The biomarkers of hyperprogressive disease in PD-1/PD-L1 blockage therapy

Abstract

Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies (Abs) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) Abs, are effective for patients with various cancers. However, low response rates to ICI monotherapies and even hyperprogressive disease (HPD) have limited the clinical application of ICIs. HPD is a novel pattern of progression, with an unexpected and fast progression in tumor volume and rate, poor survival of patients and early fatality. Considering the limitations of ICI due to HPD incidence, valid biomarkers are urgently needed to predict the occurrence of HPD and the efficacy of ICI. Here, we reviewed and summarized the known biomarkers of HPD, including tumor cell biomarkers, tumor microenvironment biomarkers, laboratory biomarkers and clinical indicators, which provide a potential effective approach for selecting patients sensitive to ICI cancer treatments.

Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know

“…Overcoming these differences is necessary to facilitate the interpretation of data obtained from different clinical studies and to begin rigorous epidemiological analyses in this field and, not least, to identify possible predictive markers of HPD that, to date, are not available. The discovery of possible predictive markers follows two different paths: the study of the host or the tumor [ 32 , 33 ]. The former is focused on the patient’s general characteristics, such as age, gender, previous exposure to other therapies, or on the host immune system, such as the presence of a specific tumor-infiltrating or circulating immune cell population.…”

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

“…Furthermore, after receiving monotherapy with anti-PD1 or anti-PDL-1, some patients were found to develop rapid tumor progression, named as hyper-progressive disease (HPD). The tumor growth rate (TGR), which estimates the tumor volume expansion over time, is compared between the baseline imaging and the post- immune checkpoint inhibitor (ICI) treatment imaging, where HPD is described as the doubling of the tumor size (TGR ≥ 2) [ 130 , 131 ]. Multiple biomarkers have been associated with HPD.…”

“…It is hypothesized that PD-1/PD-L1 inhibitors induce the amplification of MDM2 through the JAK-STAT pathway (previously described). Therefore, a possible approach to overcoming HPD is combining MDM2 inhibitors with ICI [ 131 , 132 ]. Additionally, it could also be secondary to the proliferation of regulatory T-cells in the tumor micro-environment secondary to PD-1/PD-L1 blockade [ 134 ].…”

Is Weak Acid Beneficial for Addressing Checkpoint Inhibitor–Triggered Cancer Hyper Progression in Anti-PD1/PD-L1 Immunotherapies?

“…11 Several research groups have reported cases of checkpoint inhibitor-triggered cancer hyperprogression with rates ranging from 7% to 29% in various cancers, and potential mechanisms have been proposed. [12][13][14][15][16] A biochemical view can complement the biological perspectives. A hypothesis was previously postulated that cancer onset is triggered by the local buildup of hydrogen chloride, comediated by hydrogen bond donors and acceptors, and basic amino acids.…”

“…11 Several research groups have reported cases of checkpoint inhibitor–triggered cancer hyperprogression with rates ranging from 7% to 29% in various cancers, and potential mechanisms have been proposed. 12 - 16 …”