Peripheral Biomarker of Response to Immunotherapy Emerges

Carl Morrison, MD, DVM

Carl Morrison, MD, DVM

T cell receptor beta (TCRB) repertoire sequencing can create artifacts that may resemble TCR convergence and provide an idea of response to immunotherapy. However, these tests can also populate with many false negatives, which has led researchers to believe the Ion Torrent is a better form of technology for predicting response to immunotherapy.

With the Ion Torrent-based approach, the number of antigens that are detected may be less than that of the TCRB, but these are better predictors of response because they are more reliable and less likely to be false positives.

In a recent study, investigators evaluated the Ion Torrent approach to predict outcomes in patients receiving immune checkpoint inhibition as a treatment for cancer. The study demonstrated this approach was able to predict response with clonality and convergence independently and that it could also be combined to improve the accuracy of prediction.

“There is a lot more work to do, but there is an opportunity here that looks promising. This is the first study, and we need to get more people working on this process,” said Carl Morrison, MD, DVM.

In an interview withTargeted Oncology, Morrison, senior vice president Roswell Park Comprehensive Cancer Center, discussed the rationale for evaluating the Ion Torrent-based approach to predicting response to immunotherapy. He highlighted the importance of this in the clinical setting and advances are necessary to further validate this as a biomarker of response.

TARGETED ONCOLOGY: What was the rationale for the analysis?

Morrison:The rationale was to prove that this new technology does not have all the sequencing errors that you have with the older technology. The more ways you can identify specific antigens, the more likely it is that the antigen is a driver of an immune response. With the older technology, the many more ways you could identify an antigen were truly sequencing errors, so you ended with a lot of false positives that you thought were antigen targets for immunotherapy when they really weren’t, whereas Ion Torrent didn’t have the sequencing errors. Therefore, what they identified with convergence was at a much lower rate than the other technology. While it was a much lower rate, it was a true rate.

TARGETED ONCOLOGY: What were the findings from this analysis?

Morrison:Many things were done to prove that, but if you get far away from the fact that the take-home point was is if you want to evaluate convergence, which is likely to be a better marker of response to immunotherapy than any other aspect of TCR data, such as the number of clones, that unless you are using a technology you can rely on, you’re never going to get to having a translational research outcome that shows the benefit of sequencing TCR data.

TARGETED ONCOLOGY: From a clinical aspect, what is the importance of these findings?Morrison:There are 2 important findings. The first is that we can identify response to immunotherapy in a prospective fashion because you don’t need tumor to do this particular assay. You can use peripheral white blood cells. You can test a patient at any time in their continuum of treatment. If you understand immunotherapy as opposed to chemotherapy and targeted therapy, there is quite a bit of difference in terms of how you evaluate the response to treatment. With chemotherapy and targeted therapy, you get a relatively fast and readily recognizable response by doing CT scans or MRIs. With this type of therapy, the response is very prolonged and slow. Sometimes, it is 6 months into the treatment before you discover the patient is starting to respond. If you can accurately identify convergence and use that as a peripheral biomarker, you can test a patient every 6 weeks or every month when they are starting on immunotherapy to give an indication of whether or not they are responding.

The other aspect in terms of clinical care is we have numerous cellular therapies now that are indicated for specific antigens. You can take white blood cells out of someone and if you can identify the appropriate antigen they are responding to and amplify those T cells, that is why accurately identifying the antigens that the T cells are responding to using the concept of convergence is so important. It’s the second most important resource of immunotherapy.

TARGETED ONCOLOGY: Are there next steps that need to be taken?

Morrison: