Monitoring immune-checkpoint blockade: response evaluation and biomarker development

Abstract

Cancer immunotherapy using immune-checkpoint blockade (ICB) has created a paradigm shift in the treatment of advanced-stage cancers. The promising antitumour activity of monoclonal antibodies targeting the immune-checkpoint proteins CTLA-4, PD-1, and PD-L1 led to regulatory approvals of these agents for the treatment of a variety of malignancies. Patients might experience clinical benefits from treatment with these agents, despite unconventional patterns of tumour response that can be misinterpreted as disease progression, warranting a new, specific approach to evaluate responses to immunotherapy. In addition, biomarkers that can predict responsiveness to ICB are being extensively investigated to further advance precision immunotherapy. Herein, we review the biological mechanisms underlying the unconventional response patterns associated with ICB, describe strategies for the objective assessments of such responses, and also highlight the ongoing efforts to identify biomarkers, in order to guide treatment with ICB. We provide state-of-the-art knowledge of immune-related response evaluations, identify unmet needs requiring further investigations, and propose future directions to maximize the benefits of ICB therapy.

Figure 1. Ligand–receptor interactions between tumour cells and immune cells in the tumour microenvironment

An overview of the immune-checkpoint molecules involved in the regulation of the antitumour immune response.

Figure 2. Response after initial increase in total tumour burden in a 77-year-old male with advanced-stage melanoma treated with ipilimumab

a | The baseline CT scan demonstrated a lung lesion (arrow) measuring 19 mm in the longest diameter. b | After 12 weeks of therapy, the lesion (arrow) measured 29 mm (53% increase compared with the baseline), indicating progressive disease by RECIST. c | The patient remained on therapy, and another follow-up CT scan (24 weeks after therapy initiation) showed a reduction in the size of the lesion (arrow), to 12 mm, indicative of an immune-related response to therapy. Reprinted from Nishino, M., Tirumani, S.H., Ramaiya, N.H. & Hodi, F.S. Cancer immunotherapy and immune-related response assessment: the role of radiologists in the new arena of cancer treatment, Eur. J. Radiol., 84, 1259–1268, Copyright (2015), with permission from Elsevier.

Figure 3. Response after appearance of a new lesion in a 56-year-old woman with metastatic melanoma treated with ipilimumab3

Contrast-enhanced CT scans of the abdomen a | before and b | 12 weeks after initiation of ipilimumab therapy revealed new subcutaneous nodule (arrow), suspected to be a new site of metastasis. c | A follow-up CT scan 24 weeks after initiation of therapy revealed resolution of the nodule, indicating response after appearance of a new lesion. Reprinted with permission from Nishino, M. 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. 198, 737–745 (2012).

Figure 4. Key elements in biomarker development for immune-checkpoint inhibitor therapy

Consideration of the tumour, tumour microenvironment, and immune system must be incorporated in the ongoing efforts in biomarker development for immune-checkpoint inhibitor therapy.