INTRODUCTION:

Acute myeloid leukaemia (AML) is a disease defined by the uncontrolled clonal proliferation of immature myeloid cells in the bone marrow, liver, blood or other tissue. This clonal expansion occurs due to a transformation of haematopoietic stem cells and is thought to be a multistep process, which leads to the accumulation of numerous genetic and epigenetic events that result in the activation of key oncogenes and the deactivation of tumour suppressors. The accumulation of these genetic mutations and the fact that research has shown that the mutational spectrum for AML is correlated with patient age is the likely reason as to why current treatments fail to elicit a long-term survival cure in older patients and why AML is the most common form of acute leukaemia in adults^{1, 2}.

The most common form of acute leukaemia in adults, with around 3,110 new cases diagnosed each year (2010 data) in the UK. It is more common in men and the disease can occur at any age, with a marked increase in incidence in the over 45-year-old age group. There is considerable geographical variation in incidence. In much of northern Europe, AML affects between three and four per 100,000 individuals annually. In the age group 15–24, the frequency rises in males to be approximately 6.4 per 100,000 and in females to 4.2 per 100,000. There is a higher incidence in the USA and Europe and lower incidence in blacks of Africa, Arabia, China, and Japan. In recent years, the immune system has emerged as a key player in the pathogenesis and treatment of cancer, including AML. Among the various components of the immune system, T cells have garnered particular attention due to their ability to recognize and eliminate malignant cells through antigen-specific cytotoxic mechanisms³. The intricate interplay between T cells and AML cells, encompassing both immune surveillance and tumour immune evasion mechanisms, shapes the dynamic landscape of AML pathogenesis and therapeutic response⁴.

The immune system serves critical roles in maintaining homeostasis and preventing the development of cancer. It is therefore not surprising that a variety of mechanisms have evolved to suppress potentially deleterious immune responses, thus theoretically reducing the chance of developing cancer and quelling uncontrolled inflammatory responses. Regulatory T cells are believed to provide protection from autoimmunity. Myeloid-derived suppressor cells contribute to the suppression of ongoing inappropriate immune responses, such as those induced by a chronic bacterial infection or non-infectious injury. Macrophages maintain immune system homeostasis by phagocytosing effete cells, and their clearance prevents the release of inflammatory DNA, RNA, or proteins that could incite adaptive immune reactions. Macrophages also have key roles in tissue repair following injury⁵.

In the subsequent sections of this article, we will delve into the mechanisms underlying T cell responses in AML, including the recognition of leukaemic antigens, the immunosuppressive tumour microenvironment, and emerging immunotherapeutic strategies aimed at harnessing T cell-mediated immunity to combat AML. Through a comprehensive examination of preclinical models, clinical trials, and translational research findings, we will explore the current state of knowledge and future directions in this rapidly evolving field^6,7.

Overall, the elucidation of T cell responses in AML holds promise for revolutionizing the treatment landscape of this devastating disease, offering new avenues for precision medicine and personalized therapeutic interventions tailored to the immunological profiles of individual patients. By unraveling the complexities of T cell-mediated immunity in AML, we aim to pave the way for the development of innovative immunotherapeutic strategies that can improve patient outcomes and ultimately transform the paradigm of AML therapy^8,9.

METHODOLOGY:

A comprehensive search of electronic databases including PubMed, Scopus, Web of Science, and Embasewas conducted to identify relevant studies investigating T cell responses in acute myeloid leukaemia (AML). Search terms such as "acute myeloid leukaemia," "AML," "T cells," "immunotherapy," and "immune evasion" were used in various combinations to ensure comprehensive coverage of the topic¹⁰.

RESULT AND DISCUSSION:

T Cell Recognition of Leukemic Antigens:

Immune evasion strategies used by tumor cells and evidence for the expression of leukemia-associated antigens allow the immunotherapeutic targeting of acute myeloid leukemia (AML). Several strategies, including the introduction of chimeric antigen receptor T cells (CAR-T cells) and the transfer of transgenic T-cell receptors, are expected to enter the clinic in the near future. Results from studies on how to increase the efficacy of immunotherapy are expected to provide critical information for the clinical translation. The failure of T cell responses to recognize or respond to acute leukemia is not due to their inability to recognize leukemia-associated antigens. Leukemic cells, in addition to containing unique antigens such as patient-specific mutations, often express a range of developmental and tissue-specific differentiation antigens which, in turn, can serve as targets for T cells. These antigens also represent potential targets for immune responses aimed at preventing relapse, as long as these antigens can stimulate potent anti-tumor responses. A number of approaches are being used to overcome the immune inhibitory pathways induced by leukemia or conditions leading to depletion of functionally competent cells. These include genetic modification of T cells and procedures aiming at increasing the presence or activity of in vitro generated immune cells. Illustrative examples of successful clinical studies are discussed along with potential reasons why such responses were achieved in the clinic.^11-13.

