The potential mechanism, recognition and clinical significance of tumor pseudoprogression after immunotherapy

Abstract

As immunotherapy has gained increasing interest as a new foundation for cancer therapy, some atypical response patterns, such as pseudoprogression and hyperprogression, have garnered the attention of physicians. Pseudoprogression is a phenomenon in which an initial increase in tumor size is observed or new lesions appear, followed by a decrease in tumor burden; this phenomenon can benefit patients receiving immunotherapy but often leads to premature discontinuation of treatment owing to the false judgment of progression. Accurately recognizing pseudoprogression is also a challenge for physicians. Because of the extensive attention on pseudoprogression, significant progress has been made. Some new criteria for immunotherapy, such as irRC, iRECIST and imRECIST, were proposed to accurately evaluate the response to immunotherapy. Many new detection indexes, such as ctDNA and IL-8, have also been used to identify pseudoprogression. In this review, the definition, evaluation criteria, mechanism, monitoring, management and prognosis of pseudoprogression are summarized, and diagnostic and treatment processes for patients with progression but with a suspicion of pseudoprogression are proposed; these processes could be helpful for physicians in clinical practice and enhances the understanding of pseudoprogression.

Keywords: Cancer; IL-8; RECIST; ctDNA; immunotherapy; pseudoprogression.

1

The mechanism of pseudoprogression after immunotherapy. (A) T cells were inactivated by the PD-L1 and CTLA-4 presented by tumor cells or antigen-presenting cells (APCs). (B) T cells were reactivated after the administration of immune checkpoint inhibitors such as anti-PD-1/PD-L1/CTLA-4. (C) Activated T cells infiltrate tumor lesions and kill the tumor cell. (D) Antigens released by the death of tumor cells attract more infiltrating inflammatory cells. (E) Shrinking tumor tissues can cause vascular tears and hemorrhage in locoregional lesions. (F) The inflammatory response and hemorrhage cause the edema of lesions. (G) The necrotic byproducts of dead tumor cells cannot be absorbed immediately and accumulate in locoregional lesions. Inflammatory cell infiltration, hemorrhage, edema and necrosis enlarged the lesions in imageologic assessments and indicate pseudoprogression.

2

The diagnosis and treatment process for patients with progressive disease with suspicion of pseudoprogression.