CAR TCR: Which Therapy Wins Against Leukemia?

Cell-based immunotherapies have transformed leukemia treatment by harnessing T cells to target cancer. Two leading strategies—CAR (chimeric antigen receptor) and TCR (T-cell receptor) therapies—offer distinct advantages and challenges. The choice depends on antigen specificity, sensitivity, and compatibility with a patient’s immune system.

CAR Engineering For Antigen Specificity

Chimeric antigen receptor (CAR) therapy enables T cells to recognize surface antigens directly, bypassing the need for major histocompatibility complex (MHC) molecules. This is achieved by engineering synthetic receptors with an extracellular antigen-binding domain, typically derived from a monoclonal antibody, fused to intracellular signaling domains that activate T cells upon antigen engagement. CD19, a common leukemia target, exemplifies this approach, as CAR-T cells against CD19 have shown strong efficacy in B-cell malignancies like acute lymphoblastic leukemia (ALL).

The specificity of CAR-T cells is dictated by the single-chain variable fragment (scFv) in the receptor’s extracellular domain, ensuring selective binding to malignant cells while sparing normal tissues. However, leukemic cells can escape detection by downregulating or mutating target antigens. To address this, researchers have developed dual-targeting CARs that recognize multiple antigens, such as CD19 and CD22, reducing relapse risk. Clinical trials show that patients receiving dual-targeting CAR-T cells experience longer remissions than those treated with single-antigen CAR therapy.

Beyond antigen selection, the structural design of CAR constructs influences function. The hinge and transmembrane domains affect receptor stability and antigen binding, while intracellular signaling domains determine T-cell activation strength and duration. First-generation CARs had limited persistence due to a single CD3ζ signaling domain. Second- and third-generation CARs incorporated costimulatory domains like CD28 or 4-1BB, enhancing T-cell expansion and survival. Fourth-generation CARs, known as TRUCKs (T cells redirected for universal cytokine killing), refine specificity by incorporating inducible cytokine expression, allowing for more controlled immune responses.

TCR Configuration And Peptide Sensitivity

T-cell receptor (TCR) therapy harnesses T cells’ natural ability to recognize intracellular antigens presented by MHC molecules. Unlike CAR therapy, which targets surface proteins, TCR-engineered T cells detect peptide fragments from intracellular proteins, expanding potential leukemia targets. This is especially useful for malignancies lacking highly expressed surface antigens.

TCR specificity is determined by α and β chains forming a heterodimer that interacts with peptide-MHC complexes. Complementarity-determining regions (CDRs) within these chains dictate binding affinity and selectivity. Engineering TCRs for leukemia therapy involves optimizing these regions to enhance binding while minimizing off-target effects. High-affinity TCRs improve tumor recognition but risk cross-reactivity with normal tissues, potentially causing toxicity. Researchers use affinity tuning to balance strong tumor recognition with safety.

Peptide sensitivity is also crucial, as even minor variations in peptide sequence or MHC presentation affect recognition. Leukemic cells often alter antigen processing, influencing how peptides are displayed to TCRs. This necessitates selecting TCRs with broad peptide recognition while maintaining tumor specificity. Studies show that TCR-engineered T cells targeting WT1, an intracellular protein overexpressed in leukemia, can eliminate malignant cells while sparing normal hematopoietic progenitors. However, peptide heterogeneity remains a challenge, as mutations or antigen processing changes can lead to immune evasion.

HLA Requirements

Human leukocyte antigen (HLA) compatibility is critical for TCR-based leukemia therapies. Since T-cell receptors rely on HLA molecules to present intracellular peptides, TCR therapy must be tailored to a patient’s HLA type. This restriction limits eligibility, as many TCR therapies target HLA-A02:01, a common allele in Caucasian populations, leaving patients with other HLA types without options. Expanding available TCR therapies or developing strategies to bypass HLA dependency is necessary to address this limitation.

HLA polymorphism adds complexity, as each individual inherits unique HLA alleles that influence antigen presentation. Even minor HLA variations can alter peptide binding, affecting engineered TCR recognition. Rigorous patient screening ensures the chosen TCR effectively engages leukemia-associated antigens. Advances in bioinformatics and sequencing have improved HLA typing accuracy, helping clinicians match patients with suitable TCR therapies. However, the need for precise HLA matching remains a barrier to widespread accessibility.

CAR therapy avoids this issue, as it functions independently of HLA molecules, making it applicable across diverse patient populations. While this broadens CAR therapy’s reach, TCR therapies can target intracellular antigens that CAR-T cells cannot access. Researchers are exploring ways to reduce HLA restrictions, such as engineering TCRs with enhanced cross-reactivity to recognize multiple HLA subtypes. Another promising approach involves TCR-mimic antibodies, which combine TCRs’ intracellular antigen recognition with CARs’ HLA independence, potentially bridging the gap between these therapies.

Targets In Leukemia

Identifying molecular targets that distinguish leukemic cells from normal hematopoietic populations is key to effective treatment. These targets must be consistently expressed on leukemic blasts while minimizing toxicity to healthy tissues. CD19 has been one of the most successful targets in B-cell leukemias, given its uniform expression on malignant B cells and absence on essential non-hematopoietic tissues. CD19-directed therapies, including CAR-T cell treatments, have led to durable remissions in relapsed or refractory ALL. However, antigen escape, where leukemic cells downregulate CD19, has led to the search for alternative targets.

CD22 has emerged as a secondary target in B-cell malignancies, offering a treatment option for patients who relapse after CD19 therapy. Clinical trials of CD22-targeted CAR-T cells have shown promising responses, particularly in CD19-negative relapse cases. CD123, expressed on leukemic stem cells in acute myeloid leukemia (AML), is another potential target. However, its low-level expression on normal hematopoietic progenitors raises concerns about off-target toxicity. Researchers are optimizing antigen affinity and adjusting therapeutic dosing to mitigate these risks while maintaining efficacy.