Peking University People’s Hospital Presents Phase I Results for Novel CD5 CAR-T Therapy

Peking University People’s Hospital Reports Mixed Phase I Results for CD5 CAR-T

Peking University People’s Hospital presented Phase I results from its CONQUER trial at the ASCO Annual Meeting 2026, evaluating SL105, a novel nanobody-based autologous CD5 CAR-T therapy for relapsed/refractory T-cell acute lymphoblastic leukaemia (T-ALL), peripheral T-cell lymphoblastic lymphoma (PTCL), and cutaneous TCL. The trial in 22 adult patients showed a three-month maximum objective response rate (ORR) of 81.8% and a combined complete response (CRc) of 54.5%, with all responders achieving minimal residual disease (MRD)-negativity. While cytokine release syndrome was manageable (72.7%, mostly Grade 1/2), a striking 90.9% of patients experienced Grade 3 or higher infections, leading to seven infection-related deaths and a median overall survival of 3.6 months.

• The CONQUER trial demonstrated promising initial efficacy, achieving an 81.8% objective response rate and a 54.5% combined complete response rate at three months. All patients who responded were confirmed to be minimal residual disease-negative, indicating deep and meaningful responses in a challenging patient population with limited treatment options.
• While cytokine release syndrome was observed in 72.7% of patients, it was predominantly Grade 1 or 2 and manageable. However, a significant safety concern emerged with 90.9% of patients experiencing Grade 3 or higher infections, including high rates of EBV and CMV. These severe infections led to seven deaths and contributed to a median overall survival of only 3.6 months, highlighting a critical area for protocol modification.
• SL105 utilizes a unique nanobody-based approach to block CD5 expression on CAR-T cells, preventing fratricide and allowing targeting of CD5-positive malignant T-cells. Researchers plan to apply a recommended Phase II dose of 2.0 x10^6 CAR-T cells/kg in a larger cohort and introduce protocol modifications to ensure earlier allogeneic hematopoietic cell transplantation (HCT) post-CAR-T administration to mitigate infection risks and improve long-term survival.

Why Novel Therapies are Crucial for T-cell Malignancies

T-cell acute lymphoblastic leukemia (T-ALL) presents significant therapeutic challenges that distinguish it from B-precursor ALL, with frequent relapse, chemotherapy resistance, and poorer overall prognosis. Despite improved treatment protocols, a substantial portion of T-ALL patients still experience treatment failure, and progress in T-cell ALL has notably lagged behind advances in B-lineage ALL.

• Limited prognostic biomarkers and therapeutic targets: Many treatment challenges reflect the lack of prognostic cytogenetic or molecular abnormalities on which to base therapy, including targeted approaches, with molecularly targeted therapy further hindered by significant heterogeneity in T-ALL

• Dismal outcomes in relapsed/refractory disease: Patients with refractory or relapsed T-ALL show cure rates below 10% with limited therapeutic options, as pediatric patients often do not derive additional benefit from intensified conventional chemotherapy approaches that have been maximized in the upfront setting

• Immunotherapy development barriers: The lack of tumor-restricted T-cell antigens hampers immunotherapy progress, while targeting surface antigens (CD2, CD5, CD7, CD38) faces challenges including T-cell fratricide during manufacturing, T-cell depletion during treatment, and high frequency of target-negative relapse

• Resistance mechanisms: Loss of PTEN is common in primary T-ALLs and results in resistance to γ-secretase inhibitors (GSIs) that target Notch1 mutations, while repressing p53-mediated apoptosis

• Poor transplant outcomes: In allogeneic hematopoietic cell transplantation studies, overall survival at 5 years was only 34%, with relapse being the most common cause of death (58% of patients) and cumulative incidence of relapse at 41%

• Treatment-related mortality: The emergence of treatment-related morbidity and mortality alongside relapse remain major challenges, with non-relapse mortality reaching 26% in transplant studies

Peking University's SL105 CAR-T: Early Efficacy and Safety

Recent clinical studies in T-cell acute lymphoblastic leukemia have demonstrated promising advances across multiple therapeutic modalities, with particular progress in novel targeted approaches and conditioning regimens. A comprehensive analysis of current research reveals significant developments in both efficacy outcomes and safety profiles for this challenging malignancy.

A notable phase 1/2 study (NCT02553460) evaluated the combination of bortezomib and vorinostat with chemotherapy backbone in 50 infant ALL patients, demonstrating manageable toxicity profiles despite concerning infectious complications. The study showed no dose-limiting toxicities at lower vorinostat doses, though grade 3-4 adverse events during induction included hypertension (48%), infections (44%), and fever with neutropenia (42%). Treatment-related deaths occurred in 4 patients, all due to infectious events including parainfluenza, cytomegalovirus, and Aspergillus fumigatus, highlighting the persistent challenge of immunosuppression-related mortality extending beyond the induction phase. Additional studies examining conditioning regimens revealed that total body irradiation plus cyclophosphamide may provide superior composite outcomes compared to modified busulfan plus cyclophosphamide, with 3-year graft-versus-host disease-free, relapse-free survival significantly higher at 52% versus 22% after propensity score matching.

Emerging targeted therapies have shown considerable promise, particularly menin inhibitors and BET protein degraders for treatment-resistant disease. Menin inhibitors including ziftomenib demonstrated efficacy in reducing tumor burden without major toxicity in xenograft models, with MEF2C S222 phosphorylation identified as a predictive biomarker for treatment sensitivity. For nelarabine-resistant T-ALL, BET family protein degraders ARV-771 and ARV-825 successfully targeted MYC addiction pathways, significantly reducing leukemia burden and extending survival in preclinical models. Novel fusion targets such as TPR::ABL2 have shown sensitivity to tyrosine kinase inhibitors, while oleandrin demonstrated dose-dependent anti-leukemic effects with IC₅₀ values of 16-31 nM and no significant toxicity in mouse models, supporting the continued expansion of precision medicine approaches in T-ALL management.

CD5 CAR-T: A Glimmer of Hope, Shadowed by Infection Risk

The recent Phase I data for SL105, a nanobody-based autologous CD5 CAR-T therapy, presents a compelling, yet complex, picture for the future of T-cell malignancy treatment. For patients battling relapsed/refractory T-cell acute lymphoblastic leukaemia, peripheral T-cell lymphoblastic lymphoma, and cutaneous TCL—conditions notoriously difficult to treat with very poor prognoses—the reported objective response rate of 81.8% and complete response rate of 54.5% are undeniably encouraging. Achieving minimal residual disease-negativity in all responders further underscores the potent anti-tumor activity of this novel CAR-T construct. This level of efficacy in T-cell malignancies, where CAR-T development has historically faced unique challenges like T-cell fratricide and aplasia, suggests a significant step forward in addressing a high unmet medical need.

However, the enthusiasm is tempered by a stark safety signal: a staggering 90.9% of patients experienced Grade 3 or higher infections, leading to seven infection-related deaths. While cytokine release syndrome was manageable, this severe infection burden is a critical concern. It highlights the delicate balance between potent anti-tumor activity and systemic toxicity inherent in CAR-T therapies. The median overall survival of 3.6 months, despite the high initial response rates, further emphasizes that the durability of response or the impact of these severe toxicities may be undermining long-term patient benefit. Future development must strategically prioritize robust infection prophylaxis, refined patient selection, and potentially modifications to the CAR-T construct or lymphodepletion regimens to mitigate these life-threatening adverse events. The ability to improve this safety profile will be paramount in determining whether SL105 can translate its impressive initial efficacy into a viable, life-extending therapy for these aggressive T-cell cancers.