Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies

Abstract

Hematologic malignancies provide a suitable testing environment for cell-based immunotherapies, which were pioneered by the development of allogeneic hematopoietic stem cell transplant. All types of cell-based therapies, from donor lymphocyte infusion to dendritic cell vaccines, and adoptive transfer of tumor-specific cytotoxic T cells and natural killer cells, have been clinically translated for hematologic malignancies. The recent success of chimeric antigen receptor–modified T lymphocytes in B-cell malignancies has stimulated the development of this approach toward other hematologic tumors. Similarly, the remarkable activity of checkpoint inhibitors as single agents has created enthusiasm for potential combinations with other cell-based immune therapies. However, tumor cells continuously develop various strategies to evade their immune-mediated elimination. Meanwhile, the recruitment of immunosuppressive cells and the release of inhibitory factors contribute to the development of a tumor microenvironment that hampers the initiation of effective immune responses or blocks the functions of immune effector cells. Understanding how tumor cells escape from immune attack and favor immunosuppression is essential for the improvement of immune cell–based therapies and the development of rational combination approaches.

Cells to prevent/treat relapse following allogeneic stem cell transplantation

“…This can include dendritic cell dysfunction, defective tumor antigen presentation, checkpoint pathway activation, resistance of tumor cells to death through altered metabolism, and more. 7,8 Additionally, direct contact of leukemia cells with bone marrow stromal cells can trigger intracellular signals that promote cell-adhesion-mediated drug resistance. 9 Cell-based therapies have the potential to overcome malignant cell therapy resistance and circumvent or change the tumor microenvironment allowing for effective tumor control.…”

“…5 To maximize efficacy and optimize outcomes, combinations of cellular therapies and/or other treatment modalities will likely be needed. 7 Molecular profiling of tumor-associated leukocytes has revealed distinct subsets prognostic for cancer survival. 10 This raises the prospect that such an approach might be used in the setting of posttransplant cellular immunotherapy as a biomarker for clinical response, to select immune effector subsets for therapeutic use that are predicted to improve clinical outcome and to assess immune effector cell subset distribution and activation to better understand mechanisms of treatment response and resistance.…”

“…However, CTL effectiveness can be impacted by the immunogenicity of the specific antigen, the affinity of the T-cell receptors, the presence of suppressive cells such as T regulatory cells and myeloid-derived suppressor cells, as well as secreted factors from the tumor microenvironment. 7 Furthermore, CTL generation is logistically challenging, time-consuming, and not always successful. 5…”

Immunotherapy in adult acute leukemia

“…This concept constitutes a paradigm-shift towards the use of selected antigen targeted immunotherapy and bioengineering of T cells to carry a chimeric antigen receptor (CAR), composed of an extracellular antigenrecognition compound (such as a single-chain antibody or a receptor ligand) linked to an intracellular signaling domain (either a FcR receptor γ or a CD3ζ chain) by the intermediate of a hinge region and a transmembrane domain [54,55]. CAR T-cells are directed against a selectively chosen antigen, while in TIL's therapy a set of lymphocytes are reactive to a various panel of tumor neoantigens epitopes through their native T-cell receptor (TCR) and MHC-restricted engagement [56,57]. Engraftment and expansion of these cells in host requires a lymphodepleting conditioning chemotherapy and high dose of IL-2 after reinfusion [58].…”

Chimeric antigen receptor T-cells for B-cell malignancies

“…[1][2][3] It has, therefore, been a long-standing goal to devise ways to engineer components of the immune system to overcome tumor-associated evasion and suppression strategies. Adoptively acquired immunity was first described in 1954, 4 and the development of allogeneic hematopoietic stem cell transplantation (HSCT) beginning in the late 1960s represented the first major breakthrough in cellular immunotherapy.…”