The “Magic Bullet” Is Here? Cell-Based Immunotherapies for Hematological Malignancies in the Twilight of the Chemotherapy Era

Abstract

Despite the introduction of a plethora of different anti-neoplastic approaches including standard chemotherapy, molecularly targeted small-molecule inhibitors, monoclonal antibodies, and finally hematopoietic stem cell transplantation (HSCT), there is still a need for novel therapeutic options with the potential to cure hematological malignancies. Although nowadays HSCT already offers a curative effect, its implementation is largely limited by the age and frailty of the patient. Moreover, its efficacy in combating the malignancy with graft-versus-tumor effect frequently coexists with undesirable graft-versus-host disease (GvHD). Therefore, it seems that cell-based adoptive immunotherapies may constitute optimal strategies to be successfully incorporated into the standard therapeutic protocols. Thus, modern cell-based immunotherapy may finally represent the long‑awaited “magic bullet” against cancer. However, enhancing the safety and efficacy of this treatment regimen still presents many challenges. In this review, we summarize the up-to-date state of the art concerning the use of CAR-T cells and NK-cell-based immunotherapies in hemato-oncology, identify possible obstacles, and delineate further perspectives.

Molecular Aspects of Resistance to Immunotherapies—Advances in Understanding and Management of Diffuse Large B-Cell Lymphoma

“…In recent years, considerable progress in hematooncology has been achieved by developing adoptive therapies based on T cells modified with chimeric antigen receptors (CARs) [192,193]. CARs targeting CD19 have been a breakthrough in the treatment of ALL and DLBCL.…”

“…Still, it has to be underlined that in r/r DLBCL prognosis is dismal; thus, each therapeutic option counts. The encouraging results of the clinical trials resulted in the registration of four different CAR CD19 formulations varying in the composition of the intracellular co-stimulation domain, three of which, namely: tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel are approved for the treatment of DLBCL patients [193][194][195].…”

“…This type of resistance can be correlated with lower expression of death receptors connected with apoptosis pathways in neoplastic cells as demonstrated in in vitro model testing CRISPR-based genome-wide loss-of-function screen in Nalm-6 ALL cell line [209]. The potential strategies against resistance to CAR T-cell therapy in hematological malignancies, including modifications in the structure of CARs, novel therapeutic targets, and safety-related issues have been elegantly reviewed in [192,193,210].…”