Heating technology for malignant tumors: a review

The therapeutic application of heat is very effective in cancer treatment. Both hyperthermia, i.e., heating to 39-45 degrees C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50 degrees C destroy tumor cells directly are frequently applied in the clinic. Achievement of an effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance. Several types of devices, antennas and heating or power delivery systems have been proposed and developed in recent decades. These vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus. Clinically used heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating. Depending on clinical objectives and available technology, thermal therapies can be subdivided into three broad categories: local, locoregional, or whole body heating. Clinically used local heating techniques include interstitial hyperthermia and ablation, high intensity focused ultrasound (HIFU), scanned focused ultrasound (SFUS), electroporation, nanoparticle heating, intraluminal heating and superficial heating. Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion. Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, e.g., by infrared radiation. This review presents an overview of clinical hyperthermia and ablation devices used for local, locoregional, and whole body therapy. Proven and experimental clinical applications of thermal ablation and hyperthermia are listed. Methods for temperature measurement and the role of treatment planning to control treatments are discussed briefly, as well as future perspectives for heating technology for the treatment of tumors

Novel highly potent CD4bs bNAb with restricted pathway to HIV-1 escape

Purpose: Broadly HIV-1 neutralizing antibodies (bNAbs) can suppress viremia in humans and represent a novel approach for effective immunotherapy. However, bNAb monotherapy selects for antibody-resistant viral variants. Thus, we focused on the identification of new antibody combinations and/or novel bNAbs that restrict pathways of HIV-1 escape. Methods: We screened HIV-1 positive patients for their neutralizing capacities. Following, we performed single cell sorting and PCR of HIV-1 Env-reactive mature B cells of identified elite neutralizers. Found antibodies were tested for neutralization and binding capacities in vitro. Further, their antiviral activity was tested in an HIV-1 infected humanized mouse model. Results: Here we report the isolation of antibody 1–18, a VH1–46-encoded CD4 binding site (CD4bs) bNAb identified in an individual ranking among the top 1% neutralizers of 2,274 HIV-1-infected subjects. Tested on a 119-virus panel, 1–18 showed to be exceptionally broad and potent with a coverage of 97% and a mean IC50 of 0.048 lg/mL, exceeding the activity of most potent CD4bs bNAbs described to-date. A 2.4 Å cryo-EM structure of 1–18 bound to a native-like Env trimer revealed that it interacts with HIV-1 env similar to other CD4bs bNAbs, but includes additional contacts to the V3 loop of the adjacent protomer. Notably, in vitro, 1–18 maintained activity against viruses carrying mutations associated with escape from VRC01-class bNAbs. Further, its HIV-1 env wide escape profile differed critically from other CD4bs bNAbs. In humanized mice, monotherapy with 1–18 was sufficient to prevent the development of viral escape variants that rapidly emerged during treatment with other CD4bs bNAbs. Finally, 1–18 overcame classical HIV-1 mutations that are driven by VRC01-like bNAbs in vivo. Conclusion: 1–18 is a highly potent and broad bNAb that restricts escape and overcomes frequent CD4bs escape pathways, providing new options for bNAb combinations to prevent and treat HIV-1 infection

Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial

Background The administration of broadly neutralising anti-HIV-1 antibodies before latency reversal could facilitate elimination of HIV-1-infected CD4 T cells. We tested this concept by combining the broadly neutralising antibody 3BNC117 in combination with the latency-reversing agent romidepsin in people with HIV-1 who were taking suppressive antiretroviral therapy (ART). Methods We did a randomised, open-label, phase 2A trial at three university hospital centres in Denmark, Germany, and the USA. Eligible participants were virologically suppressed adults aged 18-65 years who were infected with HIV-1 and on ART for at least 18 months, with plasma HIV-1 RNA concentrations of less than 50 copies per mL for at least 12 months, and a CD4 T-cell count of greater than 500 cells per mu L. Participants were randomly assigned (1:1) to receive 3BNC117 plus romidepsin or romidepsin alone in two cycles. All participants received intravenous infusions of romidepsin (5 mg/m(2) given over 120 min) at weeks 0, 1, and 2 (treatment cycle 1) and weeks 8, 9, and 10 (treatment cycle 2). Those in the 3BNC117 plus romidepsin group received an intravenous infusion of 3BNC117 (30 mg/kg given over 60 min) 2 days before each treatment cycle. An analytic treatment interruption (ATI) of ART was done at week 24 in both groups. Our primary endpoint was time to viral rebound during analytic treatment interruption, which was assessed in all participants who completed both treatment cycles and ATI. We used a log-rank test to compare time to viral rebound during analytic treatment interruption between the two groups. This trial is registered with ClinicalTrials. gov, NCT02850016. It is closed to new participants, and all follow-up is complete. Findings Between March 20, 2017, and Aug 14, 2018, 22 people were enrolled and randomly assigned, 11 to the 3BNC117 plus romidepsin group and 11 to the romidepsin group. 19 participants completed both treatment cycles and the ATI: 11 in the 3BNC117 plus romidepsin group and 8 in the romidepsin group. The median time to viral rebound during ATI was 18 days (IQR 14-28) in the 3BNC117 plus romidepsin group and 28 days (21-35) in the romidepsin group B (p=0.0016). Although this difference was significant, prolongation of time to viral rebound was not clinically meaningful in either group. All participants in both groups reported adverse events, but overall the combination of 3BNC117 and romidepsin was safe. Two severe adverse events were observed in the romidepsin group during 48 weeks of follow-up, one of which-increased direct bilirubin-was judged to be related to treatment. Interpretation The combination of 3BNC117 and romidepsin was safe but did not delay viral rebound during analytic treatment interruptions in individuals on long-term ART. The results of our trial could serve as a benchmark for further optimisation of HIV-1 curative strategies among people with HIV-1 who are taking suppressive ART. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd

