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A novel, ultra-sensitive circulating tumor DNA (ctDNA) assay differentiated patients with metastatic kidney cancer who achieved a complete response versus partial response to immunotherapy; it also identified those at risk for disease progression.

In a small pilot study published in Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center in Duarte, California, and colleagues analyzed ctDNA of 12 patients with the group's novel TARgeted DIgital Sequencing (TARDIS) assay and found significantly lower average variant allele fractions in complete versus partial responders (0.007% vs 0.181%; P=0.014).

The researchers also found that patients with disease progression on subsequent imaging had significantly higher variant allele fractions compared with those who maintained their response to therapy (0.362% vs 0.033%, P=0.026).

"In this pilot study, TARDIS accurately differentiated partial response from complete response among patients with metastatic renal cell carcinoma receiving immunotherapy, and also prospectively identified patients at risk for subsequent progression," the team wrote.

In the following interview, first author Alexander Chehrazi-Raffle, MD, also of City of Hope, elaborated on the details.

What are the potential clinical applications of this research?

Chehrazi-Raffle: TARDIS is a personalized, ultra-sensitive ctDNA assay that offers heightened depth of sequencing to establish minimal residual disease, or MRD. We anticipate that TARDIS will ultimately help inform clinicians about when it is safe to withdraw therapy in patients, saving patients unnecessary toxicities from treatment as well as alleviating financial burdens to patients and healthcare systems.

How does TARDIS work, and what are its capabilities?

Chehrazi-Raffle: TARDIS was developed in the lab of Dr. Muhammed Murtaza in partnership with the Translational Genomics Research Institute (TGen). It offers an elevated depth of sequencing compared to competing ctDNA assays, primarily by employing linear pre-amplification to improve molecular conversion and fragment size/molecular tags to improve specificity.

As a result, TARDIS can effectively mitigate losses of input material and background errors encountered during ctDNA analysis.

How is TARDIS different from other available genetic assays, and how does it compare to them in depth of ctDNA detection?

Chehrazi-Raffle: A major challenge in kidney cancer has been achieving sufficient depth of sequencing because of its low mutational burden and low levels of tumor DNA shed into blood. Other personalized ctDNA assays such as Natera have struggled using whole exome sequencing to identify up to 16 clonal mutations. By leveraging up to 100 baseline mutations identified from whole genome sequencing, we achieved a sensitivity of 89% and a specificity of 100%.

What further research do you plan to follow up on this pilot study?

Chehrazi-Raffle: To build off of our pilot study, we have launched a follow-up study that applies TARDIS longitudinally over the course of a year to patients with solid tumors who are receiving immune checkpoint inhibitors. We hope to report out those findings in early 2024.

Is there anything else you would like to make sure oncologists understand about your research or this topic?

Chehrazi-Raffle: Circulating tumor DNA as a field is poised to raise the ceiling of cancer care. Although exploratory, our research indicates that TARDIS may be an efficacious platform for detecting molecular residual disease and relapse in metastatic renal cell carcinoma.

My hope is that TARDIS, along with other ctDNA assays in the MRD space, will more effectively guide clinicians in knowing when to withdraw or restart systemic therapy.

Read the study here.