While the mainstay of treatment for high-risk or relapsed, refractory (r/r) hematologic malignancies (including leukemias) has historically revolved around allogeneic hematopoietic stem cell transplant (allo-HSCT), targeted immunotherapies have emerged as a promising therapeutic option, especially given the poor prognosis of patients who relapse post-allo-HSCT [1,2]. Targeted immunotherapy refers to a wide range of modalities ranging from monoclonal antibodies and small molecule-based treatments to adoptive cellular therapy, which aims to harness the immune system against cancer by improving its potency and specificity [3]. Bispecific engagers and monoclonal antibodies such as blinatumomab (targeting CD19) and inotuzumab (targeting CD22), initially limited to r/r patients, have now been incorporated into therapeutic protocols for newly diagnosed children and adults in an attempt to reduce risk of relapse and toxicity related to conventional chemotherapy, which remain the major causes of morbidity and mortality [3,4]. While these agents hold significant promise, novel cellular immunotherapies that harness the cytotoxic abilities of the immune system in a targeted manner (often called “adoptive” cell therapy), have changed the way we treat r/r hematologic malignancies and continue to change the treatment landscape given the rapid evolution of these powerful, yet sophisticated precision therapies.

Adoptive cell therapy has emerged as a potentially less-toxic treatment option for leukemia patients who have been unable to achieve remission with alternative therapies (whether conventional or investigational) and can be allo-HSCT-enabling or a therapeutic option for patients in whom transplantation has failed or is contraindicated. A solid understanding of the core concepts of adoptive cell therapy is necessary for stem cell transplant physicians, nurses and ancillary staff given its proximity to the transplant field as well as its inherent complexities that require specific expertise in compliant manufacturing, clinical application, and risk mitigation.

Here we will review use of targeted cellular therapy for the treatment of r/r leukemia, focusing on chimeric antigen receptor T-cells (CAR T-cells) given the remarkable sustained clinical responses leading to commercial approval for several hematologic indications including leukemia. We will also briefly discuss several promising investigational cellular immunotherapies including CAR T-cells for non-B-cell leukemias, tumor-antigen specific T-cells, and special considerations for sustainability and scalability of cellular therapies including alternative donor sources, targeting of multiple antigens, and risk reduction.

Allo-HSCT, in addition to being the only curative option in many r/r hematologic malignancies, is the earliest example of cellular immunotherapy. As the indications for allo-HSCT for hematologic malignancies have broadened, the requirement for novel strategies to address donor availability and post-transplant complications, while ensuring broad accessibility to these potentially life-saving therapies, has arisen. Despite significant reductions in early transplantation-related mortality, largely related to enhanced understanding of patient risk factors, graft manipulation and improvements in post-transplantation supportive care [2], post-transplant relapse and toxicities such as graft vs. host disease (GVHD) are associated with high rates of morbidity and mortality [5].

To understand the evolution of cellular immunotherapy for leukemia, we must revisit its origins and original proof of principal, the Donor Lymphocyte Infusion (DLI) [1,6]. DLI has been used as a method of improving donor chimerism following transplantation and increasing the graft-versus-leukemia (GVL) effect to improve the durability of remission, and in some cases to restore virus-specific immunity [7,8]. Donor lymphocytes can be manufactured via peripheral blood apheresis and separation of donor T-cells, then cryopreserved or infused into the recipient (patient), as shown in Fig. 1. The reported response rate to DLI is >70% in patients with CML, but <30% in patients with AML and ALL [9,10]. Reduced success of DLI in acute leukemias is likely secondary to rapid leukemia proliferation, outpacing the GVL effect which can take months to fully achieve and often require very large cell doses in acute leukemia, increasing the risk of GVHD [7,10].

Given the limited efficacy and substantial risk profile of non-targeted donor lymphocytes in preventing or treating leukemic relapse coupled with the success of antibody-based targeted therapy, the field began to explore the use of antigen-targeted lymphocyte infusions as a form of adoptive cell therapy (Fig. 1). Hematologic malignancies are particularly excellent targets for antigen-targeted adoptive cell therapy due to (1) their sensitivity to immune attack (GVL effect); (2) proximity of immune cells and malignant cells in circulation, allowing for constant immune surveillance; and (3) relative ease of non-invasive disease surveillance and immune monitoring using peripheral blood and bone marrow samples. Importantly, these same features result in exceptional evasion of immune surveillance by hematologic malignancies, necessitating potent strategies to overcome well-described immune escape mechanisms.

T-lymphocytes are by far the most frequently used immune cells in adoptive cell therapy, primarily due to the key role they play in endogenous cell-mediated immune responses. Endogenous T-cells, via their native T-cell receptor (TCR), are responsible for surveilling for and exerting cytotoxicity against malignant cells. Adoptive T-cell therapy enhances the innate cytotoxicity of T-cells while redirecting them to target specific antigens expressed on malignant cells. Early attempts at adoptive T-cell therapy focused on expanding T-cells that recognized tumor antigen through their native TCR [11,12], while more contemporary attempts have aimed to augment or modify the specificity of the native TCR using genetic redirection [13,14]. Because these methods exert cytotoxicity through the native TCR and rely on antigen presentation via MHC, they are “HLA-dependent” and often restricted to patients with certain HLA haplotypes. They largely remain in the investigational realm, with modest outcomes in leukemia to date [12,15,16].