What Are T-Cell Lymphomas?
T-cell lymphomas are a rare and heterogeneous group of aggressive non-Hodgkin lymphomas (NHL) that arise from either mature (peripheral) or immature T-cells.
They account for approximately 10–15% of all NHLs in adults and have a typically poor prognosis, especially in relapsed or refractory disease.
T-cell lymphomas are classified into two categories:
Peripheral T-cell lymphomas (PTCLs)
Derived from mature post-thymic T cells, PTCLs include:
- PTCL–Not Otherwise Specified (PTCL-NOS) – the most common subtype.
- Angioimmunoblastic T-cell lymphoma (AITL) – associated with immune dysregulation.
- Anaplastic large cell lymphoma (ALCL) – ALK-positive & ALK-negative forms.
- Cutaneous T-cell lymphomas (CTCL) – includes mycosis fungoides and Sézary syndrome.
T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL)
- An aggressive malignancy of immature T-cell precursors, more common in younger patients.
- Shares many targetable antigens with PTCL but has a distinct clinical behavior.
Why Are T-Cell Lymphomas Hard to Treat?
- Lack of tumor-specific antigens: Most T-cell antigens, such as CD5 and CD7, are also found on normal T cells.
- High relapse rates: Standard chemotherapies often yield only temporary responses.
- Immunological complexity: The immune-suppressive tumor microenvironment and systemic T-cell depletion create added therapeutic risk.
Cell Therapy: A New Frontier for T-Cell Lymphomas
While CAR-T cell therapy has revolutionized B-cell malignancies, T-cell lymphomas have lagged due to several challenges:
- Fratricide: CAR-Ts that recognize T-cell antigens often kill themselves during production.
- T-cell aplasia: Depleting healthy T cells causes profound immunosuppression.
- Product contamination: Autologous CAR-T manufacturing risks expanding malignant T cells.
Despite these issues, biotech innovation and gene-editing tools have launched a new generation of therapies, led by CAR-T and CAR-NK constructs with increasingly refined targets.
CD5-Targeted Cell Therapies
CD5 is broadly expressed on both normal and malignant T cells, with particularly high expression observed in peripheral T-cell lymphoma (PTCL) and T-cell acute lymphoblastic leukemia (T-ALL).
MB-105 (March Biosciences)
- It is an autologous CD5 CAR-T cell therapy engineered to downregulate CD5 expression during manufacturing, thereby reducing fratricide among the CAR-T cells.
- Designed for r/r T-cell lymphoma & leukemia.
- In January 2025, the US FDA granted orphan drug designation to MB-105 for the treatment of relapsed/refractory CD5-positive T-cell lymphoma.
- MB-105 is currently in Phase I trial (NCT03081910) for r/r TCL and T-ALL, indicating a 44% ORR in TCL patients.
- The company intends to launch a Phase II trial in early 2025.
GCC2005 (AB-205, GC Cell/Artiva Biotherapeutics)
- It is a CD5-targeted CAR-NK cell therapy.
- Designed with fratricide-resistance for safer and more effective treatment of T-cell leukemias and lymphomas.
- Represents a key part of GC Cell’s cell therapy pipeline focused on relapsed or refractory NK and T‑cell malignancies.
- In March 2025, the first patient dosed in the Phase I trial.
CD7: A Key Target in T-ALL and PTCL
CD7 is normally expressed on immature and mature T-cell malignancies.
MB-107 (March Biosciences)
- Autologous CD7-directed CAR-T for T-ALL and TCL, designed to overcome fratricide via novel engineering.
- Currently in Phase I clinical development.
WU-CART-007 (Wugen)
- It is a CD7-targeted CAR T-cell therapy with CRISPR/Cas9 deletion of CD7 & T-cell receptor alpha constant.
- This therapy prevents fratricide and also enables the use of healthy donor allogeneic T-cells
- In March 2025, dosed the first patients in its pivotal Phase II study of WU-CART-007 in pediatric and adult patients with R/R T-ALL/LBL.
