Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma.

In multiple myeloma (MM), B cell maturation antigen (BCMA)-directed CAR T cells have emerged as a novel therapy with potential for long-term disease control. Anti-BCMA CAR T cells with a CD8-based transmembrane (TM) and CD137 (41BB) as intracellular costimulatory domain are in routine clinical use. As the CAR construct architecture can differentially impact performance and efficacy, the optimal construction of a BCMA-targeting CAR remains to be elucidated. Here, we hypothesized that varying the constituents of the CAR structure known to impact performance could shed light on how to improve established anti-BCMA CAR constructs. CD8TM.41BBIC-based anti-BCMA CAR vectors with either a long linker or a short linker between the light and heavy scFv chain, CD28TM.41BBIC-based and CD28TM.CD28IC-based anti-BCMA CAR vector systems were used in primary human T cells. MM cell lines were used as target cells. The short linker anti-BCMA CAR demonstrated higher cytokine production, whereas in vitro cytotoxicity, T cell differentiation upon activation and proliferation were superior for the CD28TM.CD28IC-based CAR. While CD28TM.CD28IC-based CAR T cells killed MM cells faster, the persistence of 41BBIC-based constructs was superior in vivo. While CD28 and 41BB costimulation come with different in vitro and in vivo advantages, this did not translate into a superior outcome for either tested model. In conclusion, this study showcases the need to study the influence of different CAR architectures based on an identical scFv individually. It indicates that current scFv-based anti-BCMA CAR with clinical utility may already be at their functional optimum regarding the known structural variations of the scFv linker.

Post-transplant-cyclophosphamide and short-term Everolimus as graft-versus-host-prophylaxis in patients with relapsed/refractory lymphoma and myeloma-Final results of the phase II OCTET-EVER trial.

BACKGROUND: Conditioning regimens and the choice of immunosuppression have substantial impact on immune reconstitution after allogeneic hematopoietic stem cell transplantation (aHSCT). The pivotal mechanism to maintain remission is the induction of the graft-versus-tumor effect. Relapse as well as graft versus host disease remain common. Classic immunosuppressive strategies implementing calcineurin inhibitors (CNI) have significant toxicities, hamper the immune recovery, and reduce the anti-cancer immune response. METHODS: We designed a phase II clinical trial for patients with relapsed and refractory lymphoid malignancies undergoing aHSCT using a CNI-free approach consisting of post-transplant cyclophosphamide (PTCy) and short-term Everolimus after reduced-intensity conditioning and matched peripheral blood stem cell transplantation. The results of the 19 planned patients are presented. Primary endpoint is the cumulative incidence and severity of acute GvHD. RESULTS: Overall incidence of acute GvHD was 53% with no grade III or IV. Cumulative incidence of NRM at 1, 2, and 4 years was 11%, 11%, and 16%, respectively, with a median follow-up of 43 months. Cumulative incidence of relapse was 32%, 32%, and 42% at 1, 2, and 4 years after transplant, respectively. Four out of six early relapses were multiple myeloma patients. Overall survival was 79%, 74%, and 62% at 1, 2, and 4 years. GvHD-relapse-free-survival was 47% after 3 years. CONCLUSIONS: Using PTCy and short-term Everolimus is safe with low rates of aGvHD and no severe aGvHD or cGvHD translating into a low rate of non-relapse mortality. Our results in this difficult to treat patient population are encouraging and warrant further studies.

Exercise Therapy in Oncology­the Impact on Quality of Life and Side Effects.

BACKGROUND: The diagnosis and treatment of cancer are highly stressful. Exercise therapy is often used to mitigate the adverse effects of treatment. But how good is the evidence base, and what has changed in recent years? In this narrative review, we present the current data and what it implies for the care of adults with cancer. METHODS: This review is based on data from meta-analyses and systematic reviews concerning 16 relevant clinical endpoints (outcomes) of exercise therapy for cancer patients RESULTS: The literature evaluated for this paper reveals that targeted exercise therapy is feasible and safe under appropriate supervision. It is highly effective for improving eight of the sixteen endpoints (anxiety, depression, fatigue, quality of life, physical function, secondary lymphedema after breast cancer, urinary incontinence, post-mastectomy pain syndrome in breast cancer) and may also have a beneficial effect on sleep quality, cardiotoxicity, and cognitive function. Less conclusive studies are currently available with respect to chemotherapy-induced polyneuropathy, nausea/vomiting, and bone health. There is currently insufficient data to suggest any benefit with respect to sexual function and risk factors for falling. CONCLUSION: The data situation shows that exercise therapy for cancer patients is safe and has manifold effects on selected clinically relevant parameters. Further studies should be performed regarding the possible utility of exercise therapy against treatment-related side effects for which the evidence is currently insufficient. On the basis of the currently available and already existing recommendations, quality-assured exercise therapy can be recommended to cancer patients suffering from a wide range of neoplastic conditions.

Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.

The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma.

BACKGROUND: BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g. profound and prolonged cytopenias) represents the most common grade ≥ 3 toxicity and can predispose for severe infectious complications. Here, we examined the utility of the CAR-HEMATOTOX (HT) score to predict toxicity and survival outcomes in patients receiving standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel. METHODS: Data were retrospectively collected from 113 r/r multiple myeloma patients treated between April 2021 and July 2022 across six international CAR-T centers. The HT score-composed of factors related to hematopoietic reserve and baseline inflammatory state-was determined prior to lymphodepleting chemotherapy. RESULTS: At lymphodepletion, 63 patients were HTlow (score 0-1) and 50 patients were HThigh (score ≥ 2). Compared to their HTlow counterparts, HThigh patients displayed prolonged severe neutropenia (median 9 vs. 3 days, p < 0.001), an increased severe infection rate (40% vs. 5%, p < 0.001), and more severe ICANS (grade ≥ 3: 16% vs. 0%, p < 0.001). One-year non-relapse mortality was higher in the HThigh group (13% vs. 2%, p = 0.019) and was predominantly attributable to fatal infections. Response rates according to IMWG criteria were higher in HTlow patients (≥ VGPR: 70% vs. 44%, p = 0.01). Conversely, HThigh patients exhibited inferior progression-free (median 5 vs. 15 months, p < 0.001) and overall survival (median 10.5 months vs. not reached, p < 0.001). CONCLUSIONS: These data highlight the prognostic utility of the CAR-HEMATOTOX score for both toxicity and treatment response in multiple myeloma patients receiving BCMA-directed CAR-T. The score may guide toxicity management (e.g. anti-infective prophylaxis, early G-CSF, stem cell boost) and help to identify suitable CAR-T candidates.

Polyclonal anti-thymocyte globulins for the prophylaxis of graft-versus-host disease after allogeneic stem cell or bone marrow transplantation in adults.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (SCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host disease (GVHD), a condition frequently occurring after an allogeneic SCT, is the result of host tissues being attacked by donor immune cells. It affects more than half of the patients after transplant either as acute and or chronic GVHD. One strategy for the prevention of GVHD is the administration of anti-thymocyte globulins (ATGs), a set of polyclonal antibodies directed against a variety of immune cell epitopes, leading to immunosuppression and immunomodulation. OBJECTIVES: To assess the effect of ATG used for the prevention of GVHD in patients undergoing allogeneic SCT with regard to overall survival, incidence and severity of acute and chronic GVHD, incidence of relapse, non-relapse mortality, graft failure and adverse events. SEARCH METHODS: For this update we searched the CENTRAL, MEDLINE, Embase, trial registers and conference proceedings on the 18th November 2022 along with reference checking and contacting study authors to identify additional studies. We did not apply language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) investigating the impact of ATG on GVHD prophylaxis in adults suffering from haematological diseases and undergoing allogeneic SCT. The selection criteria were modified from the previous version of this review. Paediatric studies and studies where patients aged < 18 years constituted more than 20 % of the total number were excluded. Treatment arms had to differ only in the addition of ATG to the standard GVHD prophylaxis regimen. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration for data collection, extraction and analyses. MAIN RESULTS: For this update we included seven new RCTs, leading to a total of ten studies investigating 1413 participants. All patients had a haematological condition which warranted an allogeneic SCT. The risk of bias was estimated as low for seven and unclear for three studies. ATG probably has little or no influence on overall survival (HR (hazard ratio) 0.93 (95 % confidence interval (CI) 0.77 to 1.13, nine studies, n = 1249, moderate-certainty evidence)). Estimated absolute effect: 430 surviving people per 1000 people not receiving ATG compared to 456 people surviving per 1000 people receiving the intervention (95 % CI 385 to 522 per 1000 people). ATG results in a reduction in acute GVHD II to IV with relative risk (RR) 0.68 (95 % CI 0.60 to 0.79, 10 studies, n = 1413, high-certainty evidence). Estimated absolute effect: 418 acute GVHD II to IV per 1000 people not receiving ATG compared to 285 per 1000 people receiving the intervention (95 % CI 251 to 331 per 1000 people). Addition of ATG results in a reduction of overall chronic GvHD with a RR of 0.53 (95 % CI 0.45 to 0.61, eight studies, n = 1273, high-certainty evidence). Estimated absolute effect: 506 chronic GVHD per 1000 people not receiving ATG compared to 268 per 1000 people receiving the intervention (95 % CI 228 to 369 per 1000 people). Further data on severe acute GVHD and extensive chronic GVHD are available in the manuscript. ATG probably slightly increases the incidence of relapse with a RR of 1.21 (95 % CI 0.99 to 1.49, eight studies,  n =1315, moderate-certainty evidence). Non relapse mortality is probably slightly or not affected by ATG with an HR of 0.86 (95 % CI 0.67 to 1.11, nine studies, n=1370, moderate-certainty evidence).   ATG prophylaxis may result in no increase in graft failure with a RR of 1.55 (95 % CI 0.54 to 4.44, eight studies, n = 1240, low-certainty evidence).  Adverse events could not be analysed due to the serious heterogeneity in the reporting between the studies, which limited comparability (moderate-certainty evidence) and are reported in a descriptive manner.   Subgroup analyses on ATG types, doses and donor type are available in the manuscript. AUTHORS' CONCLUSIONS: This systematic review suggests that the addition of ATG during allogeneic SCT probably has little or no influence on overall survival. ATG results in a reduction in the incidence and severity of acute and chronic GvHD. ATG intervention probably slightly increases the incidence of relapse and probably does not affect the non relapse mortality. Graft failure may not be affected by ATG prophylaxis. Analysis of data on adverse events was reported in a narrative manner. A limitation for the analysis was the imprecision in reporting between the studies thereby reducing the confidence in the certainty of evidence.

