CARsgen Therapeutics

Hong Ma

CAR-T therapy, chimeric antigen receptor T-cell therapy, has shown remarkable progress in treating hematological malignancies. The U.S. Food and Drug Administration (FDA) has approved CAR-T therapy for treating acute lymphoblastic leukemia, diffuse large B-cell lymphoma and multiple myeloma. However, implementing CAR-T therapy in solid tumors has been more challenging. Solid tumors have a more complex tumor immune microenvironment than liquid tumors, making it more difficult for the CAR-T cells to effectively penetrate the tumor and kill cancer cells without harming healthy cells. Researchers and clinicians are actively working to develop CAR-T therapies to treat solid tumors, such as glioblastoma, gastric, pancreatic, and lung cancers. Some approaches being investigated include using combination therapies, developing CAR-T cells with multiple targets, and engineering CAR-T cells to penetrate solid tumors better. Still, challenges limit its efficacy, such as the short persistence of the engineered T-cells and on-target off-tumor toxicities of CAR-T therapies.

The development of nanotechnology includes using precisely engineered nanoparticles that may enhance efficacy, improve pharmacokinetics, and reduce toxicity in cancer treatment. A few nanotechnology-based chemo drugs, including nab-paclitaxel and doxorubicin liposome, are already on the market. Nab-paclitaxel is a nanoparticle made from the protein albumin attached to the chemotherapy drug paclitaxel. It showed that nabpaclitaxel might change the tumor microenvironment by helping the other chemo drug gemcitabine to penetrate solid tumors to improve efficacy. Doxorubicin liposome is the chemotherapy drug doxorubicin wrapped inside a liposome, a fatty sac. The liposome-encapsulated doxorubicin has better cardiac safety and less myelosuppression, alopecia, nausea, and vomiting compared to doxorubicin alone while preserving the antitumor efficacy by optimizing biodistribution and pharmacokinetics of doxorubicin.

Like the improvement to chemo drugs, nanotechnology has the potential to address safety challenges and limited persistence and enhance the efficacy of CAR-T therapy in solid tumors. Different nanoparticle-based methods have been explored for CAR T cell therapy. Lipid nanoparticles (LNPs) are often used to deliver genetic material (mRNA) encoding CARs into T cells. LNPs are tiny particles of lipids (fats) that can encapsulate mRNA, protect it from degradation in the body, and help mRNA get into cells where it can be translated into protein. Polymeric nanoparticles can be utilized to encapsulate CAR T cells and improve their stability, circulation time, and targeting capabilities. These nanoparticles can be functionalized with targeting ligands to enhance CAR T cell specificity towards solid tumors. Additionally, gold nanoparticles have been investigated for their potential to improve CAR T cell therapy through photothermal therapy or drug delivery. By absorbing near-infrared light, gold nanoparticles can generate localized heat to kill cancer cells or serve as carriers for the targeted delivery of therapeutic agents to tumor sites.

The COVID-19 mRNA vaccines from Pfizer-BioNTech and Moderna were the first to be approved for human use. These vaccines use LNP technology to help the mRNA enter cells and produce the spike protein of the SARS-CoV-2 virus, which triggers an immune response. Following 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.