JUNE 2023LIFE SCIENCES REVIEW 19Following the success of LNP in preventive mRNA vaccine, an LNP-based therapeutic mRNA vaccine to support CLDN6 CAR-T is also being explored for cancer treatment in a clinical trial. CLDN6 is a protein that is overexpressed in ovarian and lung cancers. CLDN6 CAR-T cell therapy involves engineering a patient's T cells to express a CAR specifically targeting CLDN6 on cancer cells. When infused back into the patient, the CAR-T cells recognize and attack cancer cells expressing CLDN6. To improve the efficacy and persistence of CLDN6 CAR-T cells, researchers have developed an mRNA vaccine that encodes CLDN6, which is delivered to the patient along with the CAR-T cells. Once the CLDN6 mRNA is inside cells, it is taken up by dendritic cells and expressed on their cell surface, leading to sustained activation of CAR-T cells, improved targeting, and killing of cancer cells. Recently, LNP has been used to develop in vivo CAR-T cell therapy in solid tumors. In traditional CAR-T cell therapy, a patient's T cells are collected and engineered to express a CAR that recognizes and attacks cancer cells. These engineered T cells are then expanded in the laboratory and infused back into the patient. However, this process can be time-consuming and expensive. In contrast, in vivo CAR-T cell therapy makes functional CAR-T cells inside the body, bypassing the need for cell extraction, engineering, and expansion. To make in vivo CAR-T cell therapy more effective, researchers have explored using LNP to deliver the mRNA encoding CAR in clinical trials targeting solid tumors such as mesothelioma, pancreatic, and breast cancers. Transient mRNA expression of CAR in vivo limited its toxicity profiles. It also offers other potential advantages, such as the ability to fine-tune the expression of the CAR and the potential for repeated dosing.Nanoparticles can be engineered to penetrate tumor tissues, and this property has been harnessed to enhance the efficacy of CAR-T cell therapy in solid tumors. CLDN18.2 is a protein overexpressed in gastric cancer. To improve the effectiveness of CLDN18.2 CAR-T cell therapy, researchers have explored the use of nanoparticles to enhance the activity of the CAR-T cells. For example, in a clinical trial for patients with advanced gastric cancer, CLDN18.2 CAR-T cells were combined with nab-paclitaxel. The study used nab-paclitaxel and traditional lymphodepletion as a conditioning regimen to enhance the CAR-T cell engraftment, followed by the infusion of CLDN18.2 CAR-T cells. The trial results showed that the combination therapy generated a 60% response rate and ten months of overall survival in heavily pretreated patients with gastric cancer, an encouraging outcome for this challenging type of cancer.Overall, the use of nanotechnology in CAR-T cell therapy is a promising approach for treating solid tumors, and ongoing research in this area may lead to new and more effective treatments. However, implementing nanotechnology in CAR-T therapy requires careful consideration of safety and regulatory issues. The toxicity and biodistribution of nanoparticles must be thoroughly evaluated, and regulatory agencies must ensure that the nanoparticles are safe for use in humans. Developing effective CAR-T therapies for solid tumors using nanotechnology remains an active area of research and an important goal for improving cancer treatment. The toxicity and biodistribution of nanoparticles must be thoroughly evaluated, and regulatory agencies must ensure that the nanoparticles are safe for use in humans
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