Antibody designed to fight immunotherapy-resistant cancers

DALLAS – Feb. 14, 2025 – An investigational therapy significantly shrank lung cancer tumors that are notoriously resistant to treatment by encouraging an attack from natural killer (NK) cells in an animal model, a study led by UT Southwestern Medical Center researchers shows. The findings, published in the Journal for ImmunoTherapy of Cancer, could lead to new types of immunotherapy that rely on this novel strategy.

“The approach we studied here could eventually become a viable therapy for patients whose tumors are not responsive to current immunotherapies,” said study leader Esra Akbay, Ph.D., Assistant Professor of Pathology and a member of the Development and Cancer Research Program in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Immune checkpoint inhibitors (ICIs), a class of anticancer therapies first approved by the Food and Drug Administration in 2011, work by suppressing mechanisms that cancer cells use to inhibit the activity of T cells and thus avoid immune surveillance. By doing so, these drugs enable a patient’s own T cells to fight the cancer. ICIs have revolutionized treatment for many cancers, including non-small cell lung cancer (NSCLC), the most common type of lung cancer.

However, some cancers don’t respond to ICIs, Dr. Akbay explained. These include NSCLC tumors that carry mutations in both the KRAS and LKB1 genes. Patients with this type of cancer, known as KL mutant NSCLC, have limited treatment options if their tumors don’t respond to ICIs.

Searching for a different way to treat these tumors, Dr. Akbay and her colleagues studied NK cells, a type of white blood cell that also fights cancer. Proteins called MICA and MICB, produced on the surface of cells in NSCLC and many other cancer types, can activate NK cells and turn them into cancer killers. KL mutant tumors are especially heavy producers of these proteins. However, cancer cells also shed MICA and MICB into the area surrounding the tumor and the bloodstream. Not only does this shedding reduce the amount of MICA and MICB on cell surfaces available to activate NK cells, Dr. Akbay said, but the proteins that have been shed inactivate NK cells.

To resolve this, she and her colleagues in the Akbay Lab collaborated with Aakha Biologics, a company that makes drugs based on antibodies. These antibodies bind both to antigens (molecules recognized by the immune system) and immune cells. The team designed an antibody, named AHA-1031, that on one side binds to MICA and MICB to prevent them from shedding, and on the other side binds to NK cells to stimulate a phenomenon known as antibody-dependent cellular cytotoxicity (ADCC), which prompts immune cells to kill cancer cells.

Experiments on NSCLC cells growing in petri dishes showed that AHA-1031 bound strongly to MICA and MICB, stabilizing these proteins on the cancer cell surfaces and preventing their shedding. When the researchers introduced NK cells into the cell cultures, results showed that AHA-1031 bound to the surface of cancer cells, causing ADCC. These findings held true for other tumor types that produce MICA and MICB, including pancreatic, colon, ovarian, and prostate cancer cells.

Growth of human NSCLC tumors in mice, even those with KL mutations, was significantly inhibited or prevented with AHA-1031 treatment. This antibody therapy also prevented development of lung metastasis in a mouse model of melanoma.

Together, Dr. Akbay said, these findings suggest that AHA-1031 could have potential as a new type of cancer immunotherapy. If these findings are confirmed in future studies, she added, this antibody therapy could eventually be tested in clinical trials.

Other UTSW researchers who contributed to the study include first author Ryan R. Kowash, Ph.D., graduate student researcher; John D. Minna, M.D., Director of the Hamon Center for Therapeutic Oncology Research, Professor of Internal Medicine and Pharmacology, and co-Leader of the Experimental Therapeutics Research Program in the Simmons Cancer Center; David E. Gerber, M.D., Professor of Internal Medicine and Peter O’Donnell Jr. School of Public Health; Luc Girard, Ph.D., Associate Professor in the Hamon Center for Therapeutic Oncology Research and of Pharmacology; Qing Deng, Ph.D., postdoctoral researcher; and Nusrat U. A. Saleh, M.S., graduate student researcher. Drs. Gerber and Girard are also members of the Simmons Cancer Center.

This study was funded by a Cancer Prevention and Research Institute of Texas Scholar Award (RR160080), National Institutes of Health grants (R01CA276058 and 1R01CA289500), a National Comprehensive Cancer Network Foundation grant, National Cancer Institute training grant (5T32CA124334), National Cancer Institute Cancer Center Support Grant (P30CA142543), a Department of Defense grant (W81XWH-21-1-0856), and a Forbeck Foundation grant.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.