and CARs have now been tested in cancer patients 19 . In a clinical trial of 11 patients with CD19+ lymphomas, infusions of allogeneic CD19-CAR expressing cord blood derived NK cells induced CRs in 7 patients without causing GVHD or other T-cell associated toxicities (such as cytokine release syndrome [CRS] or neurotoxicity), although persistence has yet to be documented long-term 16 .…”

Early precursor T-cell acute lymphoblastic leukemia: current paradigms and evolving concepts

“…Therefore, CAR-T cells may attack lymphoblasts, normal T-cells, and CAR-T cells (fratricide). 71 Furthermore, strategies to circumvent fratricide such as targeting CD1a cannot be used in ETP-ALL as the latter does not express CD1a. 72 Despite these challenges, CAR-T cells targeting CD5 73 and CD7 have been reported and are in clinical trials.…”

“…72 Despite these challenges, CAR-T cells targeting CD5 73 and CD7 have been reported and are in clinical trials. 71 The progress in this field, although slower compared with B-cell ALL, is encouraging. It is currently unclear what impact CAR-T cells will have on ETP-ALL, and what would be the optimal target given its distinctive immunophenotype.…”

Leukemia’s Next Top Model? Syngeneic Models to Advance Adoptive Cellular Therapy

“…Advancements in the field of ACT have resulted in engineered cellular products that express performanceenhancing receptors, such as cytokine receptors, T cell receptors (TCRs), or chimeric antigen receptors (CARs). Overall, the innovation of genetically engineered immune cells in the ACT setting has resulted in improved outcomes, especially for patients with B-cell derived hematologic malignancies (1,2). However, challenges remain like antigen selection and overcoming an immunosuppressive microenvironment (3)(4)(5).…”