Chimeric antigen receptor (CAR) T-cell therapy is an emerging immunotherapy against several malignancies including glioblastoma, the most common and most aggressive malignant primary brain tumor in ...adults. The challenges in solid tumor immunotherapy comprise heterogenously expressed tumor target antigens and restricted trafficking of CAR T cells to and impaired long-term persistence at the tumor site, as well as the unaddressed integration of CAR T-cell therapy into conventional anticancer treatments. We addressed these questions using a NKG2D-based chimeric antigen receptor construct (chNKG2D) in fully immunocompetent orthotopic glioblastoma mouse models. ChNKG2D T cells demonstrated high IFNγ production and cytolytic activity
Upon systemic administration
, chNKG2D T cells migrated to the tumor site in the brain, did not induce adverse events, prolonged survival, and cured a fraction of glioma-bearing mice. Surviving mice were protected long-term against tumor rechallenge. Mechanistically, this was not solely the result of a classical immune memory response, but rather involved local persistence of chNKG2D T cells. A subtherapeutic dose of local radiotherapy in combination with chNKG2D T-cell treatment resulted in synergistic activity in two independent syngeneic mouse glioma models by promoting migration of CAR T cells to the tumor site and increased effector functions. We thus provide preclinical proof-of-concept of NKG2D CAR T-cell activity in mouse glioma models and demonstrate efficacy, long-term persistence, and synergistic activity in combination with radiotherapy, providing a rationale to translate this immunotherapeutic strategy to human glioma patients.
These findings provide evidence for synergy of conventional anticancer therapy and CAR T cells and heralds future studies for other treatment combinations.
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•Metastasis-directed radiotherapy (MDRT) has the potential to prolong survival.•Definitions and reporting of oligometastatic disease (OMD) are heterogeneous.•OMD is typically based on the ...imaging-detected number of metastases, but definitions in the literature are inconsistent and warrant further study. No formal clinical or molecular biomarkers currently exist to aid classification as OMD.•Currently no clinical or molecular biomarkers exist to aid classification of OMD.•Advanced technologies are mandatory to guarantee safe MDRT and improve outcome.•Consensus for extra-cranial OMD defines maximum 5 metastatic lesions off-protocol.
Recognizing the rapidly increasing interest and evidence in using metastasis-directed radiotherapy (MDRT) for oligometastatic disease (OMD), ESTRO and ASTRO convened a committee to establish consensus regarding definitions of OMD and define gaps in current evidence.
A systematic literature review focused on curative intent MDRT was performed in Medline, Embase and Cochrane. Subsequent consensus opinion, using a Delphi process, highlighted the current state of evidence and the limitations in the available literature.
Available evidence regarding the use of MDRT for OMD mostly derives from retrospective, single-centre series, with significant heterogeneity in patient inclusion criteria, definition of OMD, and outcomes reported. Consensus was reached that OMD is largely independent of primary tumour, metastatic location and the presence or length of a disease-free interval, supporting both synchronous and metachronous OMD. In the absence of clinical data supporting a maximum number of metastases and organs to define OMD, and of validated molecular biomarkers, consensus supported the ability to deliver safe and clinically meaningful radiotherapy with curative intent to all metastatic sites as a minimum requirement for defining OMD in the context of radiotherapy. Systemic therapy induced OMD was identified as a distinct state of OMD. High-resolution imaging to assess and confirm OMD is crucial, including brain imaging when indicated. Minimum common endpoints such as progression-free and overall survival, local control, toxicity and quality-of-life should be reported; uncommon endpoints as deferral of systemic therapy and cost were endorsed.
While significant heterogeneity exists in the current OMD definitions in the literature, consensus was reached on multiple key questions. Based on available data, OMD can to date be defined as 1–5 metastatic lesions, a controlled primary tumor being optional, but where all metastatic sites must be safely treatable. Consistent definitions and reporting are warranted and encouraged in ongoing trials and reports generating further evidence to optimize patient benefits.
Malignant liver tumours include a wide range of primary and secondary tumours. Although surgery remains the mainstay of curative treatment, modern therapies integrate a variety of neoadjuvant and ...adjuvant strategies and have achieved dramatic improvements in survival. Extensive tumour loads, which have traditionally been considered unresectable, are now amenable to curative treatment through systemic conversion chemotherapies followed by a variety of interventions such as augmentation of the healthy liver through portal vein occlusion, staged surgeries or ablation modalities. Liver transplantation is established in selected patients with hepatocellular carcinoma but is now emerging as a promising option in many other types of tumour such as perihilar cholangiocarcinomas, neuroendocrine or colorectal liver metastases. In this Review, we summarize the available therapies for the treatment of malignant liver tumours, with an emphasis on surgical and ablative approaches and how they align with other therapies such as modern anticancer drugs or radiotherapy. In addition, we describe three complex case studies of patients with malignant liver tumours. Finally, we discuss the outlook for future treatment, including personalized approaches based on molecular tumour subtyping, response to targeted drugs, novel biomarkers and precision surgery adapted to the specific tumour.
This study aimed to predict local tumor control (LC) after radiochemotherapy of head and neck squamous cell carcinoma (HNSCC) and human papillomavirus (HPV) status using computed tomography (CT) ...radiomics.
