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Adoptive cellular therapies: the current landscape

For many cancer types, the immune system plays an essential role in their development and growth. Based on these rather novel insights, immunotherapeutic strategies have been developed. In the past decade, immune checkpoint blockade has demonstrated a major breakthrough in cancer treatment and has currently been approved for the treatment of multiple tumor types. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) or gene-modified T cells expressing novel T cell receptors (TCR) or chimeric antigen receptors (CAR) is another strategy to modify the immune system to recognize tumor cells and thus carry out an anti-tumor effector function. These treatments have shown promising results in various tumor types, and multiple clinical trials are being conducted worldwide to further optimize this treatment modality. Most successful results were obtained in hematological malignancies with the use of CD19-directed CAR T cell therapy and already led to the commercial approval by the FDA. This review provides an overview of the developments in ACT, the associated toxicity, and the future potential of ACT in cancer treatment.</p

Response prediction and evaluation using PET in patients with solid tumors treated with immunotherapy

Simple Summary In cancer treatment, immunotherapy is increasingly becoming important as a component of first-line treatment and has improved the prognosis of patients since its introduction. A large group of patients, however, do not respond to immunotherapy, and predicting a treatment response remains challenging. Furthermore, evaluating a response using conventional computed tomography (CT) scans is not straightforward due to the different mechanism of action of immunotherapy compared to chemotherapy. This review provides an overview of positron emission tomography (PET) in predicting and evaluating treatment response to immunotherapy. In multiple malignancies, checkpoint inhibitor therapy has an established role in the first-line treatment setting. However, only a subset of patients benefit from checkpoint inhibition, and as a result, the field of biomarker research is active. Molecular imaging with the use of positron emission tomography (PET) is one of the biomarkers that is being studied. PET tracers such as conventional F-18-FDG but also PD-(L)1 directed tracers are being evaluated for their predictive power. Furthermore, the use of artificial intelligence is under evaluation for the purpose of response prediction. Response evaluation during checkpoint inhibitor therapy can be challenging due to the different response patterns that can be observed compared to traditional chemotherapy. The additional information provided by PET can potentially be of value to evaluate a response early after the start of treatment and provide the clinician with important information about the efficacy of immunotherapy. Furthermore, the use of PET to stratify between patients with a complete response and those with a residual disease can potentially guide clinicians to identify patients for which immunotherapy can be discontinued and patients for whom the treatment needs to be escalated. This review provides an overview of the use of positron emission tomography (PET) to predict and evaluate treatment response to immunotherapy.Pathogenesis and treatment of chronic pulmonary disease

Исследование свободных колебаний ортотропных цилиндрических оболочек на основе различных моделей

Досліджуються вільні коливання ортотропних циліндричних оболонок при різних граничних умовах на краях в уточненій постановці з застосуванням теорії Міндліна–Тимошенка та на основі тривимірної теорії пружності. Для розрахунку частот використовується чисельно-аналітичний підхід, який базується на застосуванні сплайн-апроксимації, а також методу колокації, дискретної ортогоналізації разом з методом покрокового пошуку. Проведено порівняння частот циліндричних оболонок з різними граничними умовами на торцях, отриманих в рамках різних моделей.A problem of natural vibrations of orthotropic cylindrical shells under various boundary conditions of its end-faces within the framework of the Mindlin–Timoshenko theory and on the basis of 3-D elasticity theory is considered. Using the method of spline-approximation and collocation, the problems are solved by the steady-state numerical method of discrete orthogonalization with incremental search. The comparison of the frequencies of cylindrical shells with different boundary conditions on their ends within various models is performed

[F-18]FDG-PET accurately identifies pathological response early upon neoadjuvant immune checkpoint blockade in head and neck squamous cell carcinoma

