Abskopale Effekte einer Radiotherapie und kombinierter mRNA-basierter Immuntherapie in vivo

Hintergrund: Die Metastasierung von Tumoren und die Tumor-Immunevasion stellen große Herausforderungen in der Behandlung von Tumorerkrankungen dar. Es konnte gezeigt werden, dass eine Radiotherapie das immunsuppressive Mikromilieu von Tumoren überwinden kann und eine zunehmende Anzahl von Fallberichten deuten sogar auf "systemische" bzw. abskopale Anti-Tumoreffekte einer lokalen Strahlentherapie mit einer einhergehenden systemischen Immunantwort hin. Das Ziel dieser Arbeit ist die Untersuchung potentieller abskopaler Effekte einer Strahlentherapie allein (RTX) und in Kombination mit einer mRNA-basierten Tumorvakzinierung (CureVac RNActive®). Methoden: Hierzu wurden C57BL/6 Mäuse mit ovalbuminexprimierenden Thymomzellen in das rechte Hinterbein (Primärtumor) und in die linke Flanke (Sekundärtumor) mit einer Verzögerung von 4 Tagen injiziert (Doppeltumor-Modell). Die Primärtumoren wurden dabei mit 3 Fraktionen à 2 Gy bestrahlt, während die Sekundärtumoren mehrfach abgeschirmt wurden, um den Einfluss einer direkten Bestrahlung größtmöglich zu minimieren. Die Therapiegruppe mit einer alleinigen Tumorvakzinierung (RNA) und die kombinierte Radioimmuntherapie (RTX+RNA) erhielten zweimal wöchentlich eine intradermale mRNA-basierte RNActive®-Vakzinierung. Zusätzlich erfolgte eine Cytokin-Microarray-Analyse der nicht-bestrahlten Sekundärtumoren, um den biologischen Hintergrund potentieller abskopaler Effekte zu analysieren. Ergebnisse: Sowohl eine alleinige Strahlentherapie, als auch die kombinierte Radioimmuntherapie führten zu einer signifikanten Verzögerung des Primärtumorwachstums und zu einer vollständigen Tumorkontrolle bei 15% (RTX) bzw. 53% (RTX+RNA) der Mäuse. In den kleineren Sekundärtumoren verlangsamte die Radioimmuntherapie die Wachstumsrate im Vergleich zur alleinigen Tumorvakzinierung (p = 0.002) und der Kontrollgruppe (p = 0.01) signifikant. Zusätzlich zeigte das Tumor-Mikromilieu der nicht-bestrahlten Sekundärtumoren signifikante Unterschiede in der Zytokin- und Chemokin-Expression in Abhängigkeit der durchgeführten Therapie und insgesamt signifikante Unterschiede bzw. Trends für die Induktion pro-immunogener Zytokine durch die kombinierte Radioimmuntherapie im Vergleich zu den anderen Versuchsgruppen. Diskussion: Zusammenfassend konnten wir zeigen, dass auch eine normofraktionierte Bestrahlung mit relativ niedrigen konventionellen Bestrahlungsdosen zu einer Wachstumsverzögerung, sowohl des bestrahlten Primär- als auch, im Falle einer kombinierten Radioimmuntherapie, des nicht-bestrahlten kontralateralen Sekundärtumors führen kann. Die geringe Streustrahlung im Bereich des Sekundärtumors ist dabei zu gering um die Reduktion der Wachstumsgeschwindigkeit vollständig zu erklären, sodass wir von einem systemischem bzw. abskopalen Bestrahlungseffekt ausgehen. Eine Kombination aus Immuntherapie und Radiotherapie kann sowohl eine lokale, als auch eine systemische Anti-Tumor-Immunität induzieren und stellt daher eine sehr vielversprechende Behandlungsstrategie von Tumorerkrankungen dar, was auch klinisch bereits unabhängig für mehrere Tumorentitäten und Tumorhistologien gezeigt werden konnte

