ReviewCancer immunotherapy and immune-related response assessment: The role of radiologists in the new arena of cancer treatment☆
Introduction
Increasing understanding of regulatory pathways of the immune response to cancer has led to the development and successful application of immunotherapeutic agents [1], [2], [3], [4], [5], [6], [7]. This is best represented by ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody, which significantly improved overall survival in metastatic melanoma patients, leading to the approval of the agent by Food and Drug Administration (FDA) for advanced melanoma [8], [9], [10]. Newer immunotherapeutic agents, such as anti-PD-1 (anti-programmed cell death-1) and anti-PD-L1 antibodies (anti-programmed cell death ligand-1), have been developed and also demonstrated marked activities in patients with advanced cancers [11], [12], [13], [14]. Immunotherapeutic agents have distinct biologic mechanisms of anti-cancer activity, which augment activation and proliferation of T cells and induce tumor infiltration by T cells and tumor regression [8], [15], [16], [17]. These distinct mechanisms result in the unique imaging manifestations in patients receiving immunotherapy, which requires specific attention and knowledge for the accurate radiological interpretations. For example, some of the patients on immunotherapy demonstrate radiologic response patterns that may not be captured by the conventional RECIST and WHO criteria, thus requiring modification in response assessment guidelines as proposed in the immune-related response criteria (irRC) [17], [18], [19]. As the role of immunotherapeutic agents expands in the treatment of advanced cancers, the knowledge of immune-related tumor response will become increasingly important for radiologists to contribute to the state-of-the-art cancer care. Furthermore, the distinct biological mechanism of immunotherapy is also associated with a variety of immune-related adverse events during therapy, where radiologists can contribute significantly in making diagnosis and help clinical decision making [20], [21], [22], [23], [24].
This article will first review the molecular basis of anti-cancer immunotherapeutic agents and discuss their clinical application in different types of cancers. The article will then provide a detailed review of immune-related response criteria by describing definitions of immune-related response and progression along with the biological background, and discuss their pitfalls. Emerging knowledge of immune-related adverse events and their imaging features will also be described. Finally, future directions will be provided based on the observations in cutting-edge clinical and radiologic investigations. The article will provide with the state-of-the-art knowledge of cancer immunotherapy, which is essential for radiologists to play a role as a key contributor in this new arena of cancer treatment.
Section snippets
Molecular basis of cancer immunotherapy
Immunotherapeutic agents such as ipilimumab and anti-PD-1 antibodies exert the anti-tumor activity through the blockade of immunologic inhibitory pathways and the augmentation of T cell activation and proliferation, as opposed to the direct cytotoxic effects to tumor cells [7], [8], [17], [25], [26]. For effective anti-tumor immunity, T cells play a major role in the immune defense against cancer. Upon encountering tumor antigens, T cells become activated, circulate and work toward elimination
Clinical application of immunotherapeutic agents in cancer treatment
Cancer immunotherapy has rapidly expanded its role in the current clinical oncology practice since the approval of ipilimumab (anti-CTLA-4 antibody) for advanced melanoma in 2011. In a phase 3 trial of ipilimumab, patients with previously treated melanoma who received ipilimumab achieved a significantly extended overall survival (median OS: 10.1 months) compared with patients who received a glycoprotein 100 peptide vaccine (median OS: 6.4 months) [8]. This was the first phase III trial that
Immune-related response criteria (irRC): overview and clinical application
Due to the distinct mechanism of anti-cancer activity of immunotherapeutic agents, some patients on anti-cancer immunotherapy demonstrate tumor response patterns that may not be captured by the conventional tumor response criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria [17], [18], [19]. Notably, in patients treated with immunotherapy, tumors may show response after an initial increase in tumor burden, or during/after the
Immune-related adverse events and their imaging manifestations
Given the unique mechanism of action, immunotherapeutic agents are associated with a wide spectrum of immune-related adverse events, such as enterocolitis, hepatitis, hypophysitis, dermatitis, thyroiditis, and sarcoid-like mediastinal and hilar lymphadenopathy (Fig. 8, Fig. 9) [20], [22], [24], [58], [59], [60]. Many of these entities are associated with radiologic manifestations, and radiologists play an essential role in the diagnosis and follow-up. In a series of 119 advanced melanoma
Future directions
With the increasing evidence of marked anti-cancer activity of immunotherapeutic agents in both solid and hematologic malignancies, cancer immunotherapy has opened a new promising field in cancer treatment and is rapidly expanding its role and significance. Radiologic assessment of tumor burden is an integral part of evaluating the efficacy and effectiveness of these agents, and the role of radiologists in this new field is also expected to expand. Unifying the strategy for immune-related tumor
Role of the funding source
The investigator, M.N., was supported by 1K23CA157631 (NCI).
Conflict of interest
Dr. Nishino served as a consultant to Bristol-Myers Squibb. Dr. Hodi has served as a non-paid consultant to Bristol-Myers Squibb and has received clinical trial support from Bristol-Myers Squibb, advisor and clinical trial support from Merck, and advisor and clinical trial support from Genentech. All other authors have nothing to disclose.
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2022, Clinical Lung CancerCitation Excerpt :While numerous pivotal studies assessing immunotherapies in NSCLC have assessed responses by RECIST v1.1, response assessments were based on irRECIST for the GARNET trial cohort reported. irRECIST is based on RECIST v1.1 but takes into account unique features of immunotherapy, including the atypical patterns of tumor response often described during treatment with anti-PD-(L)1 antibodies in solid tumors such as a reduction in tumor burden during or after the appearance of new lesions.47-50 In NSCLC, around 5% of patients experience an atypical response when receiving immunotherapy, so use of RECIST v1.1 could result in underestimation of ORR;50 response rates have been demonstrated to be concordant between RECIST v1.1 and irRECIST in advanced NSCLC,48 and the predictive value of PFS and irPFS for OS have been shown to be consistently similar across all tumor types, including NSCLC.50,51
Targeting CAFs to overcome anticancer therapeutic resistance
2022, Trends in CancerCitation Excerpt :However, only a few studies have assessed the effect of NK cells on CAFs and, thus, further investigations are needed. Cancer immunotherapy with ICB is founded on the suppression of tumor-mediated inhibition of anticancer immune reactions, in contrast to therapeutic approaches that apply direct cytotoxic force on tumor cells [146–148]. T cells play a significant part in the mechanisms of immune defense against cancer: they identify tumor antigens, become activated, disseminate, and annihilate cancer cells [146–148].
Pseudoprogression in lung cancer patients treated with immunotherapy
2022, Critical Reviews in Oncology/HematologyCitation Excerpt :The anti-tumor effects of ICIs depend on the mobilization of the body's immune system, among which CTLA-4 and PD-1 pathways are the two main immune checkpoint pathways studied at present. CTLA-4 monoclonal antibody plays an early role in the activation of immune cells, while PD-1/PD-L1 monoclonal antibody promotes the killing ability of immune cells instead of improving the direct cytotoxic effects on tumor cells (Nishino et al., 2015a). However, those drugs require immune cells to enter the tumor region and to directly contact tumor cells.
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The investigator, M.N., was supported by 1K23CA157631 (NCI).