Sanjna Sandeep

Background: Acute Myeloid Leukemia (AML) is a cancer of the stem cell precursors for hematopoietic cells, causing over 80,000 deaths yearly with a 30.5% 5-year survival rate in the US¹. Highly varied gene alterations drive AML’s progression, leading to life-threatening cytopenias¹. The “3+7” chemotherapy regimen is the standard treatment, but 75% of AML patients relapse due to high immunophenotype heterogeneity^2,3. Adoptive immunotherapy, like autologous CAR T-cells, shows promise in targeting patient-specific antigens². Finding a single AML-specific target remains challenging, and developing autologous CAR T-cells is time-intensive, expensive, and highly variable.

Methods: A PubMed search was performed using key terms, such as “acute myeloid leukemia” and “allogeneic CAR-T cell therapies,” and filtered to exclude studies published more than five years prior to this review.

Results: Understanding AML’s antigen complexity is crucial for effective treatment. Several recent studies have improved our understanding of this complexity and revealed potential novel therapeutic targets. For example, single-cell sequencing reveals a stepwise mutation acquisition alongside hematopoietic cell-surface marker differentiation, essential for targeted CAR-T cell interventions as AML progresses to a fully malignant state⁴. Differential cell surface marker expression based on mutations aids in identifying pathways for therapeutic CAR-T cell strategies. Another approach is to develop donor-derived (allogeneic) CAR-T cells which offers advantages over autologous therapies in speed, cost, quality, and clonal control⁵. ALLO-501A, an allogeneic anti-CD19 CAR T cell, shows promise in targeting B-cell malignancies, with high response rates observed in clinical trials⁶. However, alloreactivity, leading to potential GVHD, remains a concern with donor-derived CAR T cell therapies⁷. A potential innovative solution is to develop a multiplex editing approach in CAR T cells that can prevent post-treatment escape by targeting multiple antigens as AML mutates and modulating receptor expression to avoid alloreactivity. This guided CAR-T evolution could generate multi-antigen-targeting CAR T cells and minimize off-target effects ⁸. Precision genome editing with nCas9 can delete lineage-specific antigens managing CAR T cell clones undergoing exhaustion, removing them from the clonal pool⁸.

Conclusions: Understanding AML’s clonal evolution and CAR T cell exhaustion is crucial for optimizing allogeneic CAR T therapies. Multiplex-engineered CAR constructs to signal immune checkpoint regulators can modulate exhaustion, enhancing efficacy while reducing alloreactivity risk⁸. Developing a genetically engineered cellular platform technology as a general solution for personalized AML therapy has the potential to fine-tune treatments in vivo and reduce relapse rates, making this worthwhile for advancing patient care in oncology.

Works Cited:

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3. Kantarjian HM, Kadia TM, DiNardo CD, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer Journal. 2021;11(2).
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