ASCO 2020-AUTOANTIBODIES AS PREDICTIVE FACTOR IN MELANOMA TREATMENT

There is a diverse and broad autoantibody response to tumor and autoimmune disease antigens in melanoma treated with checkpoint inhibitors (CPIs). Results from a recent study presented during the ASCO20 Virtual Scientific Meeting show that some of those autoantibodies correlate to clinical outcomes and immune-related adverse events (irAEs; Abstract 10011).

Jessica C. Hassel, MD, of University Hospital in Heidelberg, Germany, said that a better characterization of the B-cell antibody repertoire “has potential” to provide biomarkers for predicting irAEs as well as clinical responses in metastasized melanoma.

Dr. Caroline Robert

For this discovery study, investigators assessed more than 300 pretreatment samples from patients with metastasized melanoma who received CPI therapy at five different European centers. The study investigators designed a cancer immunotherapy antigen array comprising 832 autoimmune and tumor antigens as well as immune and cancer pathway proteins. Statistical tests were performed separately for patients treated with ipilimumab (30%), nivolumab (6%), pembrolizumab (45%), or combined ipilimumab and nivolumab (19%). Progression-free and overall survival durations were measured from treatment initiation to tumor progression or death date, and the irAEs were recorded along with onset date and grade. Overall, 31% of patients had any-grade irAEs, and 14% had grade 3 or higher irAEs.

Study Results

“Using a feature-ranking approach, [in which] the most significant markers in different statistical tests are chosen, we found a set of 47 different antigens that could predict irAEs and, in some, the response,” Dr. Hassel said.

Anti-MIF antibodies were associated with disease progression and a lower risk of irAEs with pembrolizumab, she said. For patients treated with ipilimumab, anti-FGFR1 antibodies were associated with progressive disease, shorter survival (HR 1.27 vs. HR 1.95 when evaluating ipilimumab alone or with nivolumab, respectively; p = 0.008), and a lower rate of irAEs (HR 0.69; p = 0.04).

For MAGEB4 antibodies, the group found the opposite with ipilimumab treatment. Patients with high levels of pretreatment MAGEB4 autoantibodies experienced better survival (HR 0.77; p = 0.002) and higher rates of irAEs (HR 1.79) with ipilimumab.

“We found that autoantibodies against microphthalmia-associated transcription factor were correlated with a higher risk to develop colitis. If these autoantibodies are just bystanders or have a functional role in developing this immune-related adverse event is still not clear,” Dr. Hassel said. Patients with anti–gastrin-releasing peptide antibodies do not develop colitis.

“We found that autoantibodies against microphthalmia-associated transcription factor were correlated with a higher risk to develop colitis. If these autoantibodies are just bystanders or have a functional role in developing this immune-related adverse event is still not clear.” - Jessica C. Hassel

“Interestingly, we didn't find autoantibodies that you usually find in autoimmune diseases—for example, the typical thyroid antibodies or antinuclear antibodies,” Dr. Hassel said. “A diverse and broad autoantibody response to tumor and autoimmune disease antigens exists in the baseline samples. Further research is needed to clarify if these autoantibodies are just bystanders or [are] functionally linked to clinical outcome or irAEs.”

Findings Unlikely to Change Clinical Course

Discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Sud University, France, said it is logical to believe that, if there is a pre-existing autoantibody and the immune system is activated, “we might induce an increase level of this autoantibody, and it might create some damage.”

She commended Dr. Hassel’s group for the large number of patients and panels of autoantibodies evaluated, but noted further investigation is needed.

“We have to challenge the specificity and whether these are specific for CPIs or could we find that with other treatments,” Dr. Robert said. “And what about other cancer types?”

In summary, Dr. Robert recommends testing for autoantibodies before initiating CPI therapy but noted that “this might not influence our therapeutic choices in the metastatic setting but could have an impact in the adjuvant setting.”

— Michelle Dalton, ELS