1. To discuss the mechanism of action of immunotherapies.
2. To understand immunotherapy response and immune-related adverse events.
3. To become familiar with immune related response criteria (irRC), immune-related RECIST (irRECIST) and immune RECIST (iRECIST).
4. To discuss future directions for advanced imaging of immunotherapy.
Cancer Immunotherapies include a broad variety of interactions between applied substances and the immune system to treat cancer. Passive mechanisms include the delivery of compounds that may use the immune system. The more recently extensively used drugs lead to an active priming of the immune system via disinhibition of immune checkpoints either at the level of the lymphnode (CTLA 4 - interaction) or at/near the malignancy itself (PD(L) -1 - interaction). Checkpoint-inhibitors are a breakthrough in the treatment of a variety of human malignancies including lung, renal, bladder cancer, and of course melanoma. They led to significant improvements in response and survival rates. However, the disinhibition of mechanisms normally protecting from autoimmunity and prolonged immunoreactions can lead to both unusual tumour response patterns and atypical toxicities. Concerning the response patterns the continued application of an immune treatment after the first observation of a classical RECIST - progression (pseudoprogression) is the common difference in all the response criteria specifically suggested to be used in immunotherapies (irRC, irRECIST, iRECIST). Although there are data for several substances and entities showing a beneficial effect of an ongoing treatment with checkpoint inhibitors even beyond a confirmed progression, there is a relevant role for imaging in the early prediction of treatment success particularly due the enormous cost of the treatments and the relevant toxicities associated.
1. To discuss the concept of immunotherapy treatment in cancer.
2. To review what the radiologist needs to know when assessing immunotherapy treatment.
3. To understand the challenges of assessing immunotherapy response using imaging.
A wide range of cancer immunotherapy approaches has been developed including non-specific immune-stimulant such as cytokines (Interferon, IL2), cancer vaccines (peptide or dendritic-cell-based vaccines), adoptive T-cell therapy (TILs, CAR, TRC) and immune checkpoint inhibitors (anti-CTLA-4, anti PD1 and anti PDL1). The most commonly used are the immune checkpoint inhibitors (ICIs). Their mechanism of action signifies a true shift in oncology where instead of targeting the tumour cells, ICIs target the immune system to break the cancer tolerance and stimulate the anti-tumour immune response. These new drugs have, since 2011, received marketing authorisation for melanoma, lung, bladder, renal, and head and neck cancer with remarkable and long-lasting treatment response. The novel mechanism of action of these drugs, with immune and T-cell activation, lead to unusual patterns of response with presence pseudo-progression more pronounced and more frequent than previously described responses. Pseudo-progression that has been described in about 3-10% of patients treated using ICIs corresponds to increase of tumour burden and/or appearance of new lesions due to Infiltration of a tumour by activated T-cells before the disease responds to treatment. To overcome the limitation of RECIST criteria to assess this specific changes in tumour burden, new criteria so-called irRC and then irRECIST were proposed. The major modification involved the inclusion of the measurements of new target lesions into disease assessments and the need for a 4-week CT re-assessment to confirm progression. More recently (2017) a consensus guideline iRECIST was developed by the RECIST working group.
1. To discuss different types of immunotherapies and to review their mode of action as imaged with CT.
2. To understand the limitations of RECIST and become aware of immune response criteria.
3. To discuss the limitations of CT for assessment of immunotherapies.
Computed tomography (CT) is the most widely available imaging technique for evaluating tumour response to chemotherapy. In the last years' cancer immunotherapy is changing response evaluation criteria to treatment since new patterns of treatment response have been observed employing immunomodulating agents; such therapies indeed can be associated with a significantly delayed decrease in tumour size, and new or enlarging lesions observed soon after completion of treatment may not indicate disease progression. For this reason, in this scenario, the traditional response criteria, such as WHO and RECIST 1.1, cannot be applied and therefore, during these years, several response criteria (irRC, irRECIST, iRECIST and imRECIST) were proposed and applied in clinical trials on immunotherapy. Moreover, changes of intratumoral vascularisation, objectively assessed by Perfusion-CT and Dual-energy CT, may reflect the effects of treatment and therefore be incorporated in response criteria. Finally, CT radiomics is a promising method, applied to conventional images, that seems to be able to detect subtle differences in CT values which cannot be recognised by human eyes, providing quantitative data on tumour microenvironment by analysing the distribution and relationship of pixel intensities.
1. To discuss the framework for the use of FDG PET/CT for immunotherapy assessment.
2. To become familiar with the best response criteria for assessment of immunotherapy using PET/CT.
3. To discuss the limitations of PET/CT for assessing of immunotherapies.
In recent years a range of novel immunomodulatory cancer therapeutics were introduced into clinical use aiming to boost anti-tumour immune response in cancer patients. Among these immunotherapies, neutralising antibodies targeting the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have shown effectiveness in the treatment of different tumour entities. Unlike cytototoxic radio- and chemotherapy, which directly interferes with tumour cell growth and survival, immunotherapies target the tumour indirectly stimulating the physiological anti-tumour immune response. Established methods of assessing cytotoxic tumour therapies (e.g. RECIST) have demonstrated limitations for monitoring the early therapeutic effects of immunotherapy. This has led to the development of immune-specific related response criteria (e.g. irRC, irRECIST,iRECIST) that allow continued treatment beyond progression defined by RECIST, however with also limited applicability. The complementary acquisition of functional and molecular information using PET in line with hybrid imaging techniques may allow for a higher diagnostic accuracy in monitoring immunotherapy and the timely differentiation of responders from non-responders. The applicability of 18F-FDG PET for monitoring treatment with immune checkpoint inhibitors has been questioned because the infiltration of the tumour by immune cells may cause a transient increase in metabolic activity. Dedicated tracers for immune PET mostly aim to visualise the presence and abundance of various subsets of immune cells with different targets including PD-L1, PD-1, CTLA-4, CD3 and IFNγ. Dedicated immune PET with specific tracers may provide valuable in vivo insights into the pathophysiology of tumours under immunotherapy and new opportunities to evaluate antitumor immune response.
1. To learn the advantages and limitations of MRI for assessment of immunotherapies.
2. To describe the potential role of whole-body MRI and quantitative MRI techniques for patient follow-up.
3. To consider the potential of integrated PET/MRI for the assessment of immunotherapies.
Drugs that modulate the body immune responses are increasingly used to treat cancers, either alone in combination, such as in malignant melanoma, non-small cell lung cancer, hepatocellular carcinomas. In patients receiving immunotherapies, CT is still the most widely used imaging technique to assess the treatment response of tumours and to identify drug-related side-effects. However, anatomical MR imaging is also effective in evaluating tumour regression by size measurement criteria (e.g. iRECIST). Like CT, an increase in tumour size may be observed on MRI in pseudo-progression, which can confound response assessment. Nonetheless, the superior soft tissue contrast of MRI helps to depict subtle disease (e.g. intracranial) and specific complications (e.g. hypophysitis) that are difficult to visualise on CT. There is great interest in applying quantitative MR imaging, including whole-body MRI techniques, to study functional changes in tumour cellularity (using diffusion-weighted MRI), vascularity (using contrast-enhanced MRI) and macromolecules (magnetisation transfer). These are areas of on-going research, including the use of texture analysis and radiomics analysis. Whole body MRI can provide information about inter-tumoural heterogeneity, thus allowing insights into tumour evolution and differential response to treatment. Active research in molecular probes is being undertaken to develop PET imaging tracers that can identify and predict treatment response, which can be explored alongside multi-parametric MRI measurements on an MRI/PET hybrid system as imaging biomarkers.