Search

Simple Summary: Unlike B cell malignancies, the progress on generating an adoptive T cell therapy for relapsed/refractory acute myeloid leukemia (AML) remains insufficient. This review focuses on the main challenges in the field and novel strategies to overcome them. Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed/refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen-targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything. One must consider the fact that only around 30% of patients show a response; there are, however, consequential off-tumor effects. It is obvious that a new point of view is needed to achieve more promising results. This review first introduces the unique therapeutic challenges of not only CAR T cells but also other adoptive cellular therapies in AML. Next, recent single-cell sequencing data for AML to assess somatically acquired alterations at the DNA, epigenetic, RNA, and protein levels are discussed to give a perspective on cellular heterogeneity, intercellular hierarchies, and the cellular ecosystem. Finally, promising novel strategies are summarized, including more sophisticated next-generation CAR T, TCR-T, and CAR NK therapies; the approaches with which to tailor the microenvironment and target neoantigens; and allogeneic approaches. [ABSTRACT FROM AUTHOR]

T cells are critical in destroying cancer cells by recognizing antigens presented by MHC molecules on cancer cells or antigen-presenting cells. Identifying and targeting cancer-specific or overexpressed self-antigens is essential for redirecting T cells against tumors, leading to tumor regression. This is achieved through the identification of mutated or overexpressed self-proteins in cancer cells, which guide the recognition of cancer cells by T-cell receptors. There are two main approaches to T cell-based immunotherapy: HLA-restricted and HLA-non-restricted Immunotherapy. Significant progress has been made in T cell-based immunotherapy over the past decade, using naturally occurring or genetically engineered T cells to target cancer antigens in hematological malignancies and solid tumors. However, limited specificity, longevity, and toxicity have limited success rates. This review provides an overview of T cells as a therapeutic tool for cancer, highlighting the advantages and future strategies for developing effective T cell cancer immunotherapy. The challenges associated with identifying T cells and their corresponding antigens, such as their low frequency, are also discussed. The review further examines the current state of T cell-based immunotherapy and potential future strategies, such as the use of combination therapy and the optimization of T cell properties, to overcome current limitations and improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR T) cell therapy achieved remarkable success in B-cell leukemia and lymphoma which led to its incorporation in treatment protocols for these diseases. CAR T cell therapy for chronic lymphocytic leukemia (CLL) patients showed less success compared to other malignant tumors. In this review, we discuss the published results regarding CAR T cell therapy of CLL, possible mechanisms of failures and expected developments. [ABSTRACT FROM AUTHOR]

NK (Natural Killer) cell-mediated adoptive immunotherapy has gained attention in hematology due to the progressing knowledge of NK cell receptor structure, biology and function. Today, challenges related to NK cell expansion and persistence in vivo as well as low cytotoxicity have been mostly overcome by pioneering trials that focused on harnessing NK cell functions. Recent technological advancements in gene delivery, gene editing and chimeric antigen receptors (CARs) have made it possible to generate genetically modified NK cells that enhance the anti-tumor efficacy and represent suitable "off-the-shelf" products with fewer side effects. In this review, we highlight recent advances in NK cell biology along with current approaches for potentiating NK cell proliferation and activity, redirecting NK cells using CARs and optimizing the procedure to manufacture clinical-grade NK and CAR NK cells for adoptive immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Children with metastatic solid tumors typically have a very poor prognosis, especially when the cancer returns or is resistant to upfront treatment. There is hope that the cells in the immune system can be programmed to help patients recognize and eliminate their cancer. Natural killer (NK) cells are an important component of the immune system designed to eliminate virally infected cells and tumors. In the last 20 years, advances in cell manufacturing have allowed investigators to grow NK cells in the laboratory to high numbers and engineer the cells to become highly potent. While some clinical trials using NK cells in children with solid tumors have shown promise, we still have much to learn on how to use NK cells effectively. This review will discuss our current understanding of NK cell biology and its relevance to solid tumors that commonly affect children. Treatment of metastatic pediatric solid tumors remain a significant challenge, particularly in relapsed and refractory settings. Standard treatment has included surgical resection, radiation, chemotherapy, and, in the case of neuroblastoma, immunotherapy. Despite such intensive therapy, cancer recurrence is common, and most tumors become refractory to prior therapy, leaving patients with few conventional treatment options. Natural killer (NK) cells are non-major histocompatibility complex (MHC)-restricted lymphocytes that boast several complex killing mechanisms but at an added advantage of not causing graft-versus-host disease, making use of allogeneic NK cells a potential therapeutic option. On top of their killing capacity, NK cells also produce several cytokines and growth factors that act as key regulators of the adaptive immune system, positioning themselves as ideal effector cells for stimulating heavily pretreated immune systems. Despite this promise, clinical efficacy of adoptive NK cell therapy to date has been inconsistent, prompting a detailed understanding of the biological pathways within NK cells that can be leveraged to develop "next generation" NK cell therapies. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells represent one of the first lines of defense against malignant cells. NK cell activation and recognition are regulated by a balance between activating and inhibitory receptors, whose specific ligands can be upregulated on tumor cells surface and tumor microenvironment (TME). Hematological malignancies set up an extensive network of suppressive factors with the purpose to induce NK cell dysfunction and impaired immune-surveillance ability. Over the years, several strategies have been developed to enhance NK cells-mediated anti-tumor killing, while other approaches have arisen to restore the NK cell recognition impaired by tumor cells and other cellular components of the TME. In this review, we summarize and discuss the strategies applied in hematological malignancies to block the immune check-points and trigger NK cells anti-tumor effects through engineered chimeric antigen receptors. [ABSTRACT FROM AUTHOR]