Flare-up of rheumatoid arthritis by Anti-CTLA-4 antibody but not by Anti-PD1 therapy in a patient with metastatic melanoma

A 47-year-old female patient with rheumatoid arthritis (RA) treated with methotrexate, was diagnosed with metastatic melanoma. After surgical removal of the tumor, the patient started treatment with ipilimumab while methotrexate was stopped. One week after initiation of ipilimumab, the patient developed typical symptoms of RA. Analgetic therapy was started. After 4 cycles of ipilimumab, melanoma progression was radiologically evident. The treatment plan was changed to pembrolizumab (anti-PD1 antibody), and the patient did not show active signs of RA anymore. Despite treatment with pembrolizumab, the patient died 4 months later due to tumor progression. The exact mechanism by which ipilimumab (anti-CTLA-4 antibody) provoked RA symptoms is still not fully understood. This subject needs more investigation, especially in an era in which immunotherapies are a standard therapy for patients with malignancy

Peripheral blood TCR repertoire profiling may facilitate patient stratification for immunotherapy against melanoma

Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4, however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE50, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment liquid biopsies from melanoma patients treated with anti-CTLA4 (n = 42) or anti-PD1 (n = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA). A ROC curve determined the optimal threshold for a dichotomized analysis according to objective responses as defined by RECIST1.1. Correlations between treatment outcome, clinical variables, and DE50 were assessed in multivariate regression models and confirmed with Fisher exact tests. In samples obtained prior to treatment initiation, we showed that low DE50 values were predictive of a longer progression-free survival and good responses to PD-1 blockade, but on the other hand predicted a poor responses to CTLA4 inhibition. Multivariate logistic regression models identified DE50 as the only independent predictive factor for response to anti-CTLA4 therapy (P = 0.03) and anti-PD1 therapy (P = 0.001). Fisher exact tests confirmed the association of low DE50 with response in the anti-CTLA4 (P = 0.041) and the anti-PD1 cohort (P = 0.0016). Thus, the evaluation of basal TCR repertoire diversity in peripheral blood, using a PCR-based method, could help predict responses to anti-PD1 and anti-CTLA4 therapies