Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know
09 November 2020
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.
https://jeccr.biomedcentral.com/article ... 20-01721-9
Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know 09 November 2020
Re: Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know 09 November
Background
Immune checkpoints and immune checkpoint blockade: a brief overview
Immune checkpoints (ICs), such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 and 2 (PD-L1 and –L2), belong to complex regulation systems that are physiologically involved in fine tuning the immune response and in the prevention of autoimmune reactions [1]. However, the same mechanisms can be exploited by cancer cells to elude immune system attack [2]. Indeed, it is well known that the upregulation of these molecules in immune cells infiltrating the tumor microenvironment (TME) or on cancer cells themselves can lead to immune escape and, therefore, to poor prognosis [3]. Blockade of ICs by specific antibodies (immune checkpoint inhibitors, ICIs) determines a sort of “awakening” of antitumor immunity and represents an excellent and novel therapeutic strategy in the oncology field [4]. Several clinical studies have demonstrated the efficacy of these therapeutic approaches compared with conventional therapies. Response rates following ICI therapy (anti-CTLA4 or anti-PD-1/PD-L1 antibody therapy) were observed in 13.3 to 44% of patients with head and neck squamous cell carcinoma (HNSCC) [5], advanced melanoma [6,7,8,9,10,11], non-small cell lung cancer [12,13,14], renal cell carcinoma [15, 16], Merkel cell carcinoma [17] and metastatic urothelial carcinoma [18]. Notably, a recently published retrospective cross-sectional study, performed considering the highest response rate to ICI treatment for all tumor types, estimated that in 2018, the percentage of US cancer patients who received benefit from IC blockade was 12.46% [19]. These data indicate that most patients do not respond properly to therapy and progress despite treatment. The reasons for such a lack of benefit can be ascribed to different causes that can be grouped into two broad areas, defined as primary and acquired resistance mechanisms [20, 21]. The former, where certain characteristics of cancer cells/TME prevent ICIs from being efficacious and, therefore, patients do not respond to immunotherapy, can be determined by the lack of tumor antigenic mutations or defective antigen presentation, constitutive PD-L1 expression, impaired T cell tumor infiltration and function and an increased presence of immune suppressive cells within the tumor microenvironment TME [20, 21]. The latter, which occurs in patients who, after exhibiting an initial response to immunotherapy, eventually relapse and progress, includes phenomena such as aberrant activation of Janus kinases 1 and 2 (JAK1/2), leading to impaired sensitivity to IFN-γ produced by activated T cells and upregulation of alternative coinhibitory immune checkpoints [20, 21].
Immune checkpoints and immune checkpoint blockade: a brief overview
Immune checkpoints (ICs), such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 and 2 (PD-L1 and –L2), belong to complex regulation systems that are physiologically involved in fine tuning the immune response and in the prevention of autoimmune reactions [1]. However, the same mechanisms can be exploited by cancer cells to elude immune system attack [2]. Indeed, it is well known that the upregulation of these molecules in immune cells infiltrating the tumor microenvironment (TME) or on cancer cells themselves can lead to immune escape and, therefore, to poor prognosis [3]. Blockade of ICs by specific antibodies (immune checkpoint inhibitors, ICIs) determines a sort of “awakening” of antitumor immunity and represents an excellent and novel therapeutic strategy in the oncology field [4]. Several clinical studies have demonstrated the efficacy of these therapeutic approaches compared with conventional therapies. Response rates following ICI therapy (anti-CTLA4 or anti-PD-1/PD-L1 antibody therapy) were observed in 13.3 to 44% of patients with head and neck squamous cell carcinoma (HNSCC) [5], advanced melanoma [6,7,8,9,10,11], non-small cell lung cancer [12,13,14], renal cell carcinoma [15, 16], Merkel cell carcinoma [17] and metastatic urothelial carcinoma [18]. Notably, a recently published retrospective cross-sectional study, performed considering the highest response rate to ICI treatment for all tumor types, estimated that in 2018, the percentage of US cancer patients who received benefit from IC blockade was 12.46% [19]. These data indicate that most patients do not respond properly to therapy and progress despite treatment. The reasons for such a lack of benefit can be ascribed to different causes that can be grouped into two broad areas, defined as primary and acquired resistance mechanisms [20, 21]. The former, where certain characteristics of cancer cells/TME prevent ICIs from being efficacious and, therefore, patients do not respond to immunotherapy, can be determined by the lack of tumor antigenic mutations or defective antigen presentation, constitutive PD-L1 expression, impaired T cell tumor infiltration and function and an increased presence of immune suppressive cells within the tumor microenvironment TME [20, 21]. The latter, which occurs in patients who, after exhibiting an initial response to immunotherapy, eventually relapse and progress, includes phenomena such as aberrant activation of Janus kinases 1 and 2 (JAK1/2), leading to impaired sensitivity to IFN-γ produced by activated T cells and upregulation of alternative coinhibitory immune checkpoints [20, 21].
Debbie