PET/CT radiomics for prediction of hyperprogression in metastatic melanoma patients treated with immune checkpoint inhibitors

PurposeThis study evaluated pretreatment 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT-based radiomic signatures for prediction of hyperprogression in metastatic melanoma patients treated with immune checkpoint inhibition (ICI).Material and methodFifty-six consecutive metastatic melanoma patients treated with ICI and available imaging were included in the study and 330 metastatic lesions were individually, fully segmented on pre-treatment CT and FDG-PET imaging. Lesion hyperprogression (HPL) was defined as lesion progression according to RECIST 1.1 and doubling of tumor growth rate. Patient hyperprogression (PD-HPD) was defined as progressive disease (PD) according to RECIST 1.1 and presence of at least one HPL. Patient survival was evaluated with Kaplan-Meier curves. Mortality risk of PD-HPD status was assessed by estimation of hazard ratio (HR). Furthermore, we assessed with Fisher test and Mann-Whitney U test if demographic or treatment parameters were different between PD-HPD and the remaining patients. Pre-treatment PET/CT-based radiomic signatures were used to build models predicting HPL at three months after start of treatment. The models were internally validated with nested cross-validation. The performance metric was the area under receiver operating characteristic curve (AUC).ResultsPD-HPD patients constituted 57.1% of all PD patients. PD-HPD was negatively related to patient overall survival with HR=8.52 (95%CI 3.47-20.94). Sixty-nine lesions (20.9%) were identified as progressing at 3 months. Twenty-nine of these lesions were classified as hyperprogressive, thereby showing a HPL rate of 8.8%. CT-based, PET-based, and PET/CT-based models predicting HPL at three months after the start of treatment achieved testing AUC of 0.703 +/- 0.054, 0.516 +/- 0.061, and 0.704 +/- 0.070, respectively. The best performing models relied mostly on CT-based histogram features.ConclusionsFDG-PET/CT-based radiomic signatures yield potential for pretreatment prediction of lesion hyperprogression, which may contribute to reducing the risk of delayed treatment adaptation in metastatic melanoma patients treated with ICI

Improved Survival Prediction by Combining Radiological Imaging and S-100B Levels Into a Multivariate Model in Metastatic Melanoma Patients Treated With Immune Checkpoint Inhibition

Purpose: We explored imaging and blood bio-markers for survival prediction in a cohort of patients with metastatic melanoma treated with immune checkpoint inhibition. Materials and Methods: 94 consecutive metastatic melanoma patients treated with immune checkpoint inhibition were included into this study. PET/CT imaging was available at baseline (Tp0), 3 months (Tp1) and 6 months (Tp2) after start of immunotherapy. Radiological response at Tp2 was evaluated using iRECIST. Total tumor burden (TB) at each time-point was measured and relative change of TB compared to baseline was calculated. LDH, CRP and S-100B were also analyzed. Cox proportional hazards model and logistic regression were used for survival analysis. Results: iRECIST at Tp2 was significantly associated with overall survival (OS) with C-index=0.68. TB at baseline was not associated with OS, whereas TB at Tp1 and Tp2 provided similar predictive power with C-index of 0.67 and 0.71, respectively. Appearance of new metastatic lesions during follow-up was an independent prognostic factor (C-index=0.73). Elevated LDH and S-100B ratios at Tp2 were significantly associated with worse OS: C-index=0.73 for LDH and 0.73 for S-100B. Correlation of LDH with TB was weak (r=0.34). A multivariate model including TB change, S-100B, and appearance of new lesions showed the best predictive performance with C-index=0.83. Conclusion: Our analysis shows only a weak correlation between LDH and TB. Additionally, baseline TB was not a prognostic factor in our cohort. A multivariate model combining early blood and imaging biomarkers achieved the best predictive power with regard to survival, outperforming iRECIST

Sex-Related Differences in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition

