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

Abstract

Immune checkpoint inhibitors (ICIs) have made a breakthrough in the treatment of different types of tumors, leading to improvement in survival, even in patients with advanced cancers. Despite the good clinical results, a certain percentage of patients do not respond to this kind of immunotherapy. In addition, in a fraction of nonresponder patients, which can vary from 4 to 29% according to different studies, a paradoxical boost in tumor growth after ICI administration was observed: a completely unpredictable novel pattern of cancer progression defined as hyperprogressive disease. Since this clinical phenomenon has only been recently described, a universally accepted clinical definition is lacking, and major efforts have been made to uncover the biological bases underlying hyperprogressive disease. The lines of research pursued so far have focused their attention on the study of the immune tumor microenvironment or on the analysis of intrinsic genomic characteristics of cancer cells producing data that allowed us to formulate several hypotheses to explain this detrimental effect related to ICI therapy. The aim of this review is to summarize the most important works that, to date, provide important insights that are useful in understanding the mechanistic causes of hyperprogressive disease.

Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc Domain

“…These results tend to exclude the possibility that PD-1 blockade alone is responsible for the observed changes in gene expression in macrophages, indicating a role for the anti-PD-1 antibody Fc domain in this phenomenon, as previously hypothesized [26,48]. Blocking FcγR2b and FcγR3, which reportedly interact with the anti-PD-1 antibody Fc domain [49,50], did not reverse the effect of the combination of the anti-PD-1 antibody and CpG-ODNs on macrophage marker expression profiles (Figure 7), probably because the upregulation of the mRNA expression of these Fc receptors induced by the combinatorial treatment prevented the blockade of all FcγR2b and FcγR3 expressed on the macrophage cell membrane (Figure S7).…”

“…It is possible that even when delivered as a monotherapy, anti-PD-1 antibodies may act on macrophages in which TLR signaling has already been triggered by endogenous ligands, mirroring the biological effects described in the present study. This hypothesis might also provide a mechanistic explanation of the clinical phenomenon of hyperprogressive disease, a peculiar pattern of progression observed in patients receiving anti-PD-1 antibodies characterized by an exacerbation of tumor growth and metastatic potential, which has been proposed to be mediated by tumor-associated macrophages [48]. Therefore, if a tumor mass is abundantly infiltrated by macrophages or if it is growing in an anatomical site particularly enriched in resident macrophages, it is possible that anti-PD-1 antibodies might generate macrophages with immunoregulatory activity that are able to abolish or dampen the efficacy of anticancer therapies and eventually promote tumor progression.…”

Hyperprogression in a Patient With Hepatocellular Cancer Treated With Atezolizumab and Bevacizumab: A Case Report and Review of Literature

“…In reported literature hyperprogression incidence varied between 4% and 29% and has been reported with different types of cancer (head and neck squamous cell carcinoma, gastric cancer, non–small cell lung cancer, and melanoma). 5 Limited literature is available regarding hyperprogression in HCC. HPD defining criteria, predictors, and mechanisms of hyperprogression are not completely understood at present.…”

Maintenance Therapy with Pembrolizumab after Platinum-Doublet Chemotherapy Leading to Hyperprogression in a Patient with Metastatic Bladder Cancer

“…[ 8 11 12 13 14 ] A hypothesis of the underlying mechanism has been proposed that the expression of the amplified MDM2 gene might be further augmented by the interferon (IFN) regulatory factor-8, a transcription factor upregulated by IFN-gamma (IFN-γ) through JAK/STAT signaling in tumor cells. [ 15 ] The MDM2 might impair the patient's response to the ICI treatment by influencing the function of P53, and its inhibitor APG-115 was able to enhance the antitumor activity of anti-PD-1 agents by remodeling the tumor microenvironment, including repolarizing macrophages to the anti-tumor M1 phenotype, activating T cells, and upregulating PD-L1 expression on tumor cells. [ 15 ] What's more, co-altered genes with MDM2 amplification might also play critical roles in resistance to the anti-PD-1 immunotherapy or HPD.…”