Neoantigens: Neoantigens arise from somatic mutations or genetic alterations unique to cancer cells and are not present in normal tissues. In AML, neoantigens can result from mutations in genes encoding for proteins involved in cellular signaling, transcriptional regulation, and chromatin modification. These mutations give rise to novel peptide sequences that can be recognized as foreign by the immune system¹⁴.

Recent advances in high-throughput sequencing technologies have facilitated the identification of neoantigens in AML, enabling the development of personalized cancer vaccines and adoptive T cell therapies targeting patient-specific mutations. By harnessing the specificity of T cells for neoantigens, researchers aim to enhance the anti-leukemic immune response while minimizing off-target effects on healthy tissues^15-20.

Overall, the recognition of leukemic antigens by T cells represents a critical step in immune surveillance against AML cells. Efforts to elucidate the repertoire of TAAs and neoantigens in AML, as well as strategies to overcome immune evasion mechanisms, hold promise for the development of effective T cell-based immunotherapies in AML²¹.

T Cell Exhaustion and Immunoregulatory Pathways:

Recent studies have highlighted the therapeutic potential of immune checkpoint blockade, which aims to alleviate T cell exhaustion and restore anti-leukemic immune responses. Clinical trials evaluating the efficacy of PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, and TIM-3 inhibitors alone or in combination with conventional therapies have shown promising results in AML patients, particularly those with relapsed/refractory disease or high-risk cytogenetics^22-24.

Additionally, strategies to modulate the immunosuppressive tumor microenvironment, such as depletion of Tregs, inhibition of MDSCs, and reprogramming of M2 macrophages towards an anti-tumor phenotype, hold promise for enhancing T cell-mediated immune responses in AML²⁵.

Emerging Immunotherapeutic Strategies Targeting T Cell Responses:

In recent years, significant progress has been made in the development of novel immunotherapeutic approaches aimed at harnessing T cell responses in AML. These include chimeric antigen receptor (CAR) T cell therapy, bispecific T cell engagers (BiTEs), and adoptive T cell transfer²⁶.

CAR T Cell Therapy:

CAR T cell therapy has emerged as a promising treatment option for patients with acute myeloid leukaemia, offering potential for improved outcomes and reduced relapse rates. The therapy involves engineering T cells to express chimeric antigen receptors that recognize and target specific antigens on cancer cells, leading to enhanced cytotoxic activity In addition, CAR T cell therapy has shown promising results in clinical trials, with some patients achieving complete remission²⁷.

BiTEs:

BiTEs, or bispecific T cell engagers, are a promising immunotherapy approach for treating Acute Myeloid Leukaemia (AML) by redirecting T cell responses towards cancer cells. They are designed to target both CD3-positive T cells and a tumor-specific antigen, bringing the two cell types into close proximity for efficient killing of cancer cells. BiTEs have shown promising results in preclinical and clinical studies, demonstrating their potential as a novel immunotherapy option for AML ²⁸.

Adoptive T Cell Transfer:

To improve anti-leukemic immune responses in patients, antigen-specific T cells from healthy donors or AML patients are expanded in vivo and then infused into the patient. Tumor-infiltrating lymphocytes (TILs), T cells specific to tumor antigens, and T cells with modified T cell receptors (TCRs) have demonstrated encouraging outcomes in preclinical models and early-stage clinical studies. Overall, the emergence of these novel immunotherapeutic strategies underscores the potential of T cell-based approaches in the treatment of AML²⁹.

T Cell-Based Immunotherapies in AML:

In this case report, a 51-year old Japanese woman with late relapsed bcr-abl positive acute myeloid leukemia (AML, previously treatment related to acute myeloid leukemia), experienced clinical and molecular reaction following the administration of Graft vs Leukemia, GVLe effect induced by D8MI-1 T cells originating from the original donor, 11 years after MRD positive status documented while in long term molecular remission after donor lymphocyte infusion. Lille model, a donor memory GAIP, GRAIL, A3B superior biological risk factors, together with the claim GVLeffector cells provided a direct and final effect, eventually responsible for complex clinical observations. Conclusions: In the setting of AML relapse after allogeneic stem cell transplantation, molecular response to D816V-1 T-cell immunotherapy in an AML/MMRD patient with late relapse case, targeting an immunogenic A3 sourGFP cell proliferative advantage, GAIP and GRAIL expression, a TALL cell ts core protein CLAX, WT1, TARP, UISAMP specific sk, suggests these antigens, as strong AML aggressiveness associated, excellent therapeutic targets³⁰.