Objectives: We aimed to investigate sex-related differences in patients with advanced melanoma treated with ICI by linking the assessment of inflammatory response in peripheral blood, onset of immune-related adverse events IRAEs during therapy and treatment response in short- and long-term. Methods: For the purpose of this single-center retrospective study metastatic melanoma patients treated with ICI were included. Baseline patient characteristics, blood sample tests and the onset of immune-related adverse events IRAEs were documented based on clinical records. The short-term treatment response was assessed with 18F-2-Fluor-2-desoxy-D-glucose Positron Emission Tomography/Computed Tomography FDG-PET/CT scans performed six months after initiation of ICI. The overall survival OS and progression-free survival PFS were used as endpoints to assess the long-term response to immunotherapy. Results: In total, 103 patients with advanced melanoma (mean age 68 ± 13.83 years) were included, 29 women (mean age 60.41 ± 14.57 years) and 74 men (mean age 65.66 ± 13.34 years). The primary tumor was located on a lower extremity in one out of three women and on the head/neck in one out of three men (p < 0.001). While the superficial spreading (41%) and nodular (36%) melanoma subtypes represented together 77% of the cases in male population, women showed a more heterogenous distribution of melanoma subtypes with the superficial spreading (35%), nodular (23%), acral lentiginous (19%) and mucosal (12%) melanoma subtypes being most frequent in female population (p < 0.001). Most differences between women and men with regards to inflammatory parameters were observed six months after initiation of ICI with a higher median NLR (p = 0.038), lower counts of lymphocytes (p = 0.004) and thrombocytes (p = 0.089) in addition to lower counts of erythrocytes (p < 0.001) and monocytes (p < 0.001) in women towards men. IRAEs were more frequent in women towards men (p = 0.013). Women were more likely to display endocrinological IRAEs, such as thyroiditis being the most frequent adverse event in women. Interestingly IRAEs of the gastrointestinal tract were the most frequent ones in men. Finally, men with advanced melanoma showed a significantly better response to immunotherapy in short- (p = 0.015) and long-term (OS p = 0.015 and PFS p < 0.001) than women. In fact, every fourth man died during the course of the disease, while every second woman did not survive. (p = 0.001). Conclusion: Men with advanced melanoma showed a significantly better response to immunotherapy in short- and long-term than women. Higher immune activation in peripheral blood before and after initiation ICI might be linked to favorable treatment response during and after ICI in favor of men and decoupled from the onset of IRAEs. Given the significantly higher immunotoxicity and worse outcome experienced by women compared to men the use of ICI should be chosen carefully in women with advanced melanoma

Inflammatory Blood Parameters as Biomarkers for Response to Immune Checkpoint Inhibition in Metastatic Melanoma Patients

Objectives: We aimed to investigate whether inflammatory parameters in peripheral blood at baseline and during the first six months of treatment could predict the short- and long-term outcomes of metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs). Methods: This single-center retrospective study considered patients with metastatic melanoma treated with either single or dual checkpoint inhibition. Blood sample tests were scheduled together with 18F-2-fluor-2-desoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans at baseline and at three and six months after initiation of ICI treatment. The short-term response to ICIs was assessed using FDG-PET/CT scans. The long-term response to ICIs was assessed using the overall survival OS and progression-free survival PFS as endpoints. Results: A total of 100 patients with metastatic melanoma were included (female, n = 31; male, n = 69). The median age was 68 years (interquartile range (IQR): 53–74 years). A total of 82% of the cohort displayed a disease control (DC), while 18% presented a progressive disease (PD) after six months of ICIs. Patients with DC after six months of ICIs showed a lower median of the neutrophils-to-lymphocytes ratio (NLR) toward patients with PD, with no significant prediction power of NLR neither in the short nor in the long term. The count of neutrophils at the baseline time point (TP 0) (p = 0.037) and erythrocytes three months after treatment start (TP 1) (p = 0.010) were strong predictive parameters of a DC six months after treatment start. Erythrocytes (p p = 0.021) were strong biomarkers predictive of a favorable OS. Erythrocytes (p = 0.013) and lymphocytes (p = 0.017) also showed a significant prediction power for a favorable PFS. Conclusions: Inflammatory blood parameters predicted the short- and long-term response to ICIs with a strong predictive power. Our results suggested the validation of inflammatory blood parameters as biomarkers that predict immunotherapies’ efficacity in metastatic melanoma patients. However, confounding factors that interfere with myelopoiesis should also be taken into consideration

