Leif Ellisen, MD, PhD, Mass General Cancer Center, Boston, Massachusetts, talked about the importance of understanding mechanisms of resistance to antibody drug conjugates for breast cancer.

Dr Ellisen discusses the different mechanisms of resistance within a tumor: downregulating the target, changing the method of processing the drug, or exporting the payload from the cell.

Transcript:

Hi, I'm Dr. Leif Ellison. I'm the program director of Breast Medical Oncology at Mass General Cancer Center in Boston, and I'm here at San Antonio Breast 2022. Today I presented results and data in a session about resistance to antibody drug conjugates. Antibody drug conjugates are a very exciting new class of drugs for breast cancer. Earlier today, we heard a number of clinical trial results demonstrating the substantial benefits of antibody drug conjugates over standard chemotherapy in some breast cancer settings and benefits for newer generations of antibody drug conjugates compared to older generations of these drugs.

Nonetheless, these are quite complex drugs. We don't fully understand exactly how they work. And in particular, we have very little understanding of why patients may benefit for a period of time but then ultimately see progression of their cancer due to resistance to these antibody drug conjugates. The work in this area is really just beginning to look systematically in breast cancer at how this resistance to antibody drug conjugates occurs.

Work in other cancer areas on antibody drug conjugates has focused on really a couple of areas. But first, it's important to understand what antibody drug conjugates do. Antibody drug conjugates, as they are called, have an antibody, which is directed against a specific target on the surface of a tumor cell, and that target will bring the antibody to the tumor cell. That antibody is conjugated via something called a linker to what's called a cytotoxic payload, which is basically a tumor-killing molecule. When the antibody binds the surface of the tumor, it's typically internalized, and that payload is released to kill the tumor cell.You can imagine with that complex mechanism, there's lots of ways that the tumor might be able to evade that particular drug.

Some of the better-described ways that the tumor can evade or induce resistance are by down-regulating or shuttling off the cell surface the target, so the antibody can no longer bind. Another way the tumor cell can become resistant is by changing the way that it might process the antibody drug conjugate. The antibody drug conjugate has to be processed inside the cell, and if that processing mechanism, which involves fusion of something called a lysosome inside the cell, if that goes awry, the drug may not be processed in the cell, and that may induce resistance. And then finally, the payload, the really killing end of the antibody drug conjugate, can actually be exported from the cell as a way for the cell to essentially kick out that drug and become resistant.

Our group had done prior studies and showing one of the first mechanisms of resistance to a new promising and FDA-approved antibody drug conjugate called sacituzumab govitecan. Sacituzumab govitecan is used and approved for triple-negative breast cancer and has dramatically increased overall survival in that setting, but many patients do become resistant. And what we showed was that in one particular patient who had a very dramatic response but became resistant, parts of the tumor became resistant by mutating the target of the antibody drug conjugate, shuttling it off the cell surface. And parts of the tumor became resistant by mutating the cytotoxic payload target itself within the cell. This allowed us to understand the mechanisms of resistance but was also very sobering because it told us that within the same patient within the same patient's metastatic tumor, different metastatic lesions might develop different resistance mechanisms.

The bottom line, though, is that as we begin to understand and systematically discover these resistance mechanisms, we can find new ways to overcome them, perhaps by combining the antibody drug conjugates with other drugs or by perhaps switching to a new antibody drug conjugate. It's critical to know, though, that in order to decide which antibody drug conjugate to use next, you really have to know about the mechanism of resistance to the first antibody drug conjugate that you used. That, in a nutshell, is a lot of what we know about resistance to these agents and a lot of the reasons why understanding the resistance the tumors develop is going to be so important in the coming years.

Source:

Ellisen L. “Antibody Drug Conjugates: Future Directions and Opportunities — Mechanisms of resistance.” Presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, Texas.