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T Cell Repertoire Emerging as Potential Predictor in Neoadjuvant Lung Cancer Immunotherapy

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NEW YORK – Anticipating future approvals for neoadjuvant chemoimmunotherapy in early-stage lung cancer, a team of Spanish investigators has identified a promising biomarker signature based on genomic analysis of the T cell receptor repertoire, which outperformed existing predictors like tumor mutational burden and PD-L1.

The group published their findings in Clinical Cancer Research last month and are now hoping to validate them in a larger patient cohort with longer follow-up and survival data, which could support clinical translation.

Using T-cell receptor sequencing on samples from 40 non-small cell lung cancer patients in the Phase II NADIM trial, the team identified two biomarker signatures — a domination of the TCR repertoire by the top 1 percent of clones, and overall TCR "evenness" — that predicted which patients would be free of disease when they received surgery.

"To identify these CPR patients is key, since achieving CPR is associated with improved survival," Alberto Cruz-Bermudez, a researcher at Puerta de Hierro Majadahonda University Hospital in Madrid and co-first author on the study, said in an email.

According to Bermudez, the success of immunotherapy in later-stage lung cancer has raised hopes that the same drugs can also impact patient outcomes when the disease is identified early. Positive data has been building for regimens, which combine platinum-based chemotherapy with anti-PD-L1 immunotherapy. In the Spanish team's case, this was nivolumab (Bristol Myers Squibb's Opdivo).

More recently, investigators were able to back this up in a Phase III study, Checkmate 816, reporting at this year's annual meeting of the American Association for Cancer Research that they saw an added value of chemoimmunotherapy over chemo alone in terms of complete pathological response.

When survival outcomes from that trial are released in coming months, they could support the first regulatory approvals for this strategy, said Bermudez.

However, oncologists have cautioned that predictive biomarkers — to identify responsive patients and save unresponsive individuals from unnecessary therapy — will be crucial in this space. A commentary by a team from Australia published in the Journal of Immunotherapy of Cancer this June, for example, highlighted the importance of precision strategies, "choosing the right drugs, for the right patient, at the right time," in this emerging neoadjuvant context.

"Despite the efficacy of immunotherapy, not all patients respond favorably to it. Knowing a priori whether the patient will benefit or not … can advance the application of precision medicine. In this case, the patient is given the treatment that is likely to give the best result, avoiding unnecessary toxicities, improving the prognosis of patients, and allowing the search for other therapeutic alternatives," Bermudez said.

In their study, he and colleagues hoped to build on prior research into the connection between T-cell receptors and immunotherapy response.

"PD-L1 levels and TMB are the main biomarkers investigated in the neoadjuvant immunotherapy trials scenario," Bermudez said. But because the TCR repertoire offers a more direct view of the mechanisms whereby the adaptive immune system responds to immunotherapy and recognizes tumor antigens, investigators have hypothesized that it could provide a route to more precise predictive biomarkers.

Using Thermo Fisher Scientific's Oncomine TCR-B sequencing technology, the group analyzed TCR clonality in peripheral blood and tissue samples from 40 NSCLC patients, taken both before and after neoadjuvant chemoimmunotherapy in the NADIM clinical trial.

When they compared TCR profiles from patients who achieved pathologic complete response to those who didn't, there was a clear definition between the two groups in terms of the "evenness" or balance of the TCR between different clones.

The researchers thought that this relative uneven TCR status in better-responding patients might be because of a small number of clones dominating the total repertoire, and indeed, when they looked at the most frequency ranked clones, the top 1 percent occupied higher clonal space in complete responders than non-complete responders.

Both biomarkers — TCR evenness and top 1 percent clonal dominance — were better response predictors in the cohort than PD-L1 and TMB.

Bermudez reiterated that the team does not believe their data so far are enough to support development of a companion diagnostic strategy. But the group is working to build the type of replication study that could cement a TCR-based strategy in the clinic.

With an established response biomarker, patients could be identified up front who might be better served by chemotherapy and close monitoring, avoiding the side effects and toxicity of immunotherapy to which they are unlikely to respond.

And in the future, Bermudez said, the field could begin to study whether individuals predicted to have complete responses would need surgery at all.

"Surgery is currently considered key to cure these patients [but] the possibility of identifying these patients a priori with good sensitivity and specificity through TCR analysis opens the possibility of trials to test the usefulness of surgery in these patients," he said.

He added that TCR analysis is relatively technically robust and doesn't face significant roadblocks in terms of affordability or turnaround time. He noted, however, that considering the challenges faced by other predictors that deal with continuous variables, like TMB and PD-L1, it will be necessary to define precise thresholds for prediction and proactively seek standardization across sequencing platforms and technologies.

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