*4.3. Immunotherapy*

Immunotherapy is inducing a deep change in anticancer therapy, regulating immune cells attack against neoplastic cells. Interestingly, many reports showed that ATC presents higher PD-L1<sup>+</sup> cells compared to DTC, proposing PD/PD-L1 pathway as targetable [101,143], and, as shown above, preclinical data produced interesting result in mouse model [108]. Accordingly, PD-1 antibodies (e.g., pembrolizumab and spartalizumab), after promising data about their use in BRAF-mutated melanoma [144], have been used as single agents in patients affected by ATC [145].

Pembrolizumab induced a durable response (16 months) in one patient with unresectable ATC: after its second cycle the patient referred a significant improvement of dysphagia and after 3 cycle a complete response was almost reached [146]. However, after a severe toxicity related to pembrolizumab (grade 4 colitis), it was suspended and the patient died 8 months later, after the appearance of cerebral metastasis [146]. On the other hand, it seemed to do not produce the same result when co-administrated with chemoradiotherapy. Chintakuntlawar et al. treated 3 patients with pembrolizumab and chemoradiotherapy, but, in spite of a prompt an early tumor response, all patients passed away <6 months [147].

Spartalizumab toxicity and efficacy were evaluated in a phase I/II trial enrolling 42 patients with locally advanced and/or metastatic anaplastic thyroid carcinoma [148]. The overall response rate was 19% in the whole cohort, while it was higher in patients defined as PD-L1–positive (29%), and even better in the subset of patients with PD-L1 expression > 50% (35%). In this last subset of patients, the 1-year survival rate reached 52.1% [148]. About toxicity profile, the most frequent adverse events were diarrhea, pruritus, fatigue, and pyrexia and grade ≥ III adverse events related to treatment were observed in 10% of patients [148].
