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Advancements in CAR T-cell Immunotherapy
Immunotherapy, a treatment that uses someone’s own immune system to target and attack cancer cells is the next and best frontier of cancer treatment. CAR-T stands for Chimeric Antigen Receptor T-cell. It refers to a type of immunotherapy where T-cells are engineered to produce special receptors on their surface that help them target and kill cancer cells. Like all immunotherapy, CAR-T cell therapy harnesses the power of the immune system — in this case, by using and modifying the body’s T cells.
Therapy Overview
Blood is drawn from the patient to modify T cells for cancer treatment, and the T cells are then engineered in the lab. During this process, the T cells are genetically altered to express chimeric antigen receptors (CARs). These receptors confer two key functionalities: first, they enable the T cells to recognize specific tumor-associated antigens that they would otherwise not detect. Second, upon antigen recognition, CAR signaling activates the T cells' cytotoxic functions, directing them to eliminate the cancer cells. CAR-T cell therapy effectively arms the immune system with enhanced tumor-targeting and cytolytic capabilities, making it a potent strategy in oncological treatment.
CAR-T cell therapy has been an effective treatment for some forms of cancer — particularly for blood cancers and hard-to-treat or recurrent cancers. One study found that 18% of people with relapsing, treatment-unresponsive chronic lymphocytic leukemia (CLL) experienced full remission after a single CAR-T cell therapy treatment. Additionally, CAR-T cell therapy has the potential to keep cancer in remission for many years.
side effects
Like most cancer therapies, CAR-T cell therapy now comes with side effects. Side effects may include:
1. Cytokine release syndrome (CRS), is a severe immune system reaction that can lead to death.
2. Noticeable, but often temporary, neurological side effects such as confusion, seizures, and difficulty speaking or walking.
3. Temporary blood conditions like anemia and low platelet count.
An increased risk of infection, particularly after the first few weeks of treatment.
Scientists are working to develop next-generation methods that will reduce side effects, lower or even eliminate cancer recurrence, and better target treatment-resistant B-cell cancers. Critically, researchers also are focusing on expanding the scope of cancer targets to include a wider number of blood cancers, as well as solid tumors.
Here are some cutting-edge studies focused on improving CAR-T therapy's effectiveness and overcoming these challenges.
Improvement 1: Hydrogel Boosts CAR-T Solid Tumor Efficacy
An injectable hydrogel system with cationic polymer and α-cyclodextrin enhances CAR-T cell accumulation in solid tumors. This approach reprograms the tumor microenvironment, increasing cytokine secretion and improving intra-tumor CAR-T and cytotoxic T-cell infiltration. It represents a novel strategy for enhancing CAR-T efficacy against solid tumors.
Article name: Injectable Supramolecular Hydrogels for In Situ Programming of Car-T Cells toward Solid Tumor Immunotherapy
Authors: Chunyan Zhu, Lingjie Ke, Xiang Ao, et al.
Improvement 2: Rapid CD276 CAR-T for Pancreatic Cancer
CD276 CAR-T cells, including a rapid-manufacture variant (Dash CAR-T), are effective against pancreatic cancer. Dash CAR-T, produced in 48-72 hours, shows strong proliferation and anti-tumor effects in vitro and in vivo, offering a promising approach for quick, effective treatment.
Article name: Rapidly-manufactured CD276 CAR-T cells exhibit enhanced persistence and efficacy in pancreatic cancer
Authors: Tian Deng, Yingzhi Deng, Shih-Ting Tsao, Qinghui Xiong
Improvement 3: CRISPR Reveals CAR-T Resistance Mechanism
Genome-wide CRISPR-Cas9 screens identify IFNγR/JAK/STAT signaling as a key resistance pathway in B-cell leukemia. Loss of this pathway sensitizes leukemia cells to CAR-T therapy in vitro but induces resistance in vivo, involving NK cells, highlighting complex interactions in the tumor microenvironment.
Article name: Leukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening
Author: Azucena Ramos, Catherine E. Koch, Yunpeng Liu-Lupo
Improvement 4: CD38 Inhibition Reverses CAR-T Exhaustion
CD38 is linked to CAR-T cell exhaustion. Inhibiting CD38 improves CAR-T cell cytotoxicity and persistence by modulating related signaling pathways. This approach could enhance CAR-T therapy by preventing exhaustion and prolonging the effectiveness of the treatment.
Article name: Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism
Authors:Guimei Chen, Ling Lin, Ziyi Mai , Yan Tang, et al.
Improvement 5: P-T Cells Improve CAR-T Durability
Placental T (P-T) cells used in CAR-T therapy exhibit stemness advantages, including longer telomeres and resistance to immune checkpoint upregulation. P-T CAR-T cells provide prolonged lymphoma control compared to PBMC-derived CAR-T, offering a durable alternative for allogeneic CAR-T therapy.
Article name: Placental circulating T cells: a novel, allogeneic CAR-T cell platform with preserved T-cell stemness, more favorable cytokine profile, and durable efficacy compared to adult PBMC-derived CAR-T
Author: Natalia Ruggeri Barbaro, Theodore Drashansky
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