Influence of Adipose Tissue Distribution, Sarcopenia, and Nutritional Status on Clinical Outcomes After CD19 CAR T-cell Therapy.

Although CD19-directed chimeric antigen receptor T-cell therapy (CD19.CAR-T) has proven clinical efficacy for multiple refractory B-cell malignancies, over 50% of patients ultimately relapse. Recent evidence has underlined the critical role of the host in determining treatment responses. In this retrospective observational study of 106 patients with relapsed/refractory large B-cell lymphoma receiving standard-of-care CD19.CAR-T, we analyzed the impact of immunometabolic host features and detailed body composition measurements on post-CAR T clinical outcomes. We extracted muscle and adipose tissue distributions from prelymphodepletion CT images and assessed laboratory-based immuno-nutritional scores. Early responders displayed increased total abdominal adipose tissue deposits (TAT: 336 mm3 vs. 266 mm3, P = 0.008) and favorable immuno-nutritional scores compared to nonresponding patients. On univariate Cox regression analysis, visceral fat distribution, sarcopenia, and nutritional indices significantly impacted both progression-free (PFS) and overall survival (OS). Patients with a low skeletal muscle index (SMI; e.g.<34.5), a sarcopenia indicator, exhibited poor clinical outcomes (mOS 3.0 months vs. 17.6 months, log-rank P = 0.0026). Prognostically adverse immuno-nutritional scores were linked to inferior survival [low PNI: HROS, 6.31; 95% confidence interval (CI), 3.35-11.90; P < 0.001]. In a multivariable analysis adjusting for baseline Eastern Cooperative Oncology Group performance status, C-reactive protein, and lactate dehydrogenase, increased TAT was independently associated with improved clinical outcomes (adjusted HROS, 0.27; 95% CI, 0.08-0.90; P = 0.03). We noted particularly favorable treatment outcomes in patients with both increased abdominal fat and muscle mass (TAThigh/SMIhigh: 1-year PFS 50%, 1-year OS 83%). These real-world data provide evidence for a role of body composition and immuno-nutritional status in the context of CD19.CAR-T and suggest that the obesity paradox may extend to modern T cell-based immunotherapies. See related Spotlight by Nawas and Scordo, p. 704.

CD33 BiTE® molecule-mediated immune synapse formation and subsequent T-cell activation is determined by the expression profile of activating and inhibitory checkpoint molecules on AML cells.

