Immunotherapy as a Promising Option for the Treatment of Advanced Chordoma: A Systemic Review

Abstract

Objective: To summarize the function and efficacy of immunotherapy as an adjunctive therapy in the treatment of advanced chordoma. Methods: Literature search was conducted by two reviewers independently. Case reports, case series and clinical trials of immunotherapy for chordoma were retrieved systematically from Pubmed, Web of Science, Scoupus and Cochrane Library. Clinical outcome data extracted from the literature included median progression-free survival (PFS), median overall survival (OS), clinical responses and adverse events (AEs). Results: All studies were published between 2015 and 2022. Twenty-two eligible studies were selected for systemic review. PD-1/PD-L1 immune checkpoint inhibitors (ICIs) were the most common used immunotherapy agents in chordoma, among which Pembrolizumab was the most frequently prescribed. CTLA-4 antibody was only used as combination therapy in chordoma. Dose Limiting Toxicity (DLT) was not observed in any vaccine targeting brachyury, and injection site response was the most frequent AV. The response evaluation criteria in solid tumors (RECIST) were the most generally used evaluation standard in chordoma immunotherapy, and none of the included studies employed the Choi criteria. Conclusions: No clinical data have demonstrated that CTLA-4 ICIs combined with PD-1/PD-L1 ICIs is more effective than ICIs monotherapy in treating chordoma, and ICIs in combination with other therapies exhibit more toxicity than monotherapy. PD-1/PD-L1 ICIs monotherapy is recommended as an immunotherapy in patients with advanced chordoma, which may even benefit PD-L1-negative patients. The brachyury vaccine has shown good safety in chordoma patients, and future clinical trials should focus on how to improve its therapeutic efficacy. The use of immunomodulatory agents is a promising therapeutic option, though additional clinical trials are required to evaluate their safety and effectiveness. RECIST does not seem to be an appropriate standard for assessing medications of intratumoral immunotherapy.

Chordoma cancer stem cell subpopulation characterization may guide targeted immunotherapy approaches to reduce disease recurrence

“…Current FDA approved PD-L1 inhibitors include avelumab, durvalumab, and atezolizumab for specific uses in advanced urothelial carcinoma, renal cell carcinoma, and non-small cell lung cancer (NSCLC), among others ( 46 ). Although pembrolizumab and nivolumab (PD-1 inhibitors) have been the more commonly studied immune checkpoint inhibitors in chordoma, durvalumab and FAZ053 (monoclonal antibodies with PD-L1 targets) were applied to limited chordoma treatment regimens with some clinical benefit ( 47 , 48 ). To date, few ongoing clinical trials for PD-1/PD-L1 inhibitors include chordoma patients (NCT02936102, NCT02834013, NCT03190174).…”

DNA methylation, combined with RNA sequencing, provide novel insight into molecular classification of chordomas and their microenvironment

“…Besides a potential prognostic value, the observed biological difference between two chordoma subtypes with potentially important clinical implications in terms of the therapy. Immunotherapy, that include the use of immune checkpoint inhibitors (ICI) is a promising therapeutic avenue in chordoma and number of clinical trials on this field has been already initiated [ 58 ]. Importantly, the level of tumor-infiltrating lymphocytes is generally one of most relevant indicators of response to this therapy [ 59 ].…”

Immune microenvironment and immunotherapy for chordoma

“…In contrast to the above encouraging results, a Phase II clinical study on PD-L1 monoclonal antibody combined with CTLA-4 monoclonal antibody for advanced or metastatic bone tumors showed that among the 5 chordoma patients included in the study, only 1 patient had obvious tumor shrinkage and achieved CR after receiving a full course of twelve cycles (53). Xiang et al conducted a systematic review of 22 chordoma cases involving progression from 2015 to 2022 and found that combination therapy with PD-1/PD-L1 antibodies and CTLA-4 monoclonal antibody was no more effective than monotherapy with PD-1/PD-L1 antibodies, but it was more toxic (54). However, due to the small number of cases and inconsistent drug regimens, the reliability of this result needed to be further verified.…”