Cure Alveolar Soft Part Sarcoma International (iCureASPS)

How to differentiate pseudoprogression from true progression in cancer patients treated with immunotherapy



Abstract

Immunotherapy has achieved unprecedented clinical efficacy in patients with various types of advanced tumors; however, some patients experience delayed tumor shrinkage following an increase in tumor burden after such a therapeutic method. This phenomenon is called pseudoprogression and can lead to premature cessation of efficacious immunotherapeutic agents. Consequently, we summarized the available data on methods to differentiate pseudoprogression from true progression in patients who have been treated with immunotherapy including biomarkers, medical imaging techniques and biopsy. We also introduce hyperprogression and special pseudoprogression for improved evaluation of immunotherapy.

Keywords: Immunotherapy, psuedoprogression, ctDNA, PET, biopsy, hyperprogression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726978/

Introduction

Over the last few years, immunotherapy, which induces a persistent antitumor response in patients by stimulating immune recognition of tumors, has emerged as a promising treatment strategy for advanced tumors [1-3]. Immune checkpoint inhibitors (ICI), such as blockades that target programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated antigen (CTLA-4), are one of the most powerful tools in the immunotherapy armamentarium and offer a beneficial immunotherapeutic regimen to patients with various types of cancers [4-8]. The emergence and wide use of ICI has resulted in a dramatic breakthrough in cancer immunotherapy.

Immunotherapy is a completely new treatment pattern that is distinct from other therapeutic modalities, thus bringing major challenges to clinicians who are not familiar with it. One of these challenges is pseudoprogression, a transient increase of tumor burden followed by delayed tumor shrinkage, which clinicians may occasionally encounter while assessing the efficacy of immune checkpoint blockades.

Pseudoprogression during immunotherapy was first characterized in a phase II trial that evaluated the efficacy of ipilimumab, an anti-CTLA-4 antibody, in advanced melanoma [9]. The authors described a patient who experienced initial increased size of tumor lesions followed by a delayed partial response. Treatment with ICI targeting PD-1 or PD-L1 may also result in pseudoprogression in other types of solid tumors, such as bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, lung cancer, pancreaticoduodenal cancer, ovarian cancer, renal cell cancer, sarcoma, and uterine cancer [10].

Pseudoprogression is defined as an increase in the size of the primary tumor or the appearance of a new lesion followed by tumor regression. Pseudoprogression is not true tumor progression, which has been proven by histopathological biopsies that found infiltration and recruitment of various immune cells, such as T or B lymphocytes, in the tumor [9,10]. The occurrence of pseudoprogression has led to the development of immune-related response-evaluation criteria, such as irRC [11], irRECIST [12], and iRECIST [13]. Treatment beyond progression is permitted under these modified criteria [14], which more accurately evaluate the efficacy of immunotherapy than the conventional criteria.

The incidence of pseudoprogression reported in prior studies was less than 10% [11,14,15]. However, a recent study determined that the incidence of atypical response is as high as 20%, which included new lesions and a greater than 10% increase in the total sum of the longest dimension that subsequently returned to below the baseline [16]. Thus, pseudoprogression, referring to all types of atypical response modes with a perceptible increase in tumor burden followed by subsequent clinical benefits, was underestimated in prior studies.

Currently, pseudoprogression is diagnosed using retrospective imaging data, which critically impedes the optimal application of immune checkpoint inhibitors because clinicians cannot accurately evaluate the treatment. At the rate at which immunotherapeutics are widely being utilized to treat tumor patients, determining how to accurately discriminate pseudoprogression from true progression is quite important for helping clinicians to avoid premature cessation of immunotherapeutic treatment and initiation of alternative treatments. Several studies have elucidated that some potential methods and factors were able to predict pseudoprogression. Therefore, this review summarizes the existing studies on pseudoprogression in immunotherapy that aimed at determining earlier and more accurate methods of identifying pseudoprogression in patients receiving immunotherapeutics.

Abstract

Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) is a negative modulatory signaling pathway for activation of T cell. It is acknowledged that PD-1/PD-L1 axis plays a crucial role in the progression of tumor by altering status of immune surveillance. As one of the most promising immune therapy strategies, PD-1/PD-L1 inhibitor is a breakthrough for the therapy of some refractory tumors. However, response rate of PD-1/PD-L1 inhibitors in overall patients is unsatisfactory, which limits the application in clinical practice. Therefore, biomarkers which could effectively predict the efficacy of PD-1/PD-L1 inhibitors are crucial for patient selection. Biomarkers reflecting tumor immune microenvironment and tumor cell intrinsic features, such as PD-L1 expression, density of tumor infiltrating lymphocyte (TIL), tumor mutational burden, and mismatch-repair (MMR) deficiency, have been noticed to associate with treatment effect of anti-PD-1/anti-PD-L1 therapy. Furthermore, gut microbiota, circulating biomarkers, and patient previous history have been found as valuable predictors as well. Therefore establishing a comprehensive assessment framework involving multiple biomarkers would be meaningful to interrogate tumor immune landscape and select sensitive patients.

Keywords: PD-1/PD-L1 inhibitors, Predictive biomarkers, Tumor mutational burden, Microsatellite instability, Gut microbiota, Peripheral biomarker


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107958/