Abstract:
Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies and is making significant strides in solid tumors. While highly effective in blood cancers, challenges such as limited persistence, immune suppression, lack of suitable targets, and tumor microenvironment barriers have restricted its success in solid tumors. The 2024 European Society for Medical Oncology (ESMO) Congress showcased novel advancements in CAR-T therapy, including cytokine modulation, innovative target selection, allogeneic CAR-T cells, mRNA vaccines, in vivo delivery, and conditional activation strategies. These breakthroughs are paving the way for more effective and safer CAR-T therapies.
Advancements in CAR-T Therapy for Hematologic Malignancies
1. ssCART-19: Enhanced Safety and Efficacy for B-cell Malignancies
A new iteration of CD19-targeted CAR-T therapy, ssCART-19, integrates shRNA technology to silence IL-6 expression, reducing cytokine release syndrome (CRS). In a Phase I clinical trial for relapsed/refractory acute lymphoblastic leukemia (ALL), ssCART-19 demonstrated an overall response rate (ORR) of 87.5% and a complete response (CR) rate of 62.5%. Notably, it showed efficacy in a patient with central nervous system involvement without inducing immune effector cell-associated neurotoxicity syndrome (ICANS).
2. NT-I7: Prolonged CAR-T Persistence with IL-7 Engineering
NT-I7, a long-acting IL-7 analog, enhances CAR-T cell expansion and persistence. A Phase Ib trial in diffuse large B-cell lymphoma (DLBCL) revealed an ORR of 81.1% and a CR rate of 63.6%. This approach offers a potential solution for maintaining long-term CAR-T activity in lymphoid malignancies.
3. Tisagenlecleucel for Follicular Lymphoma
Real-world data from the DESCAR-T registry in France confirmed the efficacy of tisagenlecleucel in 129 patients with relapsed/refractory follicular lymphoma. The therapy yielded an ORR of 98.2% and a CR rate of 85.8%, reinforcing its role as a transformative treatment option.
4. BCMA-Targeted CAR-T for Multiple Myeloma
Updated findings indicate that ciltacabtagene autoleucel (cilta-cel) significantly extends overall survival in multiple myeloma patients. Notably, elderly and non-transplant-eligible individuals exhibited the highest benefit, making this a viable approach for previously underserved populations.
Advancements in CAR-T Therapy for Solid Tumors
1. QH104: B7H3-Targeted Allogeneic CAR-γδT Cells for Glioblastoma
A Phase I trial evaluating QH104, an allogeneic CAR-γδT cell therapy targeting B7H3, demonstrated a 42.9% ORR and 100% disease control rate (DCR) in relapsed glioblastoma patients following intrathecal administration. Importantly, no cases of CRS, ICANS, or graft-versus-host disease (GVHD) were reported.
2. BRG01: Epstein-Barr Virus-Specific CAR-T Therapy for Nasopharyngeal Cancer
BRG01, a first-in-class CAR-T therapy targeting the Epstein-Barr virus gp350 protein, achieved a 75% tumor shrinkage rate and over six months of progression-free survival in advanced nasopharyngeal carcinoma, surpassing immune checkpoint inhibitors.
3. CLDN6 CAR-T + CARVac: mRNA Vaccine-Enhanced CAR-T for Solid Tumors
A Phase I trial combining CLDN6-targeted CAR-T cells with an mRNA vaccine (CARVac) showed a 38% ORR and 69% DCR, with response rates improving to 55% and 86% at higher doses. This approach enhances CAR-T cell durability and tumor infiltration.
4. MT-302: First In Vivo CAR-T Therapy Targeting TROP2
MT-302, a lipid nanoparticle-encapsulated mRNA therapy, enables direct in vivo programming of TROP2-targeted CAR-T cells. This method circumvents traditional ex vivo expansion, simplifying administration and broadening accessibility.
5. EU307: GPC3-Targeted Fourth-Generation CAR-T for Hepatocellular Carcinoma
EU307 incorporates IL-18 secretion to modulate the tumor microenvironment, enhancing anti-tumor activity. Early data suggest a significant improvement in CAR-T efficacy against hepatocellular carcinoma.
6. BTRP003L: Hypoxia-Sensitive CAR-T for Gastrointestinal Cancers
BTRP003L is engineered with hypoxia-responsive elements and a TGFβRII inhibitor, activating CAR-T cells selectively in the suppressive microenvironment of gastrointestinal tumors, thereby improving safety and efficacy.
Conclusion
The latest advancements in CAR-T cell therapy presented at ESMO 2024 underscore the rapid evolution of this treatment modality. Novel engineering approaches are addressing major challenges in both hematologic and solid tumors, offering promising solutions for long-term efficacy, tumor penetration, and safety. As these therapies move towards commercialization, they hold immense potential to redefine cancer treatment paradigms.
