Comprehensive Guide to CAR-T Targets in Solid and Hematologic Malignancies

1. Overview of CAR-T Therapy and Tumor Target Selection

(1) CAR-T Mechanism of Action and Therapeutic Rationale

CAR-T therapy is an immunotherapy in which T cells are engineered to express chimeric antigen receptors (CARs). A CAR typically includes an scFv antigen-recognition domain, hinge, transmembrane region, and intracellular signaling domains such as CD3ζ with CD28 or 4-1BB co-stimulation.Its key advantage is MHC-independent recognition, allowing direct binding to native tumor surface antigens and bypassing tumor immune evasion such as MHC downregulation. Antigen engagement activates CAR signaling, driving T-cell proliferation, cytokine release, and cytotoxic killing via perforin and granzyme.

(2) Hematologic vs. Solid Tumor CAR-T Targets

CAR-T therapy has shown strong success in hematologic malignancies, with CD19 and BCMA as the most validated targets in B-cell cancers such as B-ALL. Additional targets for T-cell and other refractory hematologic malignancies are under development. In contrast, solid tumors remain challenging due to less tumor-specific antigen expression, increasing the risk of on-target/off-tumor toxicity. Moreover, the immunosuppressive tumor microenvironment (TME)-including abnormal vasculature, dense stroma, hypoxia, and inhibitory cytokines such as TGF-β-limits CAR-T infiltration and function. As a result, improving safety, tumor penetration, and TME resistance remains the key focus in solid tumor CAR-T development.

Figure 1. Extrinsic factors limiting the antitumor activity of CAR-T cells (Nature Reviews Drug Discovery, Vol. 20, Issue 7, 2021: 531-550)

(3) Criteria for Selecting CAR-T Tumor Antigens

The selection of ideal CAR-T targets is one of the most critical steps in CAR-T development and must generally meet the following criteria:

- High tumor specificity

The target should be highly expressed on tumor cells while having minimal or no expression in normal tissues to reduce off-tumor toxicity.

- Stable and homogeneous expression

The antigen should maintain relatively stable expression across patients and disease stages to reduce the risk of antigen loss and immune escape.

- Functional relevance to tumor survival

Targets involved in tumor proliferation or survival pathways are less likely to be downregulated during treatment, improving therapeutic durability.

- Surface accessibility and CAR compatibility

Ideal targets should be cell-surface molecules with suitable epitope density and spatial conformation to ensure efficient CAR binding and T-cell activation.

2. Key Hematologic CAR-T Targets and Their Clinical Insights

Figure 2. CAR-T Targets in Hematologic Malignancies

(1) CD19 and CD22: Established Targets in B-cell Malignancies

CD19 remains one of the most extensively studied and widely used CAR-T targets globally. It is expressed throughout most stages of B-cell development but is lost in terminally differentiated plasma cells. Several approved CD19 CAR-T therapies, such as Kymriah and Yescarta, are primarily based on the classical murine FMC63 scFv.

However, approximately 20-30% of relapsed cases are associated with CD19 antigen loss or downregulation. To address this limitation, CD22 has emerged as an important salvage target. CD22 is co-expressed with CD19 in most B-ALL and non-Hodgkin lymphoma (NHL) cases and can remain expressed even in CD19-negative relapsed patients. Therefore, CD19/CD22 dual-target CAR-T strategies have become an important approach to reduce antigen escape and improve remission durability.

(2) BCMA: Core Target in Multiple Myeloma

B-cell maturation antigen (BCMA) is one of the most successful CAR-T targets in multiple myeloma (MM). BCMA is primarily expressed on plasma cells and malignant myeloma cells, with limited expression in normal tissues, providing a favorable therapeutic window.

In recent years, BCMA CAR-T therapies such as Abecma and Carvykti have significantly advanced MM treatment. However, challenges such as low antigen expression, BCMA shedding, and T-cell exhaustion have emerged during clinical application. To further enhance efficacy, BCMA CAR-T is being investigated in combination with γ-secretase inhibitors, immunomodulatory agents, and anti-CD38 antibodies to improve the tumor microenvironment and CAR-T persistence.

(3) CD38 and CD138: Additional Plasma Cell Targets

In addition to BCMA, CD38 and CD138 are also important targets in plasma cell malignancies. CD38 is highly expressed on multiple myeloma cells and has been successfully validated as a therapeutic target, with the anti-CD38 antibody Daratumumab widely used in clinical practice.

Studies have shown that CD38-targeting antibodies not only directly kill tumor cells but also reshape the tumor microenvironment by depleting immunosuppressive cells, thereby providing synergistic potential for combination with BCMA CAR-T therapy. CD138 is another plasma cell surface marker with CAR-T potential; however, its expression in certain epithelial tissues raises concerns regarding safety and off-tumor toxicity, which still require further optimization.

