Review
Cancer immunotherapy and immune-related response assessment: The role of radiologists in the new arena of cancer treatment

https://doi.org/10.1016/j.ejrad.2015.03.017Get rights and content

Highlights

  • The successful clinical application of cancer immunotherapy has opened a new arena for the treatment of advanced cancers.

  • Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events.

  • The state-of-the art knowledge of immunotherapy and the related radiologic manifestations are essential for radiologists.

Abstract

The recent advances in the clinical application of anti-cancer immunotherapeutic agents have opened a new arena for the treatment of advanced cancers. Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events, which calls for radiologists’ awareness and in-depth knowledge on the topic. This article will provide the state-of-the art review and perspectives of cancer immunotherapy, including its molecular mechanisms, the strategies for immune-related response assessment on imaging and their pitfalls, and the emerging knowledge of radiologic manifestations of immune-related adverse events. The cutting edge clinical and radiologic investigations are presented to provide future directions.

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.

References (60)

  • M. Nishino et al.

    CT tumor volume measurement in advanced non-small-cell lung cancer: performance characteristics of an emerging clinical tool

    Acad Radiol

    (2011)
  • B. Zhao et al.

    Exploring intra- and inter-reader variability in uni-dimensional, bi-dimensional, and volumetric measurements of solid tumors on CT scans reconstructed at different slice intervals

    Eur J Radiol

    (2013)
  • G.J. Freeman et al.

    Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation

    J Exp Med

    (2000)
  • D.R. Leach et al.

    Enhancement of antitumor immunity by CTLA-4 blockade

    Science

    (1996)
  • J.F. Brunet et al.

    A new member of the immunoglobulin superfamily – CTLA-4

    Nature

    (1987)
  • G.J. Freeman et al.

    Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation

    Science

    (1993)
  • Y. Ishida et al.

    Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death

    EMBO J

    (1992)
  • F.S. Hodi et al.

    Adoptive transfer of antigen-specific CD4+ T cells in the treatment of metastatic melanoma

    Nat Clin Pract Oncol

    (2008)
  • F.S. Hodi et al.

    Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients

    Proc Natl Acad Sci U S A

    (2003)
  • F.S. Hodi et al.

    Improved survival with ipilimumab in patients with metastatic melanoma

    N Engl J Med

    (2010)
  • J. Weber et al.

    A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma

    Clin Cancer Res

    (2009)
  • S.L. Topalian et al.

    Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab

    J Clin Oncol

    (2014)
  • J.D. Wolchok et al.

    Nivolumab plus ipilimumab in advanced melanoma

    N Engl J Med

    (2013)
  • O. Hamid et al.

    Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma

    N Engl J Med

    (2013)
  • F.S. Hodi et al.

    The biologic importance of tumor-infiltrating lymphocytes

    J Cutan Pathol

    (2010)
  • J.D. Wolchok et al.

    Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma

    Ann N Y Acad Sci

    (2013)
  • J.D. Wolchok et al.

    Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria

    Clin Cancer Res

    (2009)
  • M. Nishino et al.

    Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements

    Clin Cancer Res

    (2013)
  • M. Nishino et al.

    Personalized tumor response assessment in the era of molecular medicine: cancer-specific and therapy-specific response criteria to complement pitfalls of RECIST

    AJR Am J Roentgenol

    (2012)
  • Y. Bronstein et al.

    Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy

    AJR Am J Roentgenol

    (2011)
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