Novel CAR T-Cell Therapy Targets HLA-DRB1 for Relapsed Acute Myeloid Leukemia

A groundbreaking study published in Nature Cancer by researchers at Osaka University and collaborating institutions has identified a promising new target for treating relapsed acute myeloid leukemia (AML). The finding centers on the molecule HLA-DRB1, offering a potential avenue for CAR T-cell therapy that spares healthy cells.

Acute myeloid leukemia, a challenging blood cancer, often sees patients undergo allogeneic hematopoietic stem cell transplantation (allo-HCT). While this procedure can be life-saving, relapse remains a critically important concern for many AML patients. Current therapeutic strategies frequently aim to target tumor-specific antigens, molecules found exclusively on cancer cells, to minimize damage to healthy tissues. However, pinpointing such precise targets in AML has been a persistent hurdle.

Chimeric antigen receptor (CAR) T-cell therapy, which engineers a patient’s own T cells to hunt down and destroy cancer cells, has shown remarkable success in other blood cancers like B-cell leukemia and multiple myeloma. Yet, many antigens currently targeted for AML CAR therapy are also present on normal cells, leading to potentially severe side effects.

“Our prior work in multiple myeloma involved an extensive screening of monoclonal antibodies to find those that reacted with myeloma cells but not with normal blood cells,” explained Shunya Ikeda, the study’s lead author. “We adopted this precise strategy to identify specific antigens in AML.”

The research team meticulously screened thousands of monoclonal antibodies (mAbs) directed against AML cells. This rigorous process narrowed the field down to 32 mAbs that specifically bound to AML cells. Among these, one mAb, designated KG2032, demonstrated a strong affinity for AML cells across more than half of the patient samples tested. Further analysis through sequencing revealed that KG2032 targets HLA-DRB1.

“What’s especially exciting is that KG2032 reacts with a specific subset of HLA-DRB1 where the protein possesses an amino acid other than aspartic acid at the 86th position,” stated Naoki Hosen, the senior author. “This specificity means KG2032 would only target AML cells in patients with a particular type of HLA-DRB1 mismatch, where the patient carries this specific amino acid residue, but their allo-HCT donor does not.”

This critical finding positions HLA-DRB1 as a viable target for treating AML patients, especially those who have relapsed post-allo-HCT.

To validate their discovery, the researchers engineered KG2032 CAR T cells designed to avoid the reactive HLA-DRB1 allele. In vitro cell culture experiments and in vivo studies using a mouse model demonstrated potent and specific anti-AML activity by these engineered cells, with no observable toxicity in the treated mice.Similar promising results were also observed with engineered cord blood-derived CAR natural killer (NK) cells.

These compelling findings suggest that KG2032-based CAR T or NK cell therapies could offer a life-altering treatment for AML patients experiencing relapse after allo-HCT. Clinical trials for both CAR T and CAR NK cell types are reportedly in the planning stages.

What are the primary challenges hindering the widespread adoption of CAR-T cell therapy for AML?

CAR-T Cell Therapy’s Advance in Acute Myeloid Leukemia Treatment

Understanding Acute Myeloid Leukemia (AML) & the Need for Novel Therapies

Acute Myeloid Leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow. Standard treatments – including chemotherapy, targeted therapy, and stem cell transplantation – have considerably improved outcomes, but relapse rates remain high, especially in older adults or those with unfavorable genetic mutations. This underscores the urgent need for innovative therapeutic approaches. AML treatment, leukemia therapy, and blood cancer treatment are key search terms driving patient inquiries. The limitations of conventional methods are pushing researchers towards immunotherapies, with CAR-T cell therapy emerging as a promising option.

what is CAR-T Cell Therapy? A Deep Dive

Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy that harnesses the power of the patient’s own immune system to fight cancer. Here’s a breakdown of the process:

1. T-Cell collection: T cells, a type of white blood cell crucial for immunity, are collected from the patient’s blood. This process is called leukapheresis.
2. Genetic Engineering: In a laboratory, these T cells are genetically engineered to express a special receptor – the CAR. This CAR is designed to recognize a specific protein (antigen) on the surface of AML cells. Currently, research focuses on identifying optimal AML antigens for CAR-T targeting.
3. Cell Expansion: The modified CAR T-cells are grown and multiplied in the lab to create a large enough dose for treatment.
4. Infusion: The CAR T-cells are infused back into the patient. these engineered cells then seek out and destroy AML cells expressing the target antigen.

This personalized approach to cancer immunotherapy offers a potential advantage over customary treatments.

CAR-T Cell Therapy in AML: Current Landscape & Challenges

While CAR-T cell therapy has revolutionized treatment for certain blood cancers like B-cell lymphomas and acute lymphoblastic leukemia (ALL), its application in AML has faced notable hurdles. AML cells frequently enough lack the ideal target antigens found on other leukemia types. Furthermore, the bone marrow microenvironment in AML can suppress T-cell activity.

Here’s a look at the current status:

Target Antigen Identification: Researchers are actively investigating various antigens expressed on AML cells, including CD33, CD123, and CLL-1. Each antigen presents unique challenges regarding on-target, off-tumor toxicity (where the CAR T-cells attack healthy cells expressing the same antigen).

clinical Trials: Numerous clinical trials are underway evaluating different CAR-T cell constructs and strategies for AML. Early results have shown promise in heavily pre-treated patients with relapsed or refractory disease. AML clinical trials are a vital resource for patients seeking cutting-edge treatment options.

Overcoming the Bone Marrow Barrier: Strategies to enhance CAR T-cell persistence and function within the suppressive bone marrow microenvironment are being explored. These include combining CAR-T therapy with other agents that modulate the immune system.

Cytokine Release Syndrome (CRS) & Neurotoxicity: Like other CAR-T therapies, AML-directed CAR-T cells can cause CRS and neurotoxicity – potentially life-threatening side effects. Managing these toxicities is a critical aspect of patient care. CAR-T side effects require careful monitoring and prompt intervention.

Emerging Strategies to Enhance CAR-T Efficacy in AML

Several innovative approaches are being investigated to improve the effectiveness of CAR-T cell therapy for AML:

Dual-Targeting CAR-T Cells: Engineering CAR T-cells to recognize two different antigens on AML cells simultaneously. This reduces the risk of antigen escape (where AML cells lose expression of the target antigen) and enhances specificity.

“Armored” CAR-T Cells: Modifying CAR T-cells to express additional molecules that enhance their activity, such as cytokines or co-stimulatory signals.

In Situ CAR-T Cell Generation: Developing methods to generate CAR T-cells directly within the patient’s body, potentially reducing manufacturing time and cost.

Combination Therapies: Combining CAR-T cell therapy with chemotherapy, targeted therapy, or other immunotherapies to enhance its anti-leukemic effect. AML combination therapy is a growing area of research.

Allogeneic CAR-T Cells: Utilizing CAR-T cells derived from healthy donors, rather than the patient’s own cells. This offers the potential for “off-the-shelf” availability and reduces manufacturing time.

While widespread adoption is still pending, several case studies demonstrate the potential of CAR-T therapy in AML. For example, a study published in The New England Journal of Medicine* (2023) showcased promising results with a CD33-targeted CAR-T cell therapy in patients with relapsed/refractory AML, demonstrating a significant rate of complete remission. another study, presented at the American Society of Hematology (ASH) annual meeting (2024), highlighted the efficacy of a CD123-targeted CAR-T cell therapy in patients with minimal residual disease (MRD) positive AML. These examples, while preliminary, offer hope