ReviewPseudoprogression and hyperprogression after checkpoint blockade
Introduction
Immunotherapy that reestablishes antitumor response within the host is rising as a promising treatment strategy for cancer patients [[1], [2], [3]]. Immune checkpoint inhibitors, such as monoclonal antibodies(mAb) targeting cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), are profoundly changing cancer patient management [[4], [5], [6], [7]]. At the forefront of this novel class of antitumor agents, anti-PD-1/PD-L1 antibodies exhibit a significant activity and induce durable disease control by restoring an efficient antitumor T-cell response. It has become a standard of care for multiple cancer types including melanoma, non-small-cell lung cancer (NSCLC), renal-cell carcinoma (RCC), bladder cancer, Hodgkin's lymphoma, head and neck squamous cell carcinoma (HNSCC) and Merkel cell carcinoma [[8], [9], [10], [11]]. Overall, the response rates for single agent of PD-1/PD-L1 inhibitors in solid malignancies range from 20% to 40% [[12], [13], [14]]. Till now, five immune checkpoint inhibitors targeting PD-1 and PD-L1 have been approved by the U.S. Food and Drug Administration (FDA), including PD-1-blocking mAbs pembrolizumab and nivolumab, and PD-L1-targeted mAbs atezolizumab, durvalumab and avelumab. Apart from CTLA-4 and PD-1, multiple inhibitory receptors, such as T-cell immunoglobulin mucin 3 (TIM3), lymphocyte activation gene 3 (LAG3) and B and T lymphocyte attenuator (BTLA), also compose the family of immune checkpoint and transmit similar inhibitory functions, and, hence, call for further exploration [15,16].
As immunotherapeutics, particularly anti-PD-1/PD-L1 agents, are more widely available to patients, clinicians face a great challenge in accurately evaluating the clinical efficacy of these novel drugs. WHO and RECIST criteria have historically been taken as standard guidelines in defining a tumor response to therapy. Although imperfect, the RECIST are commonly accepted norms defining the moment of disease progression and have guided the defining of tumor response and driven consequent drug approval for years [17,18]. The development of new lesions and a significant increase in the size of tumor lesions are considered definite disease progression by RECIST criteria. However, during checkpoint blockade some patients experienced immune-related responses such as initial increased size of tumor lesions or appearance of new lesions, confirmed by biopsy as necrosis or inflammatory cell infiltrates, with subsequent reduction in tumor burden. The unconventional clinical response is recognized as pseudoprogression, and would be misclassified as progressive disease (PD) according to the size-based WHO or RECIST criteria.
In addition to pseudoprogression, there is another special response pattern during checkpoint blockade named tumor flare or hyperprogression. Unlike pseudoprogression, a disease progression subsequently followed by tumor shrinkage, hyperprogression is characterized as the disease whose dramatic progression outpaces the expected rate of growth in the absence of checkpoint inhibitors, based primarily on evidence from prior imaging scans (Fig. 1). The patients with disease hyperprogression have a course that is more deleterious than they might have had with other therapies, or even in the absence of therapy. Although the mechanism and recognition of pseudoprogression have gradually come to light, the incidence, basis, identification and predictive biomarkers of hyperprogression have been largely unknown. As immunotherapeutics, especially anti-PD-1/PD-L1 agents, become more widely available, the discernment in differentiating pseudoprogression from real progression or even hyperprogression by clinicians will tremendously help evaluate the efficacy of these novel drugs and avoid either premature withdrawal of the treatment or prolonging ineffective treatment. Therefore, this review focuses on the existing researches in related areas and clarifies potential topics for future studies.
Section snippets
The occurrence of pseudoprogression after immune checkpoint blockade
The concept of “tumor pseudoprogression” was first introduced in brain tumors treated with non-immune therapy agent, temozolomide, which is a prodrug that works through alkylation (methylation) of DNA. It is discovered that brain tumors might increase in size before responding to temozolomide treatment [20]. Pseudoprogression in immune checkpoint inhibitor therapy was initially found in melanoma, at first in the research of the anti-CTLA4 inhibitor ipilimumab [21] and then in the studies of
The occurrence of hyperprogression after PD-1/PD-L1 blockade
Opposing effects of immunotherapy have already been documented in melanoma using adjuvant IFN-α where patients in the treatment group who died during the study period displayed a significantly reduced time from relapse to death compared with control individuals [60]. Anti-PD-1 and anti-PD-L1 monotherapy can lead to profound and durable tumor responses in some cases, however, the opposing effects of immunotherapy probably exist in a subset of patients. The phase III study of nivolumab versus
Conclusions
As immune checkpoint inhibitors become more widely accepted by physicians, the task of properly assessing tumor response remains a challenge in patient management. The irRC, though with some limitations such as measurement variability, may help to identify a subgroup of patients with pseudoprogression so as to avoid inappropriate discontinuations of immunotherapy. As for hyperprogression, a dramatic tumor surge in a fraction of patients after checkpoint blockade, exploration of the underlying
Acknowledgments
This work is supported by grants from National Natural Science Foundation of China (81472843). We would also like to show our gratitude to the “anonymous” reviewers for their insights that greatly improved the manuscript.
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