There is increasing evidence that in most patients with AML, there are functionally competent leukemia-specific CD8+ CTL that can be detected both during autologous recovery and postallo-HSCT. Moreover, over the last decade, a number of leukemia antigens against which CTL respond specifically have been cloned and sequenced. By using ex-vivo technology, such as Lymphocyte Adherence Unrelated Stimulated Expansion of AML specific-Lymphocytes (LAU-1) and CD5-specific enrichment BMT (CEMB), the number of leukemia-specific T-cells can be expanded to a potentially therapeutic level. Such ex-vivo technology has led to CTL activity against the Wilms' tumor antigen, the Wilms' tumor-like protein 1 (WT1), identified by the laboratory of Dr. Hanley from Oxford. DMF5 is a human leukemia antigen (hPLA1) allele specific TCR transduced T cell. DMF5-CTL can lyse and eliminate hPLA1 expressing AML in vitro and attenuate CD34+ hPLA1 leukemia stem cells (LSC) in vivo³¹.

Nanoparticle-Based Delivery Systems:

Nanoparticle-based delivery systems offer a promising strategy for targeted delivery of immunotherapeutic agents to AML cells while minimizing off-target effects on healthy tissues. Nanoparticles can be engineered to encapsulate immunomodulatory agents, such as cytokines, chemokines, or immune checkpoint inhibitors, and deliver them specifically to the tumor microenvironment^32,33.

For example, nanoparticles coated with antibodies targeting AML-specific antigens can facilitate the selective uptake of immunomodulatory cargo by leukemic cells, leading to localized activation of T cell responses within the tumor microenvironment. Additionally, nanoparticles can be functionalized with ligands targeting receptors expressed on T cells, such as CD3 or CD28, to enhance T cell activation and proliferation^34-36.

Novel Pathways and Targets for T Cell Modulation:

Non-coding RNAs: In AML, non-coding RNAs—such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs)—are essential for controlling immunological responses and gene expression. In the tumor microenvironment, dysregulated production of non-coding RNAs can influence T cell activity and aid in immune evasion³⁷.

Targeting non-coding RNAs represents a novel approach for modulating T cell responses in AML. Small molecule inhibitors, antisense oligonucleotides, and RNA interference (RNAi) strategies can be employed to selectively target dysregulated non-coding RNAs in AML, thereby enhancing T cell activation and effector function³⁸.

Discovery of Novel T Cell Subsets and Functional States:

Advancements in single-cell technologies, such as single-cell RNA sequencing (scRNA-seq) and mass cytometry (CyTOF), have enabled the discovery of novel T cell subsets and functional states in AML. These discoveries provide insights into the heterogeneity of T cell responses within the tumor microenvironment and may inform the development of targeted immunotherapies^39-43.

Regulatory T Cell Plasticity:

A subpopulation of CD4+ T cells known as regulatory T cells (Tregs) have immunosuppressive properties that help to preserve immunological tolerance and avoid autoimmunity. On the other hand, Tregs can enhance immune evasion and inhibit anti-tumor immune responses in the setting of malignancy, including AML^44-47.

Recent studies have identified heterogeneity within the Treg population, with distinct subsets exhibiting pro-tumorigenic or anti-tumorigenic functions. Targeting pro-tumorigenic Treg subsets while preserving anti-tumorigenic Tregs represents a potential strategy for overcoming immune suppression in AML.

Exhausted T Cell States:

Exhausted T cells represent a dysfunctional subset of T cells characterized by reduced effector function and proliferative capacity. Exhausted T cells arise from chronic antigen stimulation and exposure to inhibitory signals within the tumor microenvironment^48.

Challenges and Future Directions:

A combined approach of therapy and immunomodulation with alternative CD40 antibody delivery methods (other than administered intravenously to patients for risk of cytokine release syndrome cytopenias) as costimulator could overcome advantages and reduce the risk of intravenously administered CD40 antibodies cytopenia post stem cell transplant. It may also need a better understanding of the biology of NK cell transfer biology translation to increase any such NK cell selection, expansion and optimization through CAR-NK receptor trackers harboring the corresponding uniform system. Additionally, advanced molecular sequencing technology could be helpful to detect host dendritic cell licensing (pretransplantation) and optimal CD34+ (posttransplantation) for further potential generation of immune responses in patients which helps prevent relapse and graft versus host disease⁴⁹.

