New Hope for Tough Kidney Cancer: Reinventing Antibody Therapies

The Wistar Institute

PHILADELPHIA, PA — Advanced clear cell renal cell carcinoma (ccRCC) is a formidable form of kidney cancer, causing an alarming mortality rate as even recent immunotherapies leave survival chances in the single-digit percentages. However, groundbreaking work by scientists at The Wistar Institute could change this landscape dramatically.

Bispecific T cell engagers (BTEs), types of antibody therapies, have displayed success in treating certain blood cancers, although their application in solid tumors like ccRCC has proven challenging. The issue lies in their fleeting half-life, demanding rapid replacement. However, a refined version of these antibodies, aptly named Persistent Multivalent T Cell Engager (CA9-PMTE), promises prolonged treatment effectiveness in pre-clinical trials.

A breakthrough in this study was the successful delivery of this potent therapy using synthetic DNA. This technique permits direct therapeutic production within patients, a significant step towards a promising kidney cancer treatment.

Clear cell renal cell carcinoma is notorious for its camouflage, masking itself from immune cells, thus remaining undetected by the killer T-cells responsible for eradicating cancers. This muddles the application of immunotherapies that boost the killing potency of T cells without aiding their ability to identify their targets.

The latest iteration of bispecific T cell engagers might overcome this obstacle. These molecules operate as a ‘double-sided tape’, with one end adhering to the T-cell and the other engineered to bind to the specific tumor cells. This augmentation allows T-cells to attack and kill the elusive cancer.

BTEs, although promising, aren’t without their drawbacks, the primary one being their short half-life, which significantly limits their functioning duration.

In their preclinical experiments, the Wistar team trialed novel anti-ccRCC BTE variants, designed to foster interactions between T cells and the targeted cancer, and delivered through synthetic DNA technology, a method enabling the body to construct the required drug design from DNA-based instructions. Initial results showed that while the updated design reduced overall anticancer potency, the new iteration – a Persistent Multivalent T Cell Engager – demonstrated high potency and an extended half-life.

David Weiner, Ph.D., the executive vice president of The Wistar Institute, lauds this new format as a potentially vital tool for cancer therapy. “Bispecifics in general are an important technology that offer significant advantages in on-target anticancer potency,” he says. “The new PMTEs appear not only more effective at binding to tumor cells and killing the cancer, but they also require a much lower dose and, we have reason to believe, a lower frequency of therapy — which could potentially translate to improved outcomes and a better patient experience at a lower cost.”

The research team is currently exploring these new PMTEs in combination with other immunotherapies and expanding their designs to address other challenging cancers.

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