Bispecific T-cell engager (BiTE®) molecules recruit T cells to cancer cells through CD3ε binding, independently of T-cell receptor (TCR) specificity. Whereas physiological T-cell activation is dependent on signal 1 (TCR engagement) and signal 2 (co-stimulation), BiTE molecule-mediated T-cell activation occurs without additional co-stimulation. As co-stimulatory and inhibitory molecules modulate the strength and nature of T-cell responses, we studied the impact of the expression profile of those molecules on target cells for BiTE molecule-mediated T-cell activation in the context of acute myeloid leukemia (AML). Accordingly, we created a novel in vitro model system using murine Ba/F3 cells transduced with human CD33 ± CD86 ± PD-L1. T-cell fitness was assessed by T-cell function assays in co-cultures and immune synapse formation by applying a CD33 BiTE molecule (AMG 330). Using our cell-based model platform, we found that the expression of positive co-stimulatory molecules on target cells markedly enhanced BiTE molecule-mediated T-cell activation. The initiation and stability of the immune synapse between T cells and target cells were significantly increased through the expression of CD86 on target cells. By contrast, the co-inhibitory molecule PD-L1 impaired the stability of BiTE molecule-induced immune synapses and subsequent T-cell responses. We validated our findings in primary T-cell-AML co-cultures, demonstrating a PD-L1-mediated reduction in redirected T-cell activation. The addition of the immunomodulatory drug (IMiD) lenalidomide to co-cultures led to stabilization of immune synapses and improved subsequent T-cell responses. We conclude that target cells modulate CD33 BiTE molecule-dependent T-cell activation and hence, combinatorial strategies might contribute to enhanced efficacy.

Survival and immunotoxicities in association with sex-specific body composition patterns of cancer patients undergoing immune-checkpoint inhibitor therapy - A systematic review and meta-analysis.

BACKGROUND: Imbalanced body composition is mechanistically connected to dysregulated immune activities. Whether overweight/obesity or sarcopenia has an impact on treatment results in cancer patients undergoing immune checkpoint inhibitor (ICI) therapy is currently under debate. We aimed to answer if survival rates and occurrence of immune-related adverse events (irAEs) were different in obese or sarcopenic patients. METHODS: A systematic search was conducted in PubMed, Embase and CENTRAL for all records published until July 2022 using specific search terms for body composition in combination with terms for ICI regimens. Two authors screened independently. All studies that reported on body mass index or sarcopenia measures were selected for further analysis. RESULTS: 48 studies reporting on overweight/obesity comprising of 19,767 patients, and 32 studies reporting on sarcopenia comprising of 3193 patients fulfilled the inclusion criteria. In the entire cohort, overweight/obesity was significantly associated with better progression-free survival (PFS; p = 0.009) and overall survival (OS; p <0.00001). Subgroup analyses stratified by sex revealed that overweight/obese males had the strongest survival benefit (PFS: p = 0.05; OS: p = 0.0005), and overweight/obese female patients did not show any. However, overweight/obese patients of both sexes had a higher risk to develop irAEs grade ≥3 (p = 0.0009). Sarcopenic patients showed significantly shorter PFS (p <0.0001) and OS (p <0.0001). The frequency of irAEs did not differ between sarcopenic and non-sarcopenic patients. CONCLUSION: This meta-analysis suggests that body composition is associated in a sex-specific manner with survival and irAEs in cancer patients undergoing ICI treatment.

Exercise interventions for adults with cancer receiving radiation therapy alone.

