Mechanism underlying the immune checkpoint inhibitor-induced hyper-progressive state of cancer

Abstract

Immune checkpoint inhibitors (ICIs) are gradually replacing chemotherapy as the cornerstone of the treatment of advanced malignant tumors because of their long-lasting and significant effect in different tumor types and greatly prolonging the survival time of patients. However, not all patients can respond to ICIs, and even rapid tumor growth after treatment with ICI has been observed in a number of clinical studies. This rapid progression phenomenon is called hyper-progressive disease (HPD). The occurrence of HPD is not uncommon. Past statistics show that the incidence of HPD is 4%-29% in different tumor types, and the progression-free survival and overall survival of patients with HPD are significantly shorter than those of the non-HPD progressor group. With the deepening of the study of HPD, we have established a preliminary understanding of HPD, but the diagnostic criteria of HPD are still not unified, and the addition of biomarkers may break this dilemma. In addition, quite a few immune cells have been found to be involved in the occurrence and development of HPD in the tumor microenvironment, indicating that the molecular mechanism of HPD may be triggered by a variety of ongoing events at the same time. In this review, we summarize past findings, including case reports, clinical trials, and fundamental research; compare the diagnostic criteria, incidence, and clinical prognostic indicators of HPD in different studies; and explore the molecular mechanism and future research direction of HPD.

Hyperprogressive Disease In a Metastatic Renal Cell Carcinoma Patient After Receiving Immune Checkpoint Inhibitors: A Case Report

“…It was called HPD and was described for the first time in a wall newspaper in 2016. Since then, more interest grew in the scientific community to establish a common ground for physicians to identify and diagnose HPD [5]. Several hypotheses are currently under investigation to find a plausible underlying mechanism of HPD; murine double minute 2/4 (MDM2/MDM4) amplification, epidermal growth factor receptor (EGFR) mutations, T cells, B cells, fragment crystallizable (Fc) receptor, and cluster of differentiation 4 (CD4+) regulatory T cells (Treg) are involved in the pathogenesis of HPD [12].…”

“…However, there are no current definitive diagnostic criteria for HPD. Patients who develop HPD have significantly lower overall survival outcomes in comparison with non-HPD patients [5].…”

Targeting T regulatory (Treg) cells in immunotherapy-resistant cancers

“…Studies of immunotherapy and other anti-cancer treatments were selected to determine whether T reg cells are potentially related to treatment outcomes, either as a negative or positive predictive marker [ 120 ] . For example, patients with hyperprogression during immunotherapy have elevated T reg cells, which is associated with treatment failure [ 121 , 122 ] . In such patients, T reg cells expand and copious amounts of immune suppressive cytokines (e.g., TGF-β1, IL-10) are secreted.…”

In vitro models as tools for screening treatment options of head and neck cancer

“…Unfortunately, not all immunotherapy agents deliver equal survival outcomes in similar clinical settings and there is a serious risk for immune-associated toxicities and hyper progression during therapy ( 17 , 18 ). Especially the last-mentioned risk of hyper progression indicates that inhibitor treatment is due to a combination of innate, adaptive or quickly acquired de novo resistances ( 19 , 20 ). This frustrating observation suggests that immunotherapy is not a “one-size-fits all” approach.…”