Dosimetric analysis of local failures in skull-base chordoma and chondrosarcoma following pencil beam scanning proton therapy

Background Despite combined modality treatment involving surgery and radiotherapy, a relevant proportion of skull-base chordoma and chondrosarcoma patients develop a local recurrence (LR). This study aims to analyze patterns of recurrence and correlate LR with a detailed dosimetric analysis. Methods 222 patients were treated with proton radiotherapy for chordoma (n = 151) and chondrosarcoma (n = 71) at the PSI between 1998 and 2012. All patients underwent surgery, followed by pencil-beam scanning proton therapy to a mean dose of 72.5 ± 2.2GyRBE. A retrospective patterns of recurrence analysis was performed: LR were contoured on follow-up MRI, registered with planning-imaging and the overlap with initial target structures (GTV, PTVhigh-dose, PTVlow-dose) was calculated. DVH parameters of planning structures and recurrences were calculated and correlated with LR using univariate and multivariate cox regression. Results After a median follow-up of 50 months, 35 (16%) LR were observed. Follow-up MRI imaging was available for 27 (77%) of these recurring patients. Only one (3.7%) recurrence was located completely outside the initial PTV (surgical pathway recurrence). The mean proportions of LR covered by the initial target structures were 48% (range 0–86%) for the GTV, 70% (range 0–100%) for PTVhigh and 83% (range 0–100%) for PTVlow. In the univariate analysis, the following DVH parameters were significantly associated with LR: GTV(V < 66GyRBE, p = 0.01), GTV(volume, p = 0.02), PTVhigh(max, p = 0.02), PTVhigh(V < 66GyRBE, p = 0.03), PTVhigh(V < 59GyRBE, p = 0.02), PTVhigh(volume, p = 0.01) and GTV(D95, p = 0.05). In the multivariate analysis, only histology (chordoma vs. chondrosarcoma, p = 0.01), PTVhigh(volume, p = 0.05) and GTV(V < 66GyRBE, p = 0.02) were independent prognostic factors for LR. Conclusion This study identified DVH parameters, which are associated with the risk of local recurrence after proton therapy using pencil-beam scanning for patients with skull-base chordoma and chondrosarcoma

Malignancy Rate of Indeterminate Findings on FDG-PET/CT in Cutaneous Melanoma Patients

Background: The use of 18F-2-Fluor-2-desoxy-D-glucose Positron Emission Tomography/Computed Tomography FDG-PET/CT in clinical routine for staging, treatment response monitoring and post treatment surveillance in metastatic melanoma patients has noticeably increased due to significant improvement of the overall survival rate in melanoma patients. However, determining the dignity of the findings with increased metabolic activity on FDG-PET/CT can be sometimes challenging and may need further investigation. Purpose: We aimed to investigate the malignancy rate of indeterminate findings on FDG-PET/CT in metastatic cutaneous melanoma patients. Methods: This single-center retrospective study included cutaneous melanoma patients who underwent FDG-PET/CT in clinical routine between 2015 and 2017 with findings reported as indeterminate and therefore requiring further evaluation. The dignity of the included findings was determined by subsequent imaging and, if required, additional histopathology. The impact of the outcome on the clinical management was also reported. Results: A total of 842 FDG-PET/CT reports of 244 metastatic cutaneous melanoma patients were reviewed. Sixty indeterminate findings were included. Almost half of all indeterminate findings were lymph nodes, lung nodules and cerebral lesions. In total, 43.3% of all included findings proved to be malignant. 81% of all malignant lesions were metastases of cutaneous melanoma, while 19% of all malignant lesions could be attributed to other primary malignancies, such as lung, breast, thyroid and colorectal cancers. Malignant findings influenced clinical management in 60% of the cases. Conclusion: Indeterminate findings on FDG-PET/CT in metastatic cutaneous melanoma patients should be further investigated. Almost one out of every two indeterminate findings on FDG-PET/CT is malignant. The majority of the findings are melanoma manifestations, however, in a significant percentage, other primary tumors are found. Upon verification, patient management is changed in most cases.Peer Reviewe