BACKGROUND: Radiation therapy (RT) is given to about half of all people with cancer. RT alone is used to treat various cancers at different stages. Although it is a local treatment, systemic symptoms may occur. Cancer- or treatment-related side effects can lead to a reduction in physical activity, physical performance, and quality of life (QoL). The literature suggests that physical exercise can reduce the risk of various side effects of cancer and cancer treatments, cancer-specific mortality, recurrence of cancer, and all-cause mortality. OBJECTIVES: To evaluate the benefits and harms of exercise plus standard care compared with standard care alone in adults with cancer receiving RT alone. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), CINAHL, conference proceedings and trial registries up to 26 October 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled people who were receiving RT without adjuvant systemic treatment for any type or stage of cancer. We considered any type of exercise intervention, defined as a planned, structured, repetitive, objective-oriented physical activity programme in addition to standard care. We excluded exercise interventions that involved physiotherapy alone, relaxation programmes, and multimodal approaches that combined exercise with other non-standard interventions such as nutritional restriction. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and the GRADE approach for assessing the certainty of the evidence. Our primary outcome was fatigue and the secondary outcomes were QoL, physical performance, psychosocial effects, overall survival, return to work, anthropometric measurements, and adverse events. MAIN RESULTS: Database searching identified 5875 records, of which 430 were duplicates. We excluded 5324 records and the remaining 121 references were assessed for eligibility. We included three two-arm RCTs with 130 participants. Cancer types were breast and prostate cancer. Both treatment groups received the same standard care, but the exercise groups also participated in supervised exercise programmes several times per week while undergoing RT. Exercise interventions included warm-up, treadmill walking (in addition to cycling and stretching and strengthening exercises in one study), and cool-down. In some analysed endpoints (fatigue, physical performance, QoL), there were baseline differences between exercise and control groups. We were unable to pool the results of the different studies owing to substantial clinical heterogeneity. All three studies measured fatigue. Our analyses, presented below, showed that exercise may reduce fatigue (positive SMD values signify less fatigue; low certainty). • Standardised mean difference (SMD) 0.96, 95% confidence interval (CI) 0.27 to 1.64; 37 participants (fatigue measured with Brief Fatigue Inventory (BFI)) • SMD 2.42, 95% CI 1.71 to 3.13; 54 participants (fatigue measured with BFI) • SMD 1.44, 95% CI 0.46 to 2.42; 21 participants (fatigue measured with revised Piper Fatigue Scale) All three studies measured QoL, although one provided insufficient data for analysis. Our analyses, presented below, showed that exercise may have little or no effect on QoL (positive SMD values signify better QoL; low certainty). • SMD 0.40, 95% CI -0.26 to 1.05; 37 participants (QoL measured with Functional Assessment of Cancer Therapy-Prostate) • SMD 0.47, 95% CI -0.40 to 1.34; 21 participants (QoL measured with World Health Organization QoL questionnaire (WHOQOL-BREF)) All three studies measured physical performance. Our analyses of two studies, presented below, showed that exercise may improve physical performance, but we are very unsure about the results (positive SMD values signify better physical performance; very low certainty) • SMD 1.25, 95% CI 0.54 to 1.97; 37 participants (shoulder mobility and pain measured on a visual analogue scale) • SMD⁠⁠⁠⁠⁠⁠ 3.13 (95% CI 2.32 to 3.95; 54 participants (physical performance measured with the six-minute walk test) Our analyses of data from the third study showed that exercise may have little or no effect on physical performance measured with the stand-and-sit test, but we are very unsure about the results (SMD 0.00, 95% CI -0.86 to 0.86, positive SMD values signify better physical performance; 21 participants; very low certainty). Two studies measured psychosocial effects. Our analyses (presented below) showed that exercise may have little or no effect on psychosocial effects, but we are very unsure about the results (positive SMD values signify better psychosocial well-being; very low certainty). • SMD 0.48, 95% CI -0.18 to 1.13; 37 participants (psychosocial effects measured on the WHOQOL-BREF social subscale) • SMD 0.29, 95% CI -0.57 to 1.15; 21 participants (psychosocial effects measured with the Beck Depression Inventory) Two studies recorded adverse events related to the exercise programmes and reported no events. We estimated the certainty of the evidence as very low. No studies reported adverse events unrelated to exercise. No studies reported the other outcomes we intended to analyse (overall survival, anthropometric measurements, return to work). AUTHORS' CONCLUSIONS: There is little evidence on the effects of exercise interventions in people with cancer who are receiving RT alone. While all included studies reported benefits for the exercise intervention groups in all assessed outcomes, our analyses did not consistently support this evidence. There was low-certainty evidence that exercise improved fatigue in all three studies. Regarding physical performance, our analysis showed very low-certainty evidence of a difference favouring exercise in two studies, and very low-certainty evidence of no difference in one study. We found very low-certainty evidence of little or no difference between the effects of exercise and no exercise on quality of life or psychosocial effects. We downgraded the certainty of the evidence for possible outcome reporting bias, imprecision due to small sample sizes in a small number of studies, and indirectness of outcomes. In summary, exercise may have some beneficial outcomes in people with cancer who are receiving RT alone, but the evidence supporting this statement is of low certainty. There is a need for high-quality research on this topic.

Stereotactic radiosurgery and combined immune checkpoint therapy with ipilimumab and nivolumab in patients with melanoma brain metastases: A retrospective monocentric toxicity analysis.