Tumor targeting of MMP-2/9 activatable cell-penetrating imaging probes is caused by tumor-independent activation

Activatable cell-penetrating peptides (ACPPs) are a new class of promising molecular imaging probes for the visualization of enzymes in vivo. The cell-penetrating function of a polycationic peptide is efficiently blocked by intramolecular electrostatic interactions with a polyanionic peptide. Proteolysis of a cleavable linker present between the polycationic cell-penetrating peptide and polyanionic peptide affords dissociation of both domains and enables the activated cell-penetrating peptide to enter cells. Here, we aimed to develop an ACPP sensitive to matrix metalloproteinase-2 and -9 (MMP-2/9) for nuclear imaging purposes. Methods: MMP-2/9 ACPPs and nonactivatable cell-penetrating peptides (non-ACPP) were prepared by 9- fluorenylmethyloxycarbonyl solid-phase peptide synthesis and labeled with 177Lu or 177Lu/125I for dual-isotope studies. The in vivo biodistribution of these probes was assessed in MMP-2/9– positive tumor-bearing mice (n 5 6) and healthy mice (n 5 4) using g-counting. Furthermore, a radiolabeled cell-penetrating peptide serving as a positive control was evaluated in tumorbearing mice (n 5 6). Results: Biodistribution studies showed a5-fold-higher retention of ACPP in tumor than in muscle (P , 0.01) and a 6-fold-higher tumor retention relative to non-ACPP (P , 0.01), supporting earlier studies on fluorescently labeled ACPPs proposing activation by tumor-associated MMP-2/9. Surprisingly, however, the uptake of ACPP was significantly higher than that of non-ACPP in almost all tissues (P , 0.01). To unravel the activation process of ACPP in vivo, we developed dual-isotope ACPP analogs (dACPPs) that allowed us to discriminate between uncleaved dACPP and activated dACPP. In vivo biodistribution of dACPP indicated that the tissue-associated counts originated from activated dACPP. Interestingly dACPPadministration to healthy mice, compared with MMP- 2/9–positive tumor-bearing mice, resulted in a similar dACPP biodistribution. Furthermore, a radiolabeled cell-penetrating peptide showed tumor-to-tissue ratios equal to those found for ACPP (P . 0.05). Conclusion: This study demonstrates that the tumor targeting of radiolabeled MMP-2/9 ACPPs is most likely caused by the activation in the vascular compartment rather than tumor-specific activation, as suggested earlier. The results in the present paper indicate that different and more tissue-specific enzyme–ACPP combinations are needed to unleash the full potential of the elegant ACPP concept in living animals

Tumor targeting of MMP-2/9 activatable cell-penetrating imaging probes is caused by tumor-independent activation

