Improving shared decision making for lung cancer treatment by developing and validating an open-source web based patient decision aid for stage I-II non-small cell lung cancer.

The aim of this study was to develop and evaluate a proof-of-concept open-source individualized Patient Decision Aid (iPDA) with a group of patients, physicians, and computer scientists. The iPDA was developed based on the International Patient Decision Aid Standards (IPDAS). A previously published questionnaire was adapted and used to test the user-friendliness and content of the iPDA. The questionnaire contained 40 multiple-choice questions, and answers were given on a 5-point Likert Scale (1-5) ranging from "strongly disagree" to "strongly agree." In addition to the questionnaire, semi-structured interviews were conducted with patients. We performed a descriptive analysis of the responses. The iPDA was evaluated by 28 computer scientists, 21 physicians, and 13 patients. The results demonstrate that the iPDA was found valuable by 92% (patients), 96% (computer scientists), and 86% (physicians), while the treatment information was judged useful by 92%, 96%, and 95%, respectively. Additionally, the tool was thought to be motivating for patients to actively engage in their treatment by 92%, 93%, and 91% of the above respondents groups. More multimedia components and less text were suggested by the respondents as ways to improve the tool and user interface. In conclusion, we successfully developed and tested an iPDA for patients with stage I-II Non-Small Cell Lung Cancer (NSCLC).

Charged Particle and Conventional Radiotherapy: Current Implications as Partner for Immunotherapy.

Radiotherapy (RT) has been shown to interfere with inflammatory signals and to enhance tumor immunogenicity via, e.g., immunogenic cell death, thereby potentially augmenting the therapeutic efficacy of immunotherapy. Conventional RT consists predominantly of high energy photon beams. Hypofractionated RT regimens administered, e.g., by stereotactic body radiation therapy (SBRT), are increasingly investigated in combination with cancer immunotherapy within clinical trials. Despite intensive preclinical studies, the optimal dose per fraction and dose schemes for elaboration of RT induced immunogenic potential remain inconclusive. Compared to the scenario of combined immune checkpoint inhibition (ICI) and RT, multimodal therapies utilizing other immunotherapy principles such as adoptive transfer of immune cells, vaccination strategies, targeted immune-cytokines and agonists are underrepresented in both preclinical and clinical settings. Despite the clinical success of ICI and RT combination, e.g., prolonging overall survival in locally advanced lung cancer, curative outcomes are still not achieved for most cancer entities studied. Charged particle RT (PRT) has gained interest as it may enhance tumor immunogenicity compared to conventional RT due to its unique biological and physical properties. However, whether PRT in combination with immune therapy will elicit superior antitumor effects both locally and systemically needs to be further investigated. In this review, the immunological effects of RT in the tumor microenvironment are summarized to understand their implications for immunotherapy combinations. Attention will be given to the various immunotherapeutic interventions that have been co-administered with RT so far. Furthermore, the theoretical basis and first evidences supporting a favorable immunogenicity profile of PRT will be examined.

Toxicity of L19-Interleukin 2 Combined with Stereotactic Body Radiation Therapy: A Phase 1 Study.

PURPOSE: The immunocytokine L19-IL2 delivers interleukin-2 to the tumor by exploiting the selective L19-dependent binding of extradomain B of fibronectin on tumor blood vessels. In preclinical models, L19-IL2 has been shown to enhance the local and abscopal effects of radiation therapy. The clinical safety of L19-IL2 monotherapy has been established previously. In this study, the safety and tolerability of L19-IL2 after stereotactic body radiation therapy (SBRT) was assessed. METHODS AND MATERIALS: Patients with oligometastatic solid tumors received radical SBRT to all visible metastases. Within 1 week after SBRT, intravenous L19-IL2 using a 3 + 3 dose escalation design was administered. Safety and tolerability were analyzed as the primary endpoint using the Common Terminology Criteria for Adverse Events 4.03 scoring system, with progression-free and overall survival as secondary endpoints. RESULTS: A total of 6 patients in 2 L19-IL2 dose levels were included. The 15 million International Units (Mio IU) dose level was well tolerated with no dose-limiting toxicity. The most frequently reported adverse events were chills, noninfectious fever, fatigue, edema, erythema, pruritus, nausea/vomiting, and cough and dyspnea. Blood analysis revealed abnormalities in liver function tests, anemia, hypoalbuminemia, and hypokalemia. At the second dose level (ie, 22.5 Mio IU), which is the recommended dose for L19-IL2 monotherapy, all 3 included patients experienced dose-limiting toxicity but recovered without sequelae. We documented 2 long-term progression-free responders, both having non-small cell lung cancer as primary tumor. CONCLUSIONS: Based on the results of this phase 1 clinical trial, the recommended phase 2 dose for SBRT combined with L19-IL2 is 15 Mio IU. The therapeutic efficacy of this combination is currently being evaluated in the multicentric EU-funded phase 2 clinical trial, ImmunoSABR.

Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial.

BACKGROUND: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR). METHODS: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed. DISCUSSION: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023. TRIAL REGISTRATION: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.

Lymphocyte-Sparing Radiotherapy: The Rationale for Protecting Lymphocyte-rich Organs When Combining Radiotherapy With Immunotherapy.

There is now strong clinical and preclinical evidence that lymphocytes, for example, CD8+ T cells, are key effectors of immunotherapy and that irradiation of large blood vessels, the heart, and lymphoid organs (including nodes, spleen, bones containing bone marrow, and thymus in children) causes transient or persistent lymphopenia. Furthermore, there is extensive clinical evidence, across multiple cancer sites and treatment modalities, that lymphopenia correlates strongly with decreased overall survival. At the moment, we lack quantitative evidence to establish the relationship between dose-volume and dose-rate to critical normal structures and lymphopenia. Therefore, we propose that data should be systematically recorded to characterise a possible quantitative relationship. This might enable us to improve the efficacy of radiotherapy and develop strategies to predict and prevent treatment-related lymphopenia. In anticipation of more quantitative data, we recommend the application of the principle of As Low As Reasonably Achievable to lymphocyte-rich regions for radiotherapy treatment planning to reduce the radiation doses to these structures, thus moving toward "Lymphocyte-Sparing Radiotherapy."

Human fibronectin extra domain B as a biomarker for targeted therapy in cancer.

The extracellular matrix protein fibronectin contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumours, particularly in solid tumours, different types of lymphoma and some leukaemias. This domain, called the extra domain B (ED-B), thus has broad therapeutic potential. The antibody L19 has been developed to specifically target ED-B and has shown therapeutic potential when combined with cytokines, such as IL-2. In this review article, we discuss the preclinical research and clinical trials that highlight the potential of ED-B targeting for the imaging and treatment of various types of cancer. ED-B-centred studies also highlight how proper patient stratification is of utmost importance for the successful implementation of novel antibody-based targeted therapies.

Hypoxia PET Imaging with [18F]-HX4-A Promising Next-Generation Tracer.

Hypoxia-a common feature of the majority of solid tumors-is a negative prognostic factor, as it is associated with invasion, metastasis and therapy resistance. To date, a variety of methods are available for the assessment of tumor hypoxia, including the use of positron emission tomography (PET). A plethora of hypoxia PET tracers, each with its own strengths and limitations, has been developed and successfully validated, thereby providing useful prognostic or predictive information. The current review focusses on [18F]-HX4, a promising next-generation hypoxia PET tracer. After a brief history of its development, we discuss and compare its characteristics with other hypoxia PET tracers and provide an update on its progression into the clinic. Lastly, we address the potential applications of assessing tumor hypoxia using [18F]-HX4, with a focus on improving patient-tailored therapies.

Radiomics: from qualitative to quantitative imaging.

Historically, medical imaging has been a qualitative or semi-quantitative modality. It is difficult to quantify what can be seen in an image, and to turn it into valuable predictive outcomes. As a result of advances in both computational hardware and machine learning algorithms, computers are making great strides in obtaining quantitative information from imaging and correlating it with outcomes. Radiomics, in its two forms "handcrafted and deep," is an emerging field that translates medical images into quantitative data to yield biological information and enable radiologic phenotypic profiling for diagnosis, theragnosis, decision support, and monitoring. Handcrafted radiomics is a multistage process in which features based on shape, pixel intensities, and texture are extracted from radiographs. Within this review, we describe the steps: starting with quantitative imaging data, how it can be extracted, how to correlate it with clinical and biological outcomes, resulting in models that can be used to make predictions, such as survival, or for detection and classification used in diagnostics. The application of deep learning, the second arm of radiomics, and its place in the radiomics workflow is discussed, along with its advantages and disadvantages. To better illustrate the technologies being used, we provide real-world clinical applications of radiomics in oncology, showcasing research on the applications of radiomics, as well as covering its limitations and its future direction.