Purpose and objective: Adding stereotactic radiosurgery (SRS) to combined immune checkpoint therapy with ipilimumab and nivolumab (IPI + NIVO) has led to promising results for patients with melanoma brain metastases (MBM). This study retrospectively analyzes the toxicity profile depending on the timing of SRS with regard to IPI + NIVO. Materials and methods: For this study, the clinical database was searched for all patients with MBM who were treated with SRS and IPI + NIVO. The patients were separated into three groups: group A completed IPI + NIVO (usually up to four cycles) >14 days before SRS, in group B IPI + NIVO was initiated>14 days after SRS, and group C received SRS concurrently to IPI + NIVO. Treatment related toxicity was obtained from clinical and neuroradiological records. Analyses were performed using the Fisher-Yates-test. Results: 31 patients were assessed including six (19.4 %), seven (22.6 %) and 18 (58.1 %) patients, in groups A, B and C, respectively. Baseline prognostic markers between groups were balanced. In total, five (16.1 %) patients experienced neurological grade 3 toxicities related to SRS. All of these five patients were in group C, which was near-significantly correlated with a risk for grade 3 toxicities (p = 0.058). Post-hoc analyses showed that a maximum time period of seven days between SRS and IPI + NIVO was significantly correlated with grade 3 toxicity (p = 0.048). Conclusion: Application of SRS to IPI + NIVO within a seven-day span was related to higher toxicity rates in this retrospective analysis. After previous studies focused on immune checkpoint monotherapies with SRS and declared it as safe, this study indicates that concomitant application of IPI + NIVO and SRS might increase side effects. Prospective validation is warranted to corroborate these findings.

[Physical activity and exercise therapy in oncology]. / Körperliche Aktivität und Bewegungstherapie in der Onkologie.

Optimized and individualized treatment options in oncology significantly improve the prognosis of patients. Accordingly, the management of side effects and the avoidance of long-term consequences is becoming increasingly more important. Numerous studies have shown a positive impact of physical activity and targeted exercise therapy on certain patient-related outcomes. Ideally, patients are introduced to exercise therapy directly after the diagnosis is made in order to enable adequate supportive monitoring and to sustainably reduce therapy-associated side effects. Meanwhile, scientific findings have resulted in concrete recommendations for action to effectively improve the main patient-related outcomes, such as fatigue or depression. A moderate endurance training in combination with individualized strength training seems to be of particular importance. In principle, oncological training and exercise therapy can be recommended to every cancer patient regardless of the form of cancer and the timing of therapy but taking the contraindications into account. Therefore, the aim of communal as well as national efforts should be to implement a comprehensive offer of professional exercise therapy to facilitate access of cancer patients to these services as well as to ensure adequate care during and after treatment.

STING agonism turns human T cells into interferon-producing cells but impedes their functionality.

The cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) axis is the predominant DNA sensing system in cells of the innate immune system. However, human T cells also express high levels of STING, while its role and physiological trigger remain largely unknown. Here, we show that the cGAS-STING pathway is indeed functional in human primary T cells. In the presence of a TCR-engaging signal, both cGAS and STING activation switches T cells into type I interferon-producing cells. However, T cell function is severely compromised following STING activation, as evidenced by increased cell death, decreased proliferation, and impaired metabolism. Interestingly, these different phenotypes bifurcate at the level of STING. While antiviral immunity and cell death require the transcription factor interferon regulatory factor 3 (IRF3), decreased proliferation is mediated by STING independently of IRF3. In summary, we demonstrate that human T cells possess a functional cGAS-STING signaling pathway that can contribute to antiviral immunity. However, regardless of its potential antiviral role, the activation of the cGAS-STING pathway negatively affects T cell function at multiple levels. Taken together, these results could help inform the future development of cGAS-STING-targeted immunotherapies.

Risk Stratification Based on a Pattern of Immunometabolic Host Factors Is Superior to Body Mass Index-Based Prediction of COVID-19-Associated Respiratory Failure.