- It received the US FDA accelerated approval pathway designations, including RMAT, Fast Track, Orphan Drug, and Rare Pediatric Disease, as well as Priority Medicines designation (PIME) in the EU.
CTD402 (Bioheng Therapeutics)
- CD7-targeted universal CAR-T (UCAR-T) cell therapy.
- CTD402 is a genetically modified cell therapy to avoid fratricide, GvHD, and HvG while enhancing anti-tumor activity.
- In February 2025, the US FDA cleared an IND to initiate a Phase I/II trial for pediatric and adult patients with R/R T-ALL/LBL
TRBC1 CAR-T: Precision Without Aplasia
Most T cells express either TRBC1 or TRBC2, but malignant clones are usually clonal for one. Targeting TRBC1 allows for:
- Selective tumor killing while sparing TRBC2+ normal T cells.
- Reduced immunosuppression risk compared to pan-T-cell antigen targeting.
AUTO4 (Autolus Therapeutics)
- It is a first-in-class TRBC1 CAR-T for the treatment of PTCL.
- It is in Phase I/II clinical trial in patients with TRBC1-positive PTCL-NOS, AITL, and ALCL, the three most common subtypes of PTCL.
AUTO5 (Autolus Therapeutics)
- It is a TRBC2 CAR-T under evaluation for PTCL.
- It is in the preclinical development for TRBC2-positive PTCL.
CD70: A Tumor-Selective Target
CD70 is overexpressed in subsets of PTCL, CTCL, and T-ALL, with low expression in normal tissues.
CTX131 (CRISPR Therapeutics)
- CRISPR-edited, allogeneic CAR-T targeting CD70.
- It is designed to evade the immune system, prevent fratricide, enhance CAR-T potency, and reduce CAR-T exhaustion
- It is in a Phase I/II trial for T-cell lymphoma.
CAR-NK Cells: A Safer Cellular Platform
CAR-NK cells are gaining attention due to their:
- Usual resistance to fratricide.
- Lower risk of GvHD.
- Short-lived activity, providing a safety buffer.
GCC4001 (GC Cell)
- Allogeneic, unmodified, ADCC-enhanced NK cell Therapy derived from umbilical cord blood
- GCC4001 in combination with AFM13 cleared IND for a Phase II clinical trial targeting relapsed and refractory Hodgkin lymphoma and was designated for a Fast Track status in September 2023.
- It is in the Phase II clinical stage for the treatment of R/R classical HL and CD30-positive PTCL.
Next-Generation CAR Designs: Precision + Control
To refine specificity and minimize toxicity, several strategies are being employed:
- Dual-target CARs (e.g., CD5 + CD70) to prevent antigen escape.
- Logic-gated CARs (AND/NOT) for more precise activation.
- Suicide switches for emergency shutdown in case of severe toxicity.
- Off-the-shelf allogeneic technologies using CRISPR & TALEN gene editing approaches.
New Hope for a Difficult Disease
T-cell lymphomas have long stood at the margins of therapeutic innovation, burdened by biological complexity and a lack of selective targets. However, the tide is rapidly turning. The rise of engineered cell therapies spanning fratricide-resistant CAR-T cells, precision TRBC1-targeted constructs, and allogeneic CAR-NK platforms marks a new era of promise for patients facing these aggressive and frequently treatment-resistant cancers.
By targeting historically “difficult” antigens like CD5, CD7, CD70, and TRBC1, and deploying cutting-edge tools such as gene editing, logic gating, and off-the-shelf manufacturing, researchers and clinicians are beginning to crack the code of T-cell malignancies.
While challenges remain, including immune escape, manufacturing complexity, and toxicity management, the current wave of clinical innovation is both promising and unprecedented. As more therapies enter trials and move toward regulatory approval, we may soon witness a paradigm shift, one in which cell therapy offers not just remission, but durable cures for T-cell lymphoma patients worldwide.