Advancing the field of AML-directed T cell therapy could be accelerated by potential standardization of methods for TAA identification (using more sophisticated molecular genetic techniques) to enable selection of patients for monitoring of antigen loss at relapse, combined with monitoring of T cell activity using MHC multimer or TBIA approach. Serial quantitative TAA response assessment prior, during and post SCT or allo-SCT may open future opportunities for prediction of post-transplant recurrence. In a broader context, in the era of precision immunology, epitope discovery combined with TCR sequencing and single cell functional assays could guide prediction of potential TAA-derived TCRs for future TCR therapy. For future TCR T cell therapy, the use of the off-the-shelf CAR-modified T cells would also be attractive and drive future development in this field⁵⁰.

Barriers to Efficacy of T Cell Immunotherapies:

Genetic alterations within the T cells: Patient T cells infused back into the patient may have intrinsic defects which may be the reason they do not survive long or effectively control AML transformation and relapse. The adoptive transfer of allogeneic grafts carrying viral infection resistance 1 mutations can improve T cell expansion and function in lymphopenic patients after allogeneic hematopoietic stem cell transplantation. Such genetic manipulation of adoptively transferred T cells may have therapeutic potential. Due to the manner in which the T cells are isolated may uncover the inefficacy of the transferred T cells. TCR-engineered T cells reversed a complete state of hyporesponsiveness and exhaustion and showed specific antitumor activity. found that the downregulation of T cell MYC expression was necessary for AML remission and was influenced by the chemoneutralization of the leukemic microenvironment, suggesting a role for microenvironmental interventions in improving adaptive T cell activity.

Physical barriers within the bone marrow:

The bone marrow is a unique organ with a high dependence on the type of stem cell. In some patients, solid tumors can still grow after adoptive T cell transfer, suggesting that physical barriers can hinder T cell function; this may also occur in AML patients⁵¹.

CONCLUSION:

In conclusion, T cell responses play a multifaceted role in the pathogenesis and treatment of AML, encompassing immune surveillance, immune evasion,and therapeutic intervention. The recognition of leukemic antigens by T cells initiates a cascade of immune responses aimed at eliminating malignant cells, highlighting the potential for T cell-based immunotherapies in AML. However, the efficacy of T cell-mediated immune responses may be compromised by immune evasion mechanisms employed by AML cells, including T cell exhaustion and the immunosuppressive tumor microenvironment.

Acute myeloid leukaemia (AML) is an aggressive malignancy affecting rapidly dividing, undeveloped blood cells. It accounts for 80% of the cases of adult Acute Leukaemia and is still associated with low remission rates (<50%) and dismal overall survival rates (20% in the last 5 years), despite major advancements in therapeutic strategies and knowledge of the underlying biological mechanisms .Blastic cells with the potential to further differentiate into one of the 3 myeloid lineages (monocyte, neutrophil, and eosinophil) may expand uncontrollably, compromising the hemostatic system and the overall immune response. Translocations and mutations involving genes regulating the differentiation, maturation, and apoptosis/necrosis of HSC are the most common genomic alterations in AML, leading to an ongoing blockade of development and cell death.

Recent insights in cancer biology have provided evidence of a “Second Immunoediting Process” occurring during neoplastic evolution, eventually leading to the generation of tumoral cells with altered immunogenicity

The early presence of immune cells into the pre-leukemic, favorable ’Niche’ has prompted novel therapeutic approaches to Immuno-microenvironment Modulation (IMM) in support to classical chemotherapy. On one side, immunity-boosting drugs are undergoing clinical evaluation (e.g., CD47/SIRPa, anti-PD-1, anti-CTLA4, and Flt3-ligand), while on the other, allelic modulation of immune-related genes is presently investigated (e.g., SHIP1, PVR, and MHC-I) in anticipation of impending difficulties for AML resistant to anti-leukemia immunity. Despite the increasing knowledge of the biological mechanisms leading to neoplastic transformation and disease progression, chronic monitoring of cellular/molecular immune targets in AML patients undergoing treatment is still lacking.

AUTHOR CONTRIBUTION:

All author contributed equally.

CONFLICT OF INTEREST:

None.

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Received on 26.04.2024 Revised on 10.07.2024

Accepted on 16.09.2024 Published on 24.12.2024

Available online from December 27, 2024

Research J. Pharmacy and Technology. 2024;17(12):6125-6131.

DOI: 10.52711/0974-360X.2024.00929