HNSCC patients treated with definitive radiochemotherapy were included in the retrospective study approved by the local ethical commission (93 and 56 patients in the training and validation cohorts, respectively). Three hundred seventeen CT radiomic features, including those based on shape, intensity, texture, and wavelet transform, were calculated in the primary tumor region. Cox and logistic regression models were built to predict LC and HPV status, respectively. The best-performing features in the univariable analysis were included in the multivariable analysis after the exclusion of redundant features. The quality of the models was assessed using the concordance index (CI) for modeling of LC and receiver operating characteristics area under the curve (AUC) for HPV status prediction. The radiomics LC model was compared to a model incorporating clinical parameters (tumor stage, volume, and HPV status) and a mixed model.
A radiomic signature comprising 3 features was significantly associated with LC (CI
= 0.75 and CI
= 0.78), showing that tumors with a more heterogeneous CT density distribution are at risk for decreased LC. The addition of clinical parameters to the radiomics model slightly improved the model in the training cohort but not in the validation cohort. Another radiomic signature showed good performance in HPV status prediction (AUC
= 0.85 and AUC
= 0.78) and indicated that HPV-positive tumors have a more homogenous CT density distribution.
Heterogeneity of HNSCC tumor density, quantified by CT radiomics, is associated with LC after radiochemotherapy and HPV status.
Loco-regional control (LRC) is a major clinical endpoint after definitive radiochemotherapy (RCT) of head and neck cancer (HNC). Radiomics has been shown a promising biomarker in cancer research, ...however closer related to primary tumor control than composite endpoints. Radiomics studies often focus on the analysis of primary tumor (PT). We hypothesize that the combination of PT and lymph nodes (LN) radiomics better predicts LRC in HNC treated with RCT. Radiomics analysis was performed in CT images of 128 patients using Z-Rad implementation (training n = 77, validation n = 51). 285 features were extracted from PT and involved LN. Features were preselected with the maximum relevance minimum redundancy method and the multivariate Cox model was trained using least absolute shrinkage and selection operator. The mixed model was based on the combination of PT and LN radiomics, whereas the PT model included only the PT features. The mixed model showed significantly higher performance than the PT model (p < 0.01), c-index of 0.67 and 0.63, respectively; and better risk group stratification. The clinical nodal status was not a significant predictor in the combination with PT radiomics. This study shows that the LRC can be better predicted by expansion of radiomics analysis with LN features.
This study evaluated an automated inverse treatment planning algorithm, Pinnacle Auto-Planning (AP), and compared automatically generated plans with historical plans in a large cohort of head and ...neck cancer patients.
Fifty consecutive patients treated with volumetric modulated arc therapy (Eclipse, Varian Medical System, Palo Alto, CA) for head and neck were re-planned with AP version 9.10. Only one single cycle of plan optimization using one single template was allowed for AP. The dose to the planning target volumes (PTV's; 3-4 dose levels), the organs at risk (OAR's) and the effective working time for planning was evaluated. Additionally, two experienced radiation oncologists blind-reviewed and ranked 10 plans.
Dose coverage and dose homogeneity of the PTV were significantly improved with AP, however manually optimized plans showed significantly improved dose conformity. The mean dose to the parotid glands, oral mucosa, swallowing muscles, dorsal neck tissue and maximal dose to the spinal cord were significantly reduced with AP. In 64 % of the plans, the mean dose to any OAR (spinal cord excluded) was reduced by >20 % with AP in comparison to the manually optimized plans. In 12 % of the plans, the manually optimized plans showed reduced doses by >20 % in at least one OAR. The experienced radiation oncologists preferred the AP plan and the clinical plan in 80 and 20 % of the cases, respectively. The average effective working time was 3.8 min ± 1.1 min in comparison to 48.5 min ± 6.0 min using AP compared to the manually optimized plans, respectively.
The evaluated automated planning algorithm achieved highly consistent and significantly improved treatment plans with potentially clinically relevant OAR sparing by >20 % in 64 % of the cases. The effective working time was substantially reduced with Auto-Planning.
Stereotactic body radiotherapy (SBRT) has become the standard of care for medically inoperable patients with peripherally located, early stage non-small cell lung cancer (NSCLC), and for those ...refusing surgical resection. Despite the availability of national and international guidelines, there exists substantial variability in many aspects of SBRT practice.
The ESTRO ACROP guideline is based on a questionnaire covering all aspects of SBRT implementation and practice (n=114 items). The questionnaire was answered by the 11 faculty members of the ESTRO course “Clinical practice and implementation of image-guided SBRT” and their 8 institutions.
Agreement by >50% of the institutions was achieved in 72% of all items. Only 8/57 technologies and techniques were identified as mandatory for SBRT while 32/57 were considered as optional. In contrast, quality-assurance related elements were considered as mandatory in 12/24 items. A consensus of risk-adapted SBRT fractionation was achieved with 3×15Gy for peripherally located lesions and 4×12Gy (PTV D95-D99; Dmax <125% to <150%) for lesions with broad chest wall contact. For patients free from severe comorbidities and with favourable long-term OS expectancy, use of the maximum tolerated dose of 3×18Gy should be considered.
This ACROP guideline achieved detailed recommendations in all aspects of SBRT implementation and practice, which will contribute to further standardization of SBRT for peripherally located early stage NSCLC.
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