A groundbreaking clinical trial combining two CAR-T cell therapies has demonstrated remarkable survival benefits for patients with refractory or relapsed gliomas, achieving a median overall survival of 24.5 months compared to the typical 5-7 months reported in similar patient populations.
The study, conducted at Clifford Hospital in Guangdong from January 2020 to October 2021, enrolled six patients with grade IV gliomas who received dual-targeted fourth-generation CAR-T therapy combining PSMA and GD2 CAR-T cells. All patients demonstrated high expression levels of both target antigens, with median copy numbers of 1.36 × 10⁸ and 1.32 × 10⁸ for GD2 and PSMA, respectively.
Clinical Outcomes Exceed Expectations
The trial achieved an impressive 50% complete response rate, with all six patients experiencing clinical benefit defined as either complete response or stable disease. Two patients achieved complete response within four weeks of infusion, while a third patient attained complete response four months post-infusion. The remaining three patients exhibited stable disease lasting 1, 5, and 9 months respectively.
As of the August 2024 data cutoff, the median progression-free survival reached 9 months (range 1-56 months), with all patients surviving more than 13 months post-infusion. Notably, patients achieving complete response demonstrated significantly prolonged survival, with a median progression-free survival of 28 months and median overall survival of 32 months.
Safety Profile Remains Manageable
The dual-target approach demonstrated acceptable safety, with three of six patients (50%) developing grade 1 cytokine release syndrome after initial infusion, none requiring tocilizumab intervention. Hematologic toxicities occurred in five patients (83%), with four experiencing grade 2 or higher thrombocytopenia and three developing grade 2 or higher neutropenia.
Three patients developed infections associated with bone marrow suppression, all responding to appropriate antibiotic therapy. Importantly, no central nervous system toxicity, including neurotoxic effects or encephalopathy, was observed in any patient.
Tumor Burden Emerges as Critical Factor
The study revealed a strong negative correlation between tumor burden and treatment efficacy. Patients with lower tumor burden (< 3 cm) achieved superior outcomes, with 100% two-year overall survival compared to zero survival beyond two years for patients with higher tumor burdens. This finding underscores the importance of early intervention and tumor control in optimizing CAR-T therapy effectiveness.
Mathematical Modeling Provides Treatment Insights
Complementary mathematical modeling studies explored optimal dosing strategies for CAR-T therapy in glioblastoma. The research, analyzing three different CAR-T approaches targeting IL13Rα2, HER2/CMV, and EGFRvIII, revealed counterintuitive findings about dosing optimization.
For intravenous administration protocols, modeling suggested that lower doses administered at longer intervals may achieve superior outcomes compared to higher doses given more frequently. Specifically, simulations showed that 7.23 × 10⁷ CAR-T cells administered every 15 weeks achieved a time to progression of 2,140 days, outperforming higher doses at shorter intervals.
The modeling revealed that excessive tumor suppression from high doses can paradoxically weaken immune responses by depleting CAR-T cells, as their proliferation depends on tumor cell presence. Smaller doses maintained tumor cells at levels sufficient to sustain immune system activity while controlling disease progression.
Dual-Target Strategy Addresses Resistance
The combination approach specifically targets two distinct antigens to prevent tumor escape mechanisms. PSMA, initially identified in prostate cancer, is expressed in approximately one-third of glioblastomas and correlates with higher malignancy. GD2, a ganglioside overexpressed in neuroblastomas, also shows expression in certain glioblastomas.
Previous single-target CAR-T approaches for gliomas yielded suboptimal survival outcomes with median progression-free survival of approximately 7 months. The dual-target strategy demonstrated extended progression-free survival and overall survival compared to historical single-target approaches from the same research platform.
Manufacturing and Treatment Protocol
The fourth-generation CAR-T cells incorporated CD28 transmembrane and cytoplasmic domains, 4-1BB intracellular TRAF binding domain, CD3ζ chain intracellular domain, and an inducible caspase 9 suicide gene. Manufacturing required 7 days from cell collection to infusion, with transduction efficiency ≥30% and viability rate ≥90%.
Patients received lymphodepletion pretreatment with fludarabine and cyclophosphamide over three consecutive days before CAR-T infusion. Dosages ranged from 1 to 5 million CAR-T cells per kilogram of body weight.
Future Directions
The research team is planning an expanded follow-up study with 44 patients to further investigate the efficacy and safety of combined PSMA and GD2 CAR-T therapy. The sample size calculation was based on the 9-month progression-free survival observed in the current study compared to 3-month progression-free survival in historical controls.
Long-term follow-up revealed persistent CAR-T cells in several patients, with GD2 CAR copies detected in one patient 407 days post-infusion and PSMA CAR-T copies identified in another patient 292 days after treatment, indicating sustained therapeutic potential.
These preliminary results suggest that dual-target CAR-T therapy represents a promising advancement for treating refractory or relapsed gliomas, with the potential to significantly improve patient outcomes in this challenging disease setting.
