Researchers at Wistar have expanded on BTE technology to create upgraded synthetic DNA and recombinant versions of therapeutic antibodies that target CA9, known as Persistent Multivalent T Cell Engager (CA9-PMTE). This innovation has demonstrated potential in early-stage models as a strong and enduring treatment for ccRCC.Advanced clear cell renal cell carcinoma (ccRCC) is a deadly type of kidney cancer with limited treatment options. Even with new immunotherapies, only about 1 in 10 patients ultimately survive.
Antibody therapies known as bispecific T cell engagers (BTEs) have shown to be effective treatments for certain blood cancers, but have been challenging to develop for solid tumors. While first-generation BTEs have been clinically successful, they have a short half-life. Wistar scientists have now improved upon BTE technology by developing new recombinant and synthetic DNA versions of therapeutic antibodies that target CA9, known as.Persistent Multivalent T Cell Engager (CA9-PMTE) has shown potential in pre-clinical models as an effective and long-lasting treatment for ccRCC. The researchers also found that this powerful therapy could be administered using synthetic DNA, allowing for direct therapeutic production in patients. According to first author Ryan O’Connell, this may lead to a promising new therapy for kidney cancer that can be combined with checkpoint inhibitors, the current preferred treatment for this type of cancer.The research team at The Wistar Institute’s Vaccine & Immunotherapy Center has developed an enhanced bispecific antibody that is showing promising results in treating ccRCC. This improved antibody is surpassing the performance of traditional bispecific antibodies in both efficacy for treating ccRCC and in its ability to remain active in the body for a longer period of time, potentially reducing the need for additional treatment. The difficulty in treating clear cell renal cell carcinoma lies in its classification as a “cold” tumor, where cancer cells are not identifiable by the immune system. This means that killer T-cells, which normally seek out and destroy diseased cells and cancer, are unable to recognize the cancer cells.T cells are the immune system’s killer cells and are important in fighting cancer, but some tumors are able to evade T cells. This means that immunotherapies that enhance T cells’ killing power but don’t improve their ability to bind to their targets are not as effective against these types of tumors.
New bispecific T cell engagers work differently. They act like “double-sided tape” – one side of the drug molecule binds to the T-cell, while the other side is engineered to specifically bind to the type of tumor cell being treated. These molecules are “bispecific” because each end of the molecule is specific to one of two targets: the T cells and the cancer cells. This allows the T-cells to attack and kill the tumor cells.the cancer — even in cold tumors — through enhancing their ability to bind to the tumor.
However, BTEs show promise as a new therapy for many hard-to-treat cancers, but they do have limitations, including a short half-life (the time it takes for the active dose of a drug in the body to decrease by 50%). Most BTE drugs break down quickly, sometimes within hours, making them effective for only a short time.
In preclinical models, the team tested the effectiveness of newly designed anti-ccRCC BTE variants that were created to improve the interactions between T cells and the targeted cancer. These were dev rnrnThe study focused on using synthetic DNA technology for drug delivery, allowing the body to create the desired drug from DNA-based code. The researchers compared traditional BTEs with a newer format called persistent BTEs (PBTEs), which have a longer half-life but use the same targeting system as older BTEs. Although the initial PBTEs lasted longer than traditional BTEs, the new design reduced the overall anticancer potency. The research team then modified an existing PBTE by adding more binding domains to improve its effectiveness.The researchers developed a new type of cancer treatment that is known as a persistent multivalent T cell engager (PMTE). This design has proven to be very powerful and has a longer half-life compared to the traditional design. David Weiner, Ph.D., who is the senior author of the study and works at The Wistar Institute and director of the Vaccine & Immunotherapy Center, believes that this new format could be a valuable tool in improving cancer therapy. He mentioned that bispecifics, including the new PMTEs, have the potential to significantly enhance the effectiveness of anticancer treatment.The PMTEs not only effectively bind to tumor cells and eliminate cancer, but they also necessitate a lower dose and potentially a reduced frequency of treatment. This could potentially lead to better outcomes and a more positive patient experience at a lower cost. The researchers are currently investigating these new PMTEs in combination with other immunotherapies and expanding their applications to treat additional challenging cancers. Co-authors of the study include Ryan P. O’Connell and Daniel Park from The Perelman School of Medicine at the University of Pennsylvania and The Wistar Institute, as well as Kevin Liaw, Pratik S. Bhojnagarwala, Devivasha Bordoloi, Nicholas Shupin, and Da.Kulp, and David B. Weiner of The Wistar Institute; Nils Wellhausen of The Center for Cellular Immunotherapies at the Perelman School of Medicine; Carl H. June of The Center for Cellular Immunotherapies at the Perelman School of Medicine and The Parker Institute for Cancer Immunotherapy at The University of Pennsylvania; and Chris Chuckran of LUMICKS
Work was funded by: National Institutes of Health grants T32 CA11529915 and P30 CA010815; The Jill and Mark Fishman Foundation; the W.W. Smith Charitable Trust; and Inovio Pharmaceuticals.
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