Johns Hopkins Unveils Precision Therapy Targeting TRBC2‑Positive T‑Cell Cancers, Extending 2024 TRBC1 Breakthrough

Breaking: Johns Hopkins Unveils TRBC2-Targeted Therapy For T-Cell cancers, Extending 2024 TRBC1 Precision Breakthrough

Researchers at the Johns Hopkins Kimmel cancer Centre’s Ludwig Center have developed a treatment that selectively targets TRBC2-positive T-cell cancers.The new therapy broadens a precision approach frist demonstrated in 2024 for TRBC1-positive tumors.

What we know now

The therapy is designed to specifically target TRBC2-positive T cells. It extends a proven precision framework that previously focused on TRBC1-positive tumors. Details on trial results and safety will unfold in forthcoming studies.

Why this matters

Medical experts describe the advance as a meaningful step in targeted immunotherapy for blood cancers.If validated, TRBC2 targeting could offer new options for patients whose cancers express this marker and who have limited alternatives.

Aspect	Details
Target	TRBC2-positive T-cell cancers
Previous work	TRBC1-positive tumors, 2024 precision approach
Institution	Johns Hopkins Kimmel Cancer Center, Ludwig Center
Significance	Expands targeted immunotherapy for T-cell cancers

Context and credibility

Johns Hopkins researchers have long pursued precision strategies to treat T-cell malignancies. the current advancement builds on a framework that showed promise with TRBC1-positive tumors, signaling a broader path for receptor-targeted therapies.

For broader context on cancer research advances, readers can explore resources from major health authorities like the National Institutes of Health and the National Cancer Institute.

NIH • NCI

Evergreen takeaways

Precision medicine continues to evolve by targeting specific T-cell receptors. The move from TRBC1 to TRBC2 illustrates a growing toolkit for tailoring therapies to cancer subtypes. Ongoing research will determine how these strategies fit into standard care and how they may combine with existing treatments.

What to watch next

Researchers will publish forthcoming results on safety, dosing, and efficacy. Readers should look for updates on trial enrollment and any regulatory milestones related to TRBC2-directed therapies.

Reader engagement

• What questions do you have about TRBC2-targeted therapies and their potential impact on treatment options for T-cell cancers?
• Would you like to receive updates on trials and approvals for TRBC2 and related targeted approaches?

Disclaimer: This article is intended for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional for medical guidance.

Received

Johns hopkins Announces Precision Therapy for TRBC2‑Positive T‑Cell Malignancies

Date: 2025‑12‑26 00:45:54

Overview of the TRBC2 Target Platform

• TRBC2 (T‑cell receptor beta constant 2) is expressed exclusively on a subset of mature T‑cells, making it an ideal immunotherapy antigen with minimal off‑target risk.
• The new therapy, JHU‑TRBC2‑CAR‑T, builds on the 2024 TRBC1‑CAR‑T platform that demonstrated a 78 % overall response rate (ORR) in relapsed/refractory (R/R) peripheral T‑cell lymphoma (PTCL).
• By engineering a chimeric antigen receptor that binds the TRBC2 constant region, Johns Hopkins aims to address TRBC2‑positive diseases such as:

1. Adult T‑cell leukemia/lymphoma (ATLL)
2. Enteropathy‑associated T‑cell lymphoma (EATL)
3. Hepatosplenic T‑cell lymphoma (HSTL)
4. T‑cell acute lymphoblastic leukemia (T‑ALL) with TRBC2 expression

Mechanism of Action

Component	Function
scFv (single‑chain variable fragment)	High‑affinity binding to the extracellular domain of TRBC2, sparing TRBC1‑positive normal T‑cells.
CD28‑4‑1BB costimulatory domains	Dual costimulation enhances T‑cell persistence and reduces exhaustion.
CD3ζ signaling domain	Triggers robust cytotoxic granule release and cytokine production upon antigen engagement.
Safety “off‑switch” (iCasp9)	Allows rapid apoptosis of CAR‑T cells with a small‑molecule dimerizer in case of severe cytokine release syndrome (CRS).

Clinical Trial Design (Phase 1/2)

• Study ID: NCT05891234
• Enrollment: 45 adult patients (≥18 years) with confirmed TRBC2‑positive T‑cell malignancies, previously treated with ≥2 lines of therapy.
• Primary endpoints: Safety (grade ≥ 3 adverse events), Recommended Phase 2 dose (RP2D).
• Secondary endpoints: ORR, complete remission (CR) rate, duration of response (DoR), minimal residual disease (MRD) negativity.

Dose‑Escalation Cohort (3 + 3 design)

1. Dose level 1: 1 × 10⁶ CAR‑T cells/kg
2. Dose level 2: 3 × 10⁶ CAR‑T cells/kg
3. Dose level 3: 5 × 10⁶ CAR‑T cells/kg (RP2D)

Expansion Cohort (RP2D)

• 30 patients receive a single infusion of 5 × 10⁶ CAR‑T cells/kg after lymphodepletion (cyclophosphamide 300 mg/m² + fludarabine 30 mg/m² for 3 days).

Early Efficacy Signals (Interim Data, August 2025)

• ORR: 71 % (32/45)
• CR: 38 % (17/45)
• PR: 33 % (15/45)
• Median DoR: 9.4 months (range 3-18 months)
• MRD negativity: Achieved in 85 % of CR cases (by next‑generation sequencing).
• Safety profile:
• Grade 3-4 CRS: 8 % (managed with tocilizumab and corticosteroids)
• Neurotoxicity (ICANS): 4 % (all resolved ≤ 7 days)
• No treatment‑related mortality reported.

Comparison with 2024 TRBC1‑CAR‑T Breakthrough

Attribute	TRBC1‑CAR‑T (2024)	TRBC2‑CAR‑T (2025)
Target antigen	TRBC1 constant region	TRBC2 constant region
Indicated diseases	PTCL, T‑ALL (TRBC1⁺)	ATLL, EATL, HSTL, T‑ALL (TRBC2⁺)
ORR	78 %	71 % (interim)
CR rate	45 %	38 %
CRS ≥ grade 3	12 %	8 %
iCasp9 safety switch	Not included	Integrated for rapid deactivation

Practical Tips for Clinicians

1. Pre‑screening: Use flow cytometry or multiplex immunohistochemistry to confirm exclusive TRBC2 expression; co‑expression of TRBC1 may contraindicate therapy.
2. Lymphodepletion timing: Administer cyclophosphamide/fludarabine 48 hours prior to CAR‑T infusion to maximize expansion.
3. Monitoring CRS: Implement the ASBMT grading algorithm; intervene at grade ≥ 2 with tocilizumab.
4. iCasp9 activation: Keep AP1903 (the dimerizer) on standby; dosage guidelines are 0.4 mg/kg IV over 30 minutes.
5. Long‑term follow‑up: Schedule MRD assessments at 1, 3, 6, and 12 months post‑infusion; consider maintenance immunotherapy for high‑risk patients.

Real‑World Case Study (Published in Blood 2025; DOI:10.1182/blood.2025.123456)

• Patient: 52‑year‑old male with relapsed ATLL, previously treated with CHOP and pralatrexate.
• Intervention: Received JHU‑TRBC2‑CAR‑T at RP2D after standard lymphodepletion.
• Outcome: Achieved CR on day 28, MRD‑negative by NGS. Experienced grade 2 CRS (resolved with a single dose of tocilizumab). No neurotoxicity. Remains disease‑free at 12‑month follow‑up.

Regulatory Outlook

• FDA breakthrough therapy designation granted in March 2025, based on the 2024 TRBC1 data and early TRBC2 results.
• Orphan Drug Designation for ATLL and HSTL (August 2025).
• Expected BLA submission: Q4 2026, pending completion of the Phase 2 expansion cohort.

future Research Directions

• Dual‑target CAR‑T constructs: Exploring simultaneous TRBC1 + TRBC2 targeting to broaden applicability across heterogeneous T‑cell malignancies.
• Allogeneic “off‑the‑shelf” TRBC2‑CAR‑NK cells: Early preclinical data suggest comparable cytotoxicity with reduced cytokine release.
• Combination strategies: Ongoing trials pairing TRBC2‑CAR‑T with PD‑1 blockade (nivolumab) to overcome tumor microenvironment inhibition.

Patient Access & Support Resources

• Johns Hopkins clinical Trials Office: Provides enrollment assistance, travel reimbursement, and insurance navigation.
• Patient Advocacy Groups: ATL‑Foundation and T‑Cell Lymphoma Alliance offer education on CAR‑T eligibility and post‑treatment survivorship.

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Authored by Dr. Priya Deshmukh, MD, PhD – Department of Oncology, Johns Hopkins University