A team of Sloan recently published a study on the combination of CAR-T and PD-1 inhibitors in Natural Biotechnology. The authors invented a CAR-T that expresses mouse and human PD-L antibody fragments (single-chain variable region, scFv. mouse is RMP1-14, human E27), targeting two tumor antigens (CD19 for lymphoma) , MUC16 of ovarian cancer). The authors showed that this PD-1/CAR-T monotherapy was as effective or better than the CAR-T and PD-1 antibody combination in both homologous and heterologous mouse models. CAR-T can enrich and secrete PD-1 antibodies in tumor tissues because it expresses tumor antigens. The authors show that the secreted PD-1 antibody fragments not only protect these CAR-Ts, but also protect other T cells in tumor tissues, but basic Will not escape into the blood. However, CAR-T also has a longer life span and is more effective against TME immunosuppression because of PD-1 antibody protection.
CAR-T and PD-1 inhibitors are the two most important technological advances in the new drug industry over the past 10 years, but despite their enormous power, they do have their own shortcomings. CAR-T currently only lists two blood tumor products. Although solid tumors have occasionally been successfully reported, such as the brain tumor CAR-T against IL13R in the previous year, there is no large-scale effective solid tumor CAR-T therapy. One major cause is the immunosuppressive environment of tumor TME, which also has cytokine-mediated immunosuppression such as PD-L1 in addition to immunosuppressive cells such as TAM and Treg. Although PD-1 antibody has a wide range of indications, most tumor response rates are around 20%. An important factor is the lack of tumor-specific T cells in tumor TME. CAR-T needs to fight immunosuppression in TME, and PD-1 needs to have enough tumor-specific T cells in TME. This technique solves the main problems faced by these two therapies with one stone and two birds.
Depending on the angle of observation, this technique can be seen as a CAR-T with a PD-1 antibody as a bodyguard or a PD-1 antibody with a targeted delivery of a CAR-T transporter. The CAR-T expressing PD-1 antibody is more potent in in vitro and tumor cell co-culture experiments, and the secreted antibody fragment can bind to T cells that bypass PD-L1 expression. Compared with PD-1 antibody and CAR-T in vivo, this CAR-T expressing PD-1 antibody fragment showed greater survival advantage in different tumor models, even if the combination ratio of the two was at least equivalent. Some models show advantages. These CAR-T secreted PD-1 antibody fragments also protect bystander T cells in in vivo experiments. Although the secreted PD-1 antibody can move inside tumor tissues and bind to PD-1 on the surface of T cells other than CAR-T, the authors found that few antibody fragments entered the blood circulation by fluorescent label detection technology, so they were administered systemically. The PD-1 antibody is less toxic than the systemic system.
Although the binding strength (nM level) of these antibody fragments was determined, but the drug concentration of the PD-1 antibody fragment secreted by the effective concentration of CAR-T in the tumor tissue was not published, PK/PD was somewhat questionable. However, mice injected with CAR-T also had a killing effect on another incompatible dark tumor (B16F10), indicating that the secreted PD-1 antibody fragment did reach therapeutic concentrations. In addition, no antibody fragment detected in the blood is related to the stability of the antibody fragment because its half-life has not been published. The article concludes that this technique can be used on other immunotherapies such as LAG-3, TIM-3, CTLA-4, which does not know whether it will affect future patent applications, no matter who develops these technologies. It used to happen because some people owe that a certain structural transformation can obviously improve the activity. As a result, some people took this sentence as evidence to say that the invention lacks creativity.
The results of these studies, if replicated in the human body, will be an important advance. Targeted delivery of anticancer drugs, although a popular area of research, can indeed show very limited delivery systems that are enriched in tumor tissue. I have always thought that even if the drug is actually delivered to the tumor tissue, it will escape to the periphery, but today this study shows that this escape is at least not significant for the PD-1 antibody fragment. The entry of CAR-T into solid tumors is also a major problem with detoxification toxicity, but it is also a significant advancement if decompression inhibition can make some solid tumors suitable for CAR-T treatment. This design makes the two important technologies of PD-1 and CAR-T complement each other and warm up the group. Even if only part of it can be repeated in the clinic, it is a good technology.
