Researchers at The University of Texas MD Anderson Cancer Center have developed a novel antibody-toxin conjugate (ATC) designed to stimulate immune-mediated eradication of tumors. According to preclinical results published today in Nature Cancer, the new approach combined the benefits of more well-known antibody-drug conjugates (ADCs) with those of immunotherapies.
ADCs have emerged as a breakthrough in recent years due to their modular design, which enables precise delivery of therapies to tumors by targeting specific proteins expressed on cancer cells. These conjugates use their tumor-targeting ability to deliver a payload, usually a chemotherapy, directly to the cancer cells, resulting in their destruction.
According to corresponding author Wen Jiang, M.D., Ph.D., associate professor of Radiation Oncology, the ATC differs in that it's not designed to kill the cancer cells directly.
"Effective ADCs are designed to destroy tumor cells, but they often do so incompletely, leading to resistance and recurrence," Jiang said. "With this new ATC approach, we aim to trigger the body's natural immune response. This should not only limit side effects but also allow the immune system to attack tumors throughout the body and potentially prevent their recurrence."
Many solid tumors express the CD47 protein on their surface, which serves as a "don't eat me" signal to the body's immune system, allowing the tumor to evade detection. The antibody in this ATC targets CD47, but instead of delivering a chemotherapy payload to destroy the tumor, it delivers a bacterial toxin.
Simplified, the CD47 antibody binds to cancer cells, marking them to be eaten by the body's immune cells. Once the immune cells engulf the tumor, the toxin is released inside, becoming activated and creating pathways that allow tumor DNA and protein fragments, which are usually destroyed, to escape. These materials are then processed to help the immune cell better recognize and mount its own antitumor defense.
"This design was inspired by bacteria, which have an incredible ability to escape from cells' internal traps, multiply and spread, all while keeping the host cell alive and functional," Jiang said. "We're harnessing that same ability to shuttle intact tumor material to the right places within immune cells. Instead of being destroyed, the tumor material teaches the body to better recognize tumor cells."
In preclinical models of breast cancer and melanoma, this approach demonstrated multiple benefits. By educating the immune system to recognize unique signatures of cancer cells that distinguish them from normal tissues, the new ATC was more effective at triggering an antitumor immune response. This allowed immune cells to eliminate tumors throughout the body.
The T cells created by this process also remained after two months, suggesting a memory effect to this approach that could prevent tumor recurrence.
"We hope this new design opens up an entirely new avenue for research that expands the possibilities for ATCs," said first author Benjamin Schrank, M.D., Ph.D., resident physician in Radiation Oncology. "We want to train the immune system to recognize and respond to these tumors so it can continue fighting cancer even after the treatment is completed."
This method also has potential as to be combined with conventional therapies, especially with radiation therapy. Many solid tumors respond to radiation therapy by trying to shield themselves with proteins, including CD47. This upregulation of CD47 would make them even more susceptible to the ATC.
"This immune-stimulating ATC concept extends beyond CD47, and we are already developing projects that target other tumor-specific receptors to create ADCs that enable the body to target a wide range of difficult-to-treat cancers," said Betty Kim, M.D., Ph.D., professor of Neurosurgery and co-lead of the study. "Our goal is to have the first of these ready for clinical testing within the next three to five years."
This work was supported in part by the National Institutes of Health (R01NS117828, P30CA016672) and the American Cancer Society (RSG-22-052-01-IBCD, PF-24-1156745-01-ET), the Radiological Society of North America (RR1644), the SITC-Merck Cancer Immunotherapy Clinical Fellowship, and the American Society of Clinical Oncology Young Investigator Award (2024YIA-0832385427).
