PDL1 over-expression has been used as a criterion to prescribe ICIs in patients with NSCLC ( 18). A variety of biomarkers have been explored to determine which patients are most likely to respond to therapy ( 29, 30). Alternatively resistance may be due to extrinsic factors, including pro-tumoral cells such as Treg or myeloid derived suppressor cells present in the tumor microenvironment, or the upregulation of alternative immune checkpoints by effector T cells present in the tumor ( 2– 4, 28).Īccordingly, a major challenge in the field of ICI is the identification of patients which have the greatest chance to benefit from these costly and potentially toxic therapies. This may be due to a tumor intrinsic factor, such as loss of HLA expression, target antigen down-regulation or mutation of JAK1/2. A majority of patients display innate resistance to ICI treatment. Melanoma is the only cancer type with a high response rate to single agent ICI therapy (around 40%). Unfortunately, only 15–40% of patients benefit from ICIs although some patients will experience long-lasting responses. Early detection of these IRAE as well as appropriate preventive and/or curative therapies have been a major preoccupation for clinicians administering ICIs to their patients. This innovative approach is associated with immune-related adverse events (IRAE) which can be severe (grade 3 or 4) and involve a variety of tissues and organs ( 26, 27). Immunotherapies targeting immune checkpoints are increasingly used in the relapse setting and are rapidly becoming a component of first-line therapies for melanoma, NSCLC, small cell lung cancer, advanced renal cell carcinoma, triple negative breast cancer, and Merkel cell carcinoma, sometimes in combination with chemotherapy and second line therapies for many tumor types (unresectable and metastatic melanoma, NSCLC, renal cell carcinoma, HNSCC, urothelial carcinoma, colorectal cancer, prostate cancer, and Hodgkin's lymphoma) with durable clinical benefits ( 15– 25). Immunotherapy Prescription and Monitoring The aim of this review is to provide an update about HPD and potential mechanisms explaining how ICI can induce this phenomenon. There are currently few data explaining the occurrence of HPD or allowing clinicians to identify patients at risk of developing HPD. This phenomenon, designated as hyperprogressive disease (HPD), corresponds to a paradoxical boost in tumor growth under treatment and has been described in non-squamous non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), urothelial bladder carcinoma, hepatocellular carcinoma, gastric cancer, and anorectal melanoma ( 6– 14), with a rate ranging between 4 and 29%. In some cases, the disease develops faster than expected and in a more aggressive manner after immune checkpoint targeting immunotherapy. Unsuccessful treatment may be due to primary resistance or acquired resistance ( 2– 5). Monoclonal antibodies targeting CTLA-4 (ipilimumab), PD-1 (nivolumab, pembrolizumab), and PD-L1 (atezolizumab, avelumab, and durvalumab) are currently approved for the treatment of numerous cancers, however, significant responses to immunotherapy remain restricted to a minority of patients and certain tumor types. Currently approved agents contribute to the activation of anti-tumor cytotoxic T cells by abrogating the immune checkpoint signaling triggered by tumor cells or microenvironment. Since approval by the Food and Drug Administration (FDA) in 2011 of the first antibody, ipilimumab, targeting an immune checkpoint inhibitors (ICI) ( 1), this class of inhibitors has rapidly developed to include a large variety of cancer indications. In this review, we have performed a literature search on hyperprogressive disease, including both retrospective studies and case reports, and discuss potential predictive biomarkers as well as potential mechanisms associated with immune-checkpoint inhibitor associated hyperprogression. The reported incidence rates of hyperprogressive disease are highly variable, ranging between 4 and 29%. This paradoxical response corresponds to an acceleration in tumor growth and a dramatic decrease of patient survival. 4Institut de Pathologie Multisites des HCL - Site Est- Hospices Civils of Lyon, Lyon, Franceįollowing the administration of immune checkpoint inhibitors, an unexpected pattern of response designated as hyperprogression may be observed in certain patients.3Respiratory Department, Louis Pradel Hospital, Hospices Civils de Lyon Cancer Institute, Bron, France.1INSERM 1052/CNRS 5286/UCBL - Cancer Research Center of Lyon, Anticancer Antibodies Laboratory, Lyon, France. Morgane Denis 1,2 Michael Duruisseaux 1,3 Marie Brevet 1,4 Charles Dumontet 1 *
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