Journal of Leukemia
Open Access

Immunotherapy in Leukemia: Promises and Challenges in the Era of Precision Medicine

Lukas Seidel^{* *}Correspondence: Lukas Seidel, Department of Oncology, University of Melbourne, Melbourne, Australia, Email:

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Description

The remarkable success of immunotherapeutic approaches in solid tumors has sparked considerable interest in their application to hematologic malignancies. Leukemias, with their accessibility in the bloodstream and expression of distinctive surface antigens, present theoretically ideal targets for immune-based interventions. The approval of Chimeric Antigen Receptor (CAR) T-cell therapy for B-cell Acute Lymphoblastic Leukemia (B-ALL) marked a watershed moment in leukemia treatment. The remarkable response rates observed with CD19-directed CAR T-cells in relapsed/refractory pediatric and young adult B-ALL demonstrated the feasibility of harnessing the immune system to target leukemic cells with exquisite specificity. Complete remission rates exceeding 80% in heavily pretreated patients represented an unprecedented breakthrough, offering hope to patients with otherwise dismal prognoses. The durability of these responses, with many patients maintaining long-term remissions, further highlighted the transformative potential of cellular immunotherapy.

However, the translation of this success to other leukemia subtypes has proven challenging. Acute Myeloid Leukemia (AML), the most common acute leukemia in adults, has shown greater resistance to immunotherapeutic approaches. The heterogeneity of AML, with diverse genetic and phenotypic characteristics, complicates the identification of universally expressed target antigens. Potential targets such as CD33 and CD123 are frequently expressed on leukemic blasts but are also present on normal hematopoietic progenitors, raising concerns about on-target, off-tumor toxicity. Strategies to mitigate this risk, including the development of dual-targeted CAR constructs and incorporation of safety switches, are under active investigation but remain in early stages of clinical development.

The immunosuppressive bone marrow microenvironment in leukemia presents another significant hurdle. Leukemic cells actively modulate their surroundings to evade immune surveillance through multiple mechanisms, including the upregulation of inhibitory receptors, secretion of immunosuppressive cytokines, and recruitment of regulatory T cells and myeloid-derived suppressor cells. These adaptive resistance mechanisms can limit the efficacy of immunotherapeutic approaches and contribute to treatment failure or relapse. Understanding and overcoming this immunosuppressive milieu represents a critical challenge in leveraging immunotherapy for leukemia treatment.

Immune checkpoint inhibitors, which have revolutionized the treatment of various solid tumors, have shown more modest activity in leukemia when used as monotherapy. The expression of immune checkpoint molecules such as PD-1/PD-L1 in leukemia is variable and often lower than in solid tumors, potentially explaining the limited efficacy observed. However, emerging evidence suggests that combining checkpoint inhibitors with standard chemotherapy, hypomethylating agents, or other immunotherapeutic approaches may enhance anti-leukemic activity. The rational design of such combinations, guided by a deeper understanding of the leukemia immune microenvironment, represents a promising direction for future research.

Bispecific T-Cell Engagers (BiTEs) and other bispecific antibody constructs have emerged as another promising immunotherapeutic strategy. Blinatumomab, a CD19/CD3 BiTE, has demonstrated impressive activity in relapsed/refractory B-ALL and is now approved for this indication. By simultaneously binding to CD19 on B-ALL cells and CD3 on T cells, blinatumomab facilitates direct cytotoxic T-cell activity against leukemic blasts, bypassing the need for antigen presentation and co-stimulation. Similar constructs targeting CD33, CD123, and other myeloid antigens are under investigation for AML, with early results showing promise. The off-the-shelf nature of these agents, avoiding the logistical complexities and manufacturing delays associated with CAR T-cell therapy, represents a significant advantage.

The concept of Leukemia Stem Cells (LSCs) as the reservoir for disease relapse has important implications for immunotherapy. Conventional treatments may eliminate the bulk leukemic population while sparing these therapy-resistant stem cells, leading to eventual disease recurrence. Immunotherapeutic approaches targeting LSC-specific antigens or pathways offer the potential to eradicate this reservoir and achieve more durable remissions.