(4) CD33, CD123, and CLL-1: Key AML Targets

In acute myeloid leukemia (AML), CD33, CD123, and CLL-1 (CLEC12A) are among the most actively investigated CAR-T targets.CD33 and CD123 are highly expressed on AML cells and leukemic stem cells but are also present on normal hematopoietic stem and progenitor cells, which may lead to prolonged myelosuppression and hematologic toxicity. In contrast, CLL-1 shows more selective expression on leukemic stem cells and limited expression on normal hematopoietic stem cells, making it a more promising next-generation AML target.

(5) CD7: Representative Target for T-cell Malignancies

CD7 is an important target for T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphomas, but its development is more challenging than B-cell targets. Because normal T cells also express CD7, CAR-T cells may undergo fratricide during manufacturing. To overcome this issue, gene-editing technologies such as CRISPR/Cas9 are used to knock out CD7 expression in T cells, preventing self-targeting. CD7 CAR-T has therefore become a key innovation in T-cell malignancy treatment and has also driven the development of allogeneic CAR-T platforms.

3. Emerging Solid Tumor CAR-T Targets

Figure 3. Hot CAR-T Targets in Solid Tumors (doi: 10.1016/j.medj.2026.101028. )

(1) HER2: Representative Target in Multiple Solid Tumors

HER2 (Human Epidermal Growth Factor Receptor 2) is one of the earliest and most classical CAR-T targets in solid tumors, with high expression in breast, gastric, ovarian, and lung cancers. Its clinical validation in antibody therapies provides a strong development foundation. However, low-level HER2 expression in normal tissues such as lung increases the risk of on-target/off-tumor toxicity. Recent strategies, including affinity tuning of scFv, localized delivery, and logic-gated CAR designs, are being explored to improve safety and tumor specificity.

(2) EGFR and EGFRvIII: Key Targets in Glioblastoma and Epithelial Tumors

EGFR is highly expressed in multiple epithelial tumors including lung, colorectal, and head and neck cancers. EGFRvIII is a tumor-specific mutant primarily found in glioblastoma (GBM) and is absent in most normal tissues, making it a highly attractive CAR-T target. EGFRvIII CAR-T has shown early clinical activity in GBM; however, tumor heterogeneity and uneven antigen expression remain major limitations. Current optimization strategies include multi-target CAR approaches and regional administration such as intracerebral or intraventricular infusion.

(3) GPC3: Hot Target in Hepatocellular Carcinoma

Glypican-3 (GPC3) is one of the most promising CAR-T targets in hepatocellular carcinoma (HCC), with high expression in most tumor tissues and limited expression in normal adult tissues, providing good tumor specificity. Early clinical studies of GPC3 CAR-T have demonstrated preliminary efficacy in HCC patients. In addition, combination strategies such as immune checkpoint inhibitors, hepatic artery infusion, and armored CAR-T approaches are being explored to enhance CAR-T persistence in the immunosuppressive liver tumor microenvironment.

(4) Mesothelin (MSLN): Broad-Spectrum Solid Tumor Target

Mesothelin (MSLN) is highly expressed in mesothelioma, pancreatic cancer, ovarian cancer, and lung cancers, making it one of the broadest solid tumor CAR-T targets. Its limited expression in normal tissues provides a favorable therapeutic window. However, MSLN CAR-T therapy still faces challenges such as poor tumor infiltration and immunosuppressive TME. Enhanced strategies, including armored CAR-T secreting IL-12/IL-18, chemokine receptor engineering, and combination with PD-1 blockade, are under active investigation.

(5) Claudin18.2 (CLDN18.2): Emerging Star Target in Gastrointestinal Tumors

Claudin18.2 (CLDN18.2) is one of the fastest-growing CAR-T targets in gastric and pancreatic cancers. In normal tissues, it is mainly restricted to tight junctions in gastric mucosal cells, while in tumors it becomes exposed and highly expressed, offering good tumor selectivity. With the rapid development of CLDN18.2-targeted antibodies and CAR-T therapies, this target has become a major focus in gastrointestinal oncology. Current research emphasizes reducing gastric toxicity and improving CAR-T persistence in solid tumor environments.

4. Hematologic and Solid Tumor CAR-T Development Trends

With the continued maturation of CAR-T technology, development in hematologic malignancies is shifting from single-target validation (e.g., CD19 and BCMA) toward more refined and platform-based optimization. Future efforts will focus on improving long-term remission rates and reducing relapse through dual/multi-target CAR-T, logic-gated CAR-T, allogeneic CAR-T, and gene-edited enhanced CAR-T platforms. These strategies aim to address antigen escape, T-cell exhaustion, and manufacturing scalability challenges.

In contrast, CAR-T therapy for solid tumors is transitioning from early exploration to accelerated clinical validation. Although targets such as HER2, GPC3, CLDN18.2, MSLN, and EGFRvIII have shown promising signals, major barriers remain, including the immunosuppressive tumor microenvironment (TME), antigen heterogeneity, and on-target/off-tumor toxicity. Therefore, armored CAR-T, localized delivery strategies, and combination therapies with immune checkpoint inhibitors are becoming key directions to improve therapeutic outcomes.

5. Learn More about CAR Targets

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