Chimeric Antigen Receptor Therapy in Acute Myeloid Leukemia

Brief Overview of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous clonal disease of myeloid-stem and progenitor cells resulting from mutations, deletions, and epigenetic alterations in genes associated with cell differentiation, proliferation, and renewal. AML represents roughly 1% of all cancers; around 20,000 new cases and 11,000 deaths were projected to occur in the United States in 2021. AML encompasses a family of unique malignancies with over 5000 driver mutations across 76 genomic regions. Often, two or more of these driver mutations are present and genetically distinct clonal populations coexist. The stratification by these mutations, including FLT-ID3, NPM1, CEBPA, cKIT, DNMT3A, TP53, has formed a structure for therapeutic management.

The mainstay of treatment for young patients and those with favorable-to-intermediate prognoses remains a combination of cytarabine and anthracycline, while the optimal regimen for older patients has yet to be established. New therapies, including hypomethylating agents and receptor tyrosine kinase inhibitors, have shown promise in older patients with AML, and research is ongoing.

Although chemotherapeutic options for AML exist, T-cell–mediated allogeneic hematopoietic cell transplant (allo-HCT) remains the only potentially curative option, with 60% to 80% achieving complete remission. Even after successful engraftment of functional T-cells, however, AML cells retain the abilities to reduce expression of major histocompatibility complex (MHC) molecules, to change ligand expression to favor inhibition and quell activation, as well as to manipulate the tumor-immune microenvironment. These inherent capabilities allow leukemic cells to evade T-cell–mediated detection and elimination, leading to residual disease. Thus, even once remission is obtained, relapse exists as an ever-constant threat because of factors including chemoresistance and immune escape: relapse rates approach 40%, and 5-year overall survival is a dismal 20% to 30%.

In addition to identifying genetic mutations responsible for clonal evolution, research identifying markers for AML—including CD123, CLL-1, CD33, and NKG2D, among others—has energized the community toward the prospect of new and evolving therapies. Numerous investigators are working on checkpoint inhibitors PD-1 and CTLA-4, bispecific T-cell engagers, and chimeric antigen receptor (CAR) T-cells. Even with the current progress in targeted therapeutics, clinical outcomes remain unsatisfactory.

Significant advances have been made over the past decade in the field of adoptive T-cell therapy. Indeed, application of CD19 CAR-T-cell therapy has generated immense excitement in the fields of B-cell acute lymphoblastic leukemia and B-cell lymphoma and received U.S. Food and Drug Administration (FDA) approval in 2017. CAR T-cell technology is now investigated for implementation in other solid and liquid malignancies.

Regarding AML, advances in CAR-T-cell therapy have been limited by the paucity of tumor-specific antigens. Unlike B-cell malignancies, most myeloid leukemias share antigenic targets with healthy myeloid lineage cells. Various surface and signaling targets for myeloid leukemias have been proposed, and clinical trials are underway; however, the significant on-target, off-tumor effects on normal myeloid lineage as well as tissue cell populations lead to profound toxicity and remain a significant hurdle.

Brief Overview of the Success of Chimeric Antigen Receptor Therapy

CARs are proteins created from the fusion of a variable extracellular antigen-binding domain (scFv) to the transmembrane and intracellular T-cell receptor (TCR) signaling domain, with addition of variable costimulatory moieties ( Fig. 14.1 ). CARs allow for antibody-mediated antigen targeting, thereby sidestepping limitations of MHC restriction and downregulation of natural costimulatory signal. This signal transmission promotes cytotoxic T-cell activation toward the target antigen, leading to T-cell–mediated tumor cell lysis. Thus, the ideal target for CAR-T-cells would be overexpressed by malignant cells and absent on healthy tissue.

The “first-generation” CARs expressed signal solely through the TCR CD3ζ domain without costimulation and demonstrated limited to no clinical effect. “Second- generation” constructs were later developed to include costimulatory domains CD28 or 4-1BB among others and demonstrated improved potency. “Third-generation” constructs contain a combination of costimulatory domains. The improvements in signal transduction and activation have led to higher-potency CAR-T-cells, and most current studies are focused on identifying antigen-binding domains to selectively unleash this potential power.

Antigenic Targets for Chimeric Antigen Receptor Therapy in Acute Myeloid Leukemia

Though the first CAR trials targeting cancer began in the 1990s, the year 2013 marked one of the first phase I trials of CAR-T-cells in AML, targeting tumor-associated antigen Lewis Y. Since 2013, multiple targets have been proposed (including CLL-1, CD123, CD25, CD32, CD33, CD38, CD44, CD47, CD96, CD7, CD70, NKG2D, TIM3, and FLT3, among others). Many prospective targets are under investigation in Phase I/II/III clinical trials; presently there are 37 trials for the clinical application of adoptive cell therapy in the setting of AML ( Table 14.1 ).