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 in Nature Cancer, the new approach combined the benefits of antibody-drug conjugates (ADCs) with those of immunotherapies.
Background
ADCs have emerged as an important therapy 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 and eradicate them.
According to researchers in the current study, the ATC differs in that it is not designed to eradicate the cancer cells directly. “Effective ADCs are designed to destroy tumor cells, but they often do so incompletely, leading to resistance and recurrence,” researchers noted. “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, and the antibody in this ATC targets CD47. But instead of delivering a chemotherapy payload, it delivers a bacterial toxin.
Study Design
The CD47 antibody binds to cancer cells, signaling the body’s immune cells. The toxin is released, 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 cells better recognize and mount their 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,” researchers 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 effective at triggering an antitumor immune response. This allowed immune cells to eliminate tumors throughout the body.
Future Potential
The T cells created by this process also remained after 2 months, suggesting a memory effect to this approach that could potentially prevent tumor recurrence. This method also has potential 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 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 researchers. Investigators are aiming to have these ATCs ready for clinical testing in 3 to 5 years.
Wen Jiang, MD, PhD, Associate Professor of Radiation Oncology at MD Anderson Cancer Center is the corresponding author of this study.
Disclosure: 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 ASCO Young Investigator Award (2024YIA-0832385427). For full disclosures of all study authors, visit Nature Cancer.
