Evaluation of response to immunotherapy: new challenges and opportunities for PET imaging.

Abstract

Cancer immunotherapy focuses on the development of agents that can activate the immune system to recognize and kill tumour cells. It encompasses different strategies, the first of which is the activation of innate and adaptive immune effector mechanisms, such as vaccination with tumour antigens, treatment with cytokines (for example, interleukin 2 or interferon α) and enhancement of antigen presentation. Another important strategy involves neutralizing the inhibitory and suppressive mechanisms and includes the use of antibodies to deplete the regulatory T cells and the use of antibodies against immune-checkpoint molecules, for example cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death (PD1) [1]. Monoclonal antibodies (mAbs) that block the immunoregulatory damping mechanisms of the host response to tumourassociated antigens have recently become a practical reality with the first approval by the US Food and Drug Administration of ipilimumab in patients with unresectable or metastatic melanoma. Ipilimumab is a fully human monoclonal immunoglobulin specific for CTLA-4, a molecule that downregulates T-cell activation via a homeostatic feedback loop. Under normal physiological conditions, this mechanism prevents autoimmunity and allows the body to establish tolerance to self-antigens. Anti-CTLA-4 mAbs block CTLA-4 signalling preventing downregulation of the immune response and increasing the proliferation of Tcells and the interaction of T cells and cancer cells [2]. Ipilimumab has been extensively tested in patients with melanoma. It was found to be the first compound to improve overall survival in a randomized, phase III trial comparing ipilimumab with or without the gp100 peptide vaccine versus gp100 alone in patients with previously treated, unresectable stage III or IV melanoma. Median overall survival in the combination ipilimumab and vaccine arm was similar to that in the ipilimumab-alone arm, but significantly higher than in the gp100 peptide vaccine-alone arm [3]. Another randomized phase III study demonstrated an increase in overall survival in patients with previously untreated stage IV melanoma receiving dacarbazine in combination with ipilimumab compared to dacarbazine alone [4]. Consistent with the mechanism of action of ipilimumab, that does not rely on the direct killing of tumour cells, the changes in tumour burden observed in clinical trials have often been very different from those observed using chemotherapeutic agents. Four distinct patterns of response have been described: (1) response in baseline target lesions, that is a “chemotherapy-like” response; (2) a slow, steady decline in tumour burden; (3) response after an increase in tumour burden, that is after progressive disease (PD) by standard response criteria; and (4) response in target and new lesions accompanied by the appearance of other new lesions. All these patterns are associated with favourable survival, although the last two may be misinterpreted as PD by standard methods [5]. Antibodies that target CTLA-4 have also been associated with several novel adverse effects that have been described as immune-related adverse events (irAEs). They are found in more than 70 % of patients and are typically responsive to interruption or discontinuation of CTLA-4 blockade in combination with immunosuppressive drugs such as corticosteroids [6]. Symptomatic irAEs have been described mainly in four organ systems: gastrointestinal tract, liver, skin and endocrine system. Clinically silent manifestations, in particular benign lymphadenopathy (sarcoid-like syndrome) and L. Gilardi (*) : C. M. Grana Division of Nuclear Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy e-mail: laura.gilardi@ieo.it