Activatable cell-penetrating peptides (ACPPs) are a new class of promising molecular imaging probes for the visualization of enzymes in vivo. The cell-penetrating function of a polycationic peptide is efficiently blocked by intramolecular electrostatic interactions with a polyanionic peptide. Proteolysis of a cleavable linker present between the polycationic cell-penetrating peptide and polyanionic peptide affords dissociation of both domains and enables the activated cell-penetrating peptide to enter cells. Here, we aimed to develop an ACPP sensitive to matrix metalloproteinase-2 and -9 (MMP-2/9) for nuclear imaging purposes. Methods: MMP-2/9 ACPPs and nonactivatable cell-penetrating peptides (non-ACPP) were prepared by 9- fluorenylmethyloxycarbonyl solid-phase peptide synthesis and labeled with 177Lu or 177Lu/125I for dual-isotope studies. The in vivo biodistribution of these probes was assessed in MMP-2/9– positive tumor-bearing mice (n 5 6) and healthy mice (n 5 4) using g-counting. Furthermore, a radiolabeled cell-penetrating peptide serving as a positive control was evaluated in tumorbearing mice (n 5 6). Results: Biodistribution studies showed a5-fold-higher retention of ACPP in tumor than in muscle (P , 0.01) and a 6-fold-higher tumor retention relative to non-ACPP (P , 0.01), supporting earlier studies on fluorescently labeled ACPPs proposing activation by tumor-associated MMP-2/9. Surprisingly, however, the uptake of ACPP was significantly higher than that of non-ACPP in almost all tissues (P , 0.01). To unravel the activation process of ACPP in vivo, we developed dual-isotope ACPP analogs (dACPPs) that allowed us to discriminate between uncleaved dACPP and activated dACPP. In vivo biodistribution of dACPP indicated that the tissue-associated counts originated from activated dACPP. Interestingly dACPPadministration to healthy mice, compared with MMP- 2/9–positive tumor-bearing mice, resulted in a similar dACPP biodistribution. Furthermore, a radiolabeled cell-penetrating peptide showed tumor-to-tissue ratios equal to those found for ACPP (P . 0.05). Conclusion: This study demonstrates that the tumor targeting of radiolabeled MMP-2/9 ACPPs is most likely caused by the activation in the vascular compartment rather than tumor-specific activation, as suggested earlier. The results in the present paper indicate that different and more tissue-specific enzyme–ACPP combinations are needed to unleash the full potential of the elegant ACPP concept in living animals

Model predictive control for MR-HIFU-mediated, uniform hyperthermia

Purpose: In local hyperthermia, precise temperature control throughout the entire target region is key for swift, safe, and effective treatment. In this article, we present a model predictive control (MPC) algorithm providing voxel-level temperature control in magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) and assess the improvement in performance it provides over the current state of the art. Materials and methods: The influence of model detail on the prediction quality and runtime of the controller is evaluated and a tissue mimicking phantom is characterized using the resulting model. Next, potential problems arising from modeling errors are evaluated in silico and in the characterized phantom. Finally, the controller?s performance is compared to the current state-of-the-art hyperthermia controller in side-by-side experiments. Results: Modeling diffusion by heat exchange between four neighboring voxels achieves high predictive performance and results in runtimes suited for real-time control. Erroneous model parameters deteriorate the MPC?s performance. Using models derived from thermometry data acquired during low powered test sonications, however, high control performance is achieved. In a direct comparison with the state-of-the-art hyperthermia controller, the MPC produces smaller tracking errors and tighter temperature distributions, both in a homogeneous target and near a localized heat sink. Conclusion: Using thermal models deduced from low-powered test sonications, the proposed MPC algorithm provides good performance in phantoms. In direct comparison to the current state-of-the-art hyperthermia controller, MPC performs better due to the more finely tuned heating patterns and therefore constitutes an important step toward stable, uniform hyperthermia

Prevalence of SARS-CoV-2 in children from a cohort of 2192 patients

Background As of 18 June 2020 a total of 187,764 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were reported in Germany and of these 6.9% were under the age of 19 years. There were initial indications that children are often asymptomatic and show a milder clinical course. Objective The aim of this study was to gain information on the prevalence of SARS-CoV-2 infections in a pediatric cohort. Material and methods Between 13 March and 18 June 2020 all children from whom a smear for SARS-CoV-2 was taken either to rule out an infection or as a suspected case were included. Data were collected on standardized patient record sheets. The analysis of data was anonymized and retrospective. Results During the given period 2192 children were investigated and 37 patients tested positive (1.7%) for SARS-CoV-2. Of these 36/37 were suspected cases and 28/37 were symptomatic. The leading symptoms were dry cough, runny nose and fever and three children had to be hospitalized. None showed a difficult course of the disease. Among those tested 505 were patients at risk due to an underlying chronic disease, 3 of whom (0.6%) were tested positive with an asymptomatic or mild course. Conclusion We can confirm the first data showing that children and adolescents often have an asymptomatic or mild clinical course of infection or disease. We found no evidence of a high grey area of SARS-CoV-2 infections in this regional pediatric cohort