Impact of Low-Dose Irradiation of the Lung and Heart on Toxicity and Pulmonary Function Parameters after Thoracic Radiotherapy

Objective: To assess the impact of (low) dose irradiation to the lungs and heart on the incidence of pneumonitis and pulmonary function changes after thoracic radiotherapy (RT). Methods/Material: Data of 62 patients treated with curative thoracic radiotherapy were analyzed. Toxicity data and pulmonary function tests (PFTs) were obtained before RT and at 6 weeks, at 12 weeks, and at 6 months after RT. PFTs included ventilation (e.g., vital capacity) and diffusion parameters (e.g., diffusion capacity for carbon monoxide (DLCO)). Dosimetric data of the lung and heart were extracted to assess the impact of dose on PFT changes and radiation pneumonitis (RP). Results: No statistically significant correlations between dose parameters and changes in ventilation parameters were found. There were statistically significant correlations between DLCO and low-dose parameters of the lungs (V5Gy&ndash;V30Gy (%)) and irradiation of the heart during the follow-up up to 6 months after RT, as well as a temporary correlation of the V60Gy (%) on the blood gas parameters at 12 weeks after RT. On multivariate analysis, both heart and lung parameters had a significant impact on DLCO. There was no statistically significant influence of any patient or treatment-related (including dose parameters) factors on the incidence of &ge;G2 pneumonitis. Conclusion: There seems to be a lasting impact of low dose irradiation to the lung as well as irradiation to the heart on the DLCO after thoracic radiotherapy. No influence on RP was found in this analysis

Malignancy Rate of Indeterminate Findings on FDG-PET/CT in Cutaneous Melanoma Patients

Background: The use of 18F-2-Fluor-2-desoxy-D-glucose Positron Emission Tomography/Computed Tomography FDG-PET/CT in clinical routine for staging, treatment response monitoring and post treatment surveillance in metastatic melanoma patients has noticeably increased due to significant improvement of the overall survival rate in melanoma patients. However, determining the dignity of the findings with increased metabolic activity on FDG-PET/CT can be sometimes challenging and may need further investigation. Purpose: We aimed to investigate the malignancy rate of indeterminate findings on FDG-PET/CT in metastatic cutaneous melanoma patients. Methods: This single-center retrospective study included cutaneous melanoma patients who underwent FDG-PET/CT in clinical routine between 2015 and 2017 with findings reported as indeterminate and therefore requiring further evaluation. The dignity of the included findings was determined by subsequent imaging and, if required, additional histopathology. The impact of the outcome on the clinical management was also reported. Results: A total of 842 FDG-PET/CT reports of 244 metastatic cutaneous melanoma patients were reviewed. Sixty indeterminate findings were included. Almost half of all indeterminate findings were lymph nodes, lung nodules and cerebral lesions. In total, 43.3% of all included findings proved to be malignant. 81% of all malignant lesions were metastases of cutaneous melanoma, while 19% of all malignant lesions could be attributed to other primary malignancies, such as lung, breast, thyroid and colorectal cancers. Malignant findings influenced clinical management in 60% of the cases. Conclusion: Indeterminate findings on FDG-PET/CT in metastatic cutaneous melanoma patients should be further investigated. Almost one out of every two indeterminate findings on FDG-PET/CT is malignant. The majority of the findings are melanoma manifestations, however, in a significant percentage, other primary tumors are found. Upon verification, patient management is changed in most cases