Introduction
Acute Myeloid Leukaemia (AML) is a life-threatening haematological malignancy characterised by the rapid proliferation of abnormal myeloid cells, which impair normal blood cell production. Despite advances in conventional therapies such as chemotherapy and stem cell transplantation, relapse rates remain high, necessitating novel therapeutic approaches (Döhner et al., 2017). Among these, chimeric antigen receptor (CAR)-T cell therapy and natural killer (NK) cell-based therapies targeting specific AML antigens, notably CD33 and CD123, have emerged as promising immunotherapeutic strategies. These therapies harness the immune system to target leukaemic cells, offering potential for improved outcomes. This essay explores the current efficacy of CD33- and CD123-targeted CAR-T and NK cell therapies in AML treatment. It examines their underlying mechanisms, highlights their therapeutic potential, and discusses the challenges limiting their widespread clinical application. By critically evaluating recent research, this review aims to provide a comprehensive overview of these innovative treatments for undergraduate students in medicine.
Mechanisms
CAR-T and NK cell therapies operate through distinct yet complementary immunological mechanisms to target AML cells. CAR-T cells are genetically engineered T cells expressing a synthetic receptor that recognises specific antigens on cancer cell surfaces. In the context of AML, CD33 and CD123 are commonly targeted due to their overexpression on leukaemic blasts. CD33, a sialic acid-binding immunoglobulin-like lectin, is expressed on approximately 90% of AML cells, while CD123, the interleukin-3 receptor alpha chain, is often upregulated in leukaemic stem cells (LSCs), which are implicated in disease relapse (Ehninger et al., 2014). Upon antigen recognition, CAR-T cells release cytotoxic molecules such as perforin and granzymes, inducing apoptosis in target cells. Additionally, they secrete cytokines to amplify the immune response, although this can lead to adverse effects, as discussed later (Maude et al., 2018).
In contrast, NK cells are innate immune effectors that do not require genetic modification to recognise tumour cells but can be engineered to express CARs for enhanced specificity. NK cells kill targets through mechanisms including natural cytotoxicity receptors and antibody-dependent cellular cytotoxicity (ADCC). When engineered to target CD33 or CD123, NK cells combine their inherent tumour-killing ability with antigen-specific recognition, offering a potentially safer alternative to CAR-T cells due to their lower risk of cytokine release syndrome (CRS) (Rezvani & Maloney, 2015). However, their efficacy depends on overcoming AML-induced immune evasion, such as the downregulation of activating ligands on tumour cells. Understanding these mechanisms is crucial for appreciating how these therapies can be optimised for clinical use, though their practical application reveals both strengths and limitations.
Potentials
The potential of CD33- and CD123-targeted CAR-T and NK cell therapies in AML treatment lies in their ability to address unmet clinical needs, particularly for patients with relapsed or refractory disease. CAR-T cell therapy has demonstrated remarkable success in other haematological malignancies, such as B-cell acute lymphoblastic leukaemia, with remission rates exceeding 80% in some trials (Maude et al., 2018). Translating this success to AML, preclinical studies targeting CD33 and CD123 have shown significant anti-leukaemic activity, with engineered T cells effectively reducing tumour burden in mouse models (Kenderian et al., 2015). Furthermore, targeting CD123 is particularly promising due to its expression on LSCs, potentially addressing the root cause of relapse by eliminating the cells responsible for disease persistence (Ehninger et al., 2014). Indeed, early-phase clinical trials have reported encouraging results, with some patients achieving complete remission, highlighting the transformative potential of this approach.
NK cell therapies, meanwhile, offer unique advantages, including a reduced risk of severe toxicities such as CRS and graft-versus-host disease (GvHD), as they can be derived from allogeneic sources without the need for patient-specific customisation (Rezvani & Maloney, 2015). This makes NK cell therapies potentially more accessible and cost-effective. Additionally, combining NK cells with CAR technology enhances their specificity and potency against AML antigens, as demonstrated by preclinical studies showing robust tumour clearance in vitro (Li et al., 2018). The dual targeting of CD33 and CD123 also holds promise for overcoming antigen escape—a phenomenon where leukaemic cells lose target antigen expression—by ensuring broader coverage of heterogeneous AML populations. Thus, both CAR-T and NK cell therapies represent innovative tools with the potential to revolutionise AML treatment, particularly for patients with limited therapeutic options.
Challenges
Despite their potential, significant challenges hinder the clinical translation of CD33- and CD123-targeted therapies. One primary concern with CAR-T cells is on-target, off-tumour toxicity. Both CD33 and CD123 are expressed on normal haematopoietic cells, leading to unintended destruction of healthy myeloid progenitors and severe cytopenias (Kenderian et al., 2015). For instance, clinical trials targeting CD33 have reported prolonged bone marrow suppression, posing risks to patient safety and complicating long-term management. Strategies such as transient CAR expression or dual-antigen targeting are being explored to mitigate these effects, but they remain experimental (Ehninger et al., 2014).
Another challenge is the immunosuppressive AML microenvironment, which impairs the function of both CAR-T and NK cells. AML cells secrete inhibitory cytokines and upregulate checkpoint molecules like PD-L1, dampening immune effector activity (Li et al., 2018). Additionally, the limited persistence of CAR-T cells in AML compared to B-cell malignancies reduces sustained anti-tumour effects, necessitating repeated infusions or combination therapies, which increase treatment complexity and cost (Maude et al., 2018). For NK cells, challenges include their short lifespan and limited expansion capacity post-infusion, which can constrain therapeutic efficacy (Rezvani & Maloney, 2015). Moreover, manufacturing hurdles and the high cost of personalised cell therapies present logistical barriers to widespread adoption, particularly in resource-limited settings.
Arguably, the risk of severe adverse events, such as CRS and neurotoxicity, remains a critical limitation of CAR-T therapy, with some trials reporting life-threatening complications that require intensive monitoring and intervention (Döhner et al., 2017). While NK cells pose a lower risk in this regard, their clinical efficacy in AML is less established, with fewer trials providing conclusive data. These challenges underscore the need for ongoing research to refine these therapies, balancing efficacy with safety to ensure they become viable options for a broader patient population.
Conclusion
In summary, CD33- and CD123-targeted CAR-T and NK cell therapies represent cutting-edge approaches to AML treatment, with distinct mechanisms that leverage the immune system to target leukaemic cells. Their potential to induce remission in relapsed or refractory patients and target disease-initiating LSCs offers hope for improved outcomes where conventional therapies fall short. However, significant challenges, including on-target toxicities, immune suppression by the AML microenvironment, and logistical barriers, currently limit their clinical utility. For these therapies to achieve their full potential, future research must focus on enhancing safety profiles, overcoming immune evasion, and improving accessibility. As the field of immunotherapy advances, these treatments may transform the AML therapeutic landscape, but their successful integration into clinical practice will require addressing the complexities and limitations highlighted in this review. This exploration underscores the importance of continued innovation and critical evaluation in the pursuit of effective AML therapies.
References
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