Overweight and obesity are associated with chronic low-grade inflammation and represent risk factors for various diseases, including COVID-19. However, most published studies on COVID-19 defined obesity by the body mass index (BMI), which does not encounter adipose tissue distribution, thus neglecting immunometabolic high-risk patterns. Therefore, we comprehensively analyzed baseline anthropometry (BMI, waist-to-height-ratio (WtHR), visceral (VAT), epicardial (EAT), subcutaneous (SAT) adipose tissue masses and liver fat, inflammation markers (CRP, ferritin, interleukin-6), and immunonutritional scores (CRP-to-albumin ratio (CAR), modified Glasgow prognostic score, neutrophile-to-lymphocyte ratio, prognostic nutritional index)) in 58 consecutive COVID-19 patients of the early pandemic phase with regard to the necessity of invasive mechanical ventilation (IMV). Here, metabolically high-risk adipose tissues represented by increased VAT, liver fat, and WtHR strongly correlated with higher levels of inflammation, pathologic immunonutritional scores, and the need for IMV. In contrast, the prognostic value of BMI was inferior and absent with regard to SAT. Multivariable logistic regression analysis identified an optimized IMV risk prediction model employing liver fat, WtHR, and CAR. In summary, we suggest an immunometabolically risk-adjusted model to predict COVID-19-induced respiratory failure better than BMI-based stratification, which warrants prospective validation.

Distinct distribution patterns of exercise-induced natural killer cell mobilization into the circulation and tumor tissue of patients with prostate cancer.

The mobilization and activation of natural killer (NK) cells have been proposed as key mechanisms promoting anti-oncogenic effects of physical exercise. Although mouse models have proven that physical exercise recruits NK cells to tumor tissue and inhibits tumor growth, this preclinical finding has not been transferred to the clinical setting yet. In this first-in-human study, we found that physical exercise mobilizes and redistributes NK cells, especially those with a cytotoxic phenotype, in line with preclinical models. However, physical exercise did not increase NK cell tumor infiltrates. Future studies should carefully distinguish between acute and chronic exercise modalities and should be encouraged to investigate more immune-responsive tumor entities.

Usability of German hospital administrative claims data for healthcare research: General assessment and use case of multiple myeloma in Munich university hospital in 2015-2017.

OBJECTIVES: To assess the usability of German hospital administrative claims data (GHACD) to determine inpatient management patterns, healthcare resource utilization, and quality-of-care in patients with multiple myeloma (PwMM). METHODS: Based on German tertiary hospital's claims data (2015-2017), PwMM aged >18 years were included if they had an International Classification of Diseases, Tenth Revision, code of C90.0 or received anti-MM therapy. Subgroup analysis was performed on stem cell transplantation (SCT) patients. RESULTS: Of 230 PwMM, 59.1% were men; 56.1% were aged ≥65 years. Hypertension and infections were present in 50% and 67.0%, respectively. Seventy percent of PwMM received combination therapy. Innovative drugs such as bortezomib and lenalidomide were given to 36.1% and 10.9% of the patients, respectively. Mean number of admissions and mean hospitalization length/patient were 3.69 (standard deviation (SD) 2.71 (1-16)) and 12.52 (SD 9.55 (1-68.5)) days, respectively. In-hospital mortality was recorded in 12.2%. Seventy-two percent of SCT patients (n = 88) were aged ≤65 years, 22.7% required second transplantation, and 89.8% received platelet transfusion at a mean of 1.42(SD 0.63 (1-3)). CONCLUSION: GHACD provided relevant information essential for healthcare studies about PwMM from routine care settings. Data fundamental for quality-of-care assessment were also captured.

[Physical activity in cancer - effectiveness of exercise therapy approaches]. / Körperliche Aktivität bei Krebs ­ Wirksamkeit bewegungstherapeutischer Ansätze.

The positive effects of oncological exercise therapy are sufficiently proven according to scientific studies. International evidence-based guidelines confirm this importance and recommend physical exercise as part of the standard therapy for cancer. The effects of physical activity on cancer-specific deficits are versatile ranging from positive impact on fatigue syndrome, mortality, incontinence, lymphoedema, CIPN, anxiety, depression to reduction of pain. According to current knowledge, sensorimotor training is recommended for the treatment of polyneuropathy. The actual effectiveness of vibration training in reducing symptom burden is undetermined. There are more than 100 randomized, controlled studies with the highest evidence rating for the management of CrF available. In this regard, exercise therapy is more effective than drug therapy in alleviating the symptomatology of CrF. In addition to the movement-therapeutic approach, a coordinated diet is necessary to avoid nutrition shortages.The evidence on physical activity in oncology must be considered not only in theory, but also in practice and be accepted as a general recommendation for oncology patients. The personalized OTT treatment concept represents a practical implementation and offers a targeted treatment option with low side effects.