For a long time, cancer treatment was a double-edged sword – treatments designed to kill cancer cells were often also administered to healthy ones.
But a new study published online in October. 30 inches ImmunityA Cell Press journal, unveils an approach to cancer treatment that researchers describe as more specific, longer-lasting and less toxic than current therapies.
The work, led by Duke University School of Medicine immunology researcher Jose Ramon Conejo-Garcia, MD, PhD, centers on the innovative use of IgA antibodies to target and kill tumor-promoting molecules found deep within cancer cells, which has not existed for a long time. Treatment options include IgA antibody treatment.
This is a proof-of-concept study, but the results are very promising. We believe this treatment can be used to target a wide range of cancer mutations.”
Conejo-Garcia, a Duke Science and Technology Scholar in the Department of Integrative Immunobiology
Early experiments in mice with lung and colon cancer revealed significant reductions in tumor growth and minimal side effects.
The research focused on a specific type of antibody called dimeric IgA (DGA). Its special structure allows it to target specific mutations associated with PIGR, a protein expressed on the surface of virtually all epithelial cancer cells that contributes to cancer cell growth and survival.
One such mutation, KRAS G12D, is a known driver of the most malignant cancers. Research has revealed that DGA binds to rogue, mutated proteins that are then pushed out of the cell in a process called transcytosis, stopping tumor growth.
When tested in mice, the KRAS G12D-specific antibody was more effective in shrinking cancer tumors than current treatments in clinical trials. Small molecule treatments often struggle to reach specific cancer cells, have short half-lives and can cause side effects.
The researchers found similar results with another cancer mutation, IDH1 R132H, which was found deep in cancer cells.
Scientists have struggled to target the mutated KRAS protein, but new findings suggest that uniquely designed antibodies can reach these intracellular molecules.
According to the researchers, IgA antibodies have the potential to be used as a targeted therapy against stubborn mutations in common, aggressive cancers, particularly epithelial cancers such as ovarian, skin, colon, cervical, prostate, breast and lung cancers.
“It’s a new way to target tumor cells using an antibody that’s very specific for point mutations or molecules that are really tumor specific,” says Conejo-Garcia. “By neutralizing them and ensuring that these tumor-promoting molecules are expelled out of the cell, we can stop tumor growth.”
Throughout her career, Conejo-Garcia has researched ways to make our body’s immune system better at fighting certain cancers.
Conejo-Garcia worked on the current study with post-doctoral fellow Subir Biswas, PhD; Gunjan Mundal, PhD; and Carmen Maria Anandan, PhD, the study’s co-senior author, finalized the research while at the H. Lee Moffitt Cancer Center and Research Institute, and after she joined the Duke faculty in 2023.
The results offer a glimpse into future cancer treatments that are more tailored, reduce damage to healthy cells, and improve patients’ quality of life.
IgA antibodies are just one part of the innovative field of immunotherapy. Treatments such as PD-1 inhibitors and CAR T-cells have shown unprecedented durable cancer remission.
“The immune system is the only system in the body that has two key properties that make it ideal for cancer treatment: specificity and memory,” said Conejo-Garcia, a member of the Duke Cancer Institute. The immune system can specifically target tumor cells and remember those cells to mount a more effective attack if the cancer returns.
Researchers are refining the antibody to make it easier to produce and administer to patients, with the goal of eventually testing it in clinical trials.
Biswas, S., etc (2023) Targeting intracellular proteins carrying oncogenic mutations with dimeric IgA promotes efflux from the cytoplasm and immune-mediated control of epithelial cancer. Immunity. doi.org/10.1016/j.immuni.2023.09.013.