Purpose To investigate the utility of [F-18]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous cell carcinoma (HNSCC) before surgery.Methods In the IMCISION trial (NCT03003637), 32 patients with stage II-IVb HNSCC were treated with neoadjuvant nivolumab with (n = 26) or without (n = 6) ipilimumab (weeks 1 and 3) before surgery (week 5). [F-18]FDG-PET/CT scans were acquired at baseline and shortly before surgery in 21 patients. Images were analysed for SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG). Major and partial pathological responses (MPR and PPR, respectively) to immunotherapy were identified based on the residual viable tumour in the resected primary tumour specimen (<= 10% and 11-50%, respectively). Pathological response in lymph node metastases was assessed separately. Response for the 2 [F-18]FDG-PET-analysable patients who did not undergo surgery was determined clinically and per MR-RECIST v.1.1. A patient with a primary tumour MPR, PPR, or primary tumour MR-RECIST-based response upon immunotherapy was called a responder.Results Median Delta SUVmax, Delta SUVmean, Delta MTV, and Delta TLG decreased in the 8 responders and were significantly lower compared to the 13 non-responders (P = 0.05, P = 0.002, P < 0.001, and P < 0.001). A Delta MTV or Delta TLG of at least - 12.5% detected a primary tumour response with 95% accuracy, compared to 86% for the EORTC criteria. None of the patients with a Delta TLG of - 12.5% or more at the primary tumour site developed a relapse (median FU 23.0 months since surgery). Lymph node metastases with a PPR or MPR (5 metastases in 3 patients) showed a significant decrease in SUVmax (median - 3.1, P = 0.04). However, a SUVmax increase (median + 2.1) was observed in 27 lymph nodes (in 11 patients), while only 13 lymph nodes (48%) contained metastases in the corresponding neck dissection specimen.Conclusions Primary tumour response assessment using [F-18]FDG-PET-based Delta MTV and Delta TLG accurately identifies pathological responses early upon neoadjuvant ICB in HNSCC, outperforming the EORTC criteria, although pseudoprogression is seen in neck lymph nodes. [F-18]FDG-PET could, upon validation, select HNSCC patients for response-driven treatment adaptation in future trials.Otorhinolaryngolog

Identification of patient-specific CD4+ and CD8+ T cell neoantigens through HLA-unbiased genetic screens

Cancer neoantigens that arise from tumor mutations are drivers of tumor-specific T cell responses, but identification of T cell-recognized neoantigens in individual patients is challenging. Previous methods have restricted antigen discovery to selected HLA alleles, thereby limiting the breadth of neoantigen repertoires that can be uncovered. Here, we develop a genetic neoantigen screening system that allows sensitive identification of CD4+ and CD8+ T cell-recognized neoantigens across patients’ complete HLA genotypes.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Diagnostic performance of early increase in S100B or LDH as outcome predictor for non-responsiveness to anti-PD-1 monotherapy in advanced melanoma

As a subset of advanced melanoma patients derive long-term benefit from anti-PD-1 therapy, early identification of non-responsiveness would enable an early switch to next line therapies. This study assessed if an early increase in S100B or lactate dehydrogenase (LDH) could be predictive for non-responsiveness to anti-PD-1. We retrospectively analysed advanced melanoma patients treated with anti-PD-1 monotherapy. Serum S100B and LDH levels were measured at baseline and before every infusion. Non-response was defined as progression or death at 6 months. Marker cut-offs were defined based on > 95% specificity and feasibility in clinical practice. For validation an independent cohort was analysed. In total, 313 patients were included (166 patients in training cohort, 147 patients in validation cohort). Increase of > 50% in LDH or > 100% in S100B above upper limit of normal at week 6 compared to baseline was determined as criterion to positively test for non-responsiveness. In the validation cohort, obtained specificity of the combination test was > 95% with a positive predictive value of 82%; obtained sensitivity was lower (21%), with a negative predictive value of 55%. Early increase in S100B or LDH is a strong parameter for non-responsiveness to anti-PD-1 in advanced melanoma. Prospective confirmation is needed before clinical implementation.</p

T cells expanded from renal cell carcinoma display tumor-specific CD137 expression but lack significant IFN-gamma, TNF-alpha or IL-2 production

Metastatic renal cell carcinoma (RCC) has a poor prognosis. Recent advances have shown beneficial responses to immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies. As only a subset of RCC patients respond, alternative strategies should be explored. Patients refractory to anti-PD-1 therapy may benefit from autologous tumor-infiltrating lymphocyte (TIL) therapy. Even though efficient TIL expansion was reported from RCC lesions, it is not well established how many RCC TIL products are tumor-reactive, how well they produce pro-inflammatory cytokines in response to autologous tumors, and whether their response correlates with the presence of specific immune cells in the tumor lesions. We here compared the immune infiltrate composition of RCC lesions with that of autologous kidney tissue of 18 RCC patients. Tcell infiltrates were increased in the tumor lesions, and CD8(+) Tcell infiltrates were primarily of effector memory phenotype. Nine out of 16 (56%) tested TIL products we generated were tumor-reactive, as defined by CD137 upregulation after exposure to autologous tumor digest. Tumor reactivity was found in particular in TIL products originating from tumors with ahigh percentage of infiltrated Tcells compared to autologous kidney, and increased CD25 expression on CD8(+) Tcells. Importantly, although TIL products had the capacity to produce the key effector cytokines IFN-gamma, TNF-alpha or IL-2, they failed to produce significant amounts in response to autologous tumor digests. In conclusion, TIL products from RCC lesions contain tumor-reactive Tcells. Their restricted tumor-specific cytokine production requires further investigation of immunosuppressive factors in RCC and subsequent optimization of RCC-derived TIL culture conditions.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease