Abstract
T-cell immunity is central for control of COVID-19, particularly in patients incapable of mounting antibody responses. CoVac-1 is a peptide-based T-cell activator composed of SARS-CoV-2 ...epitopes with documented favorable safety profile and efficacy in terms of SARS-CoV-2-specific T-cell response. We here report a Phase I/II open-label trial (NCT04954469) in 54 patients with congenital or acquired B-cell deficiency receiving one subcutaneous CoVac-1 dose. Immunogenicity in terms of CoVac-1-induced T-cell responses and safety are the primary and secondary endpoints, respectively. No serious or grade 4 CoVac-1-related adverse events have been observed. Expected local granuloma formation has been observed in 94% of study subjects, whereas systemic reactogenicity has been mild or absent. SARS-CoV-2-specific T-cell responses have been induced in 86% of patients and are directed to multiple CoVac-1 peptides, not affected by any current Omicron variants and mediated by multifunctional T-helper 1 CD4
+
T cells. CoVac-1-induced T-cell responses have exceeded those directed to the spike protein after mRNA-based vaccination of B-cell deficient patients and immunocompetent COVID-19 convalescents with and without seroconversion. Overall, our data show that CoVac-1 induces broad and potent T-cell responses in patients with B-cell/antibody deficiency with a favorable safety profile, which warrants advancement to pivotal Phase III safety and efficacy evaluation. ClinicalTrials.gov identifier NCT04954469.
Background:
Efficacy of second-line systemic chemotherapy in recurrent gastric cancer with peritoneal metastasis (RGCPM) is limited. We assessed the feasibility, safety and possible efficacy of ...pressurized intraperitoneal aerosol chemotherapy (PIPAC) in patients with RGCPM after ⩾1 line of palliative intravenous chemotherapy.
Methods:
In this open-label, single-arm, monocentric phase II ICH-GCP clinical trial, patients were scheduled for three courses of PIPAC with cisplatin 7.5 mg/m2 and doxorubicin 1.5 mg/m2 (PIPAC C/D) every 6 weeks. Patients with bowel obstruction or extraperitoneal metastasis were ineligible. The primary endpoint was clinical benefit rate (CBR) by Response Evaluation Criteria in Solid Tumors based on clinical records. Secondary endpoints included overall survival (OS), median time to progression (TTP), peritoneal carcinomatosis index (PCI), histological regression and ascites volume. Safety and tolerability were assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4, quality of life (QoL) by EORTC-QLQ30 questionnaire.
Results:
A total of 25 patients were enrolled and available for the analysis of the primary endpoint. Of those 25 patients, 10 (40%) had a radiological complete, partial response or stable disease. Median OS intention to treat (ITT) was 6.7 months, median TTP was 2.7 months. Complete or major regression on histology were observed in 9/25 patients (36%, ITT) or 6/6 100%, per protocol (PP) patients. There were no suspected unexpected serious adverse reactions, no treatment-related deaths, no CTCAE grade 4 toxicity and three (12%) grade 3 toxicities. Changes in the QLQ-C30 scores during PIPAC C/D therapy were small and not significant.
Conclusions:
PIPAC C/D was well tolerated and active in patients with RGCPM. Survival was encouraging. Randomized controlled trials should now be designed in this indication.
T cell immunity is key for the control of viral infections including SARS-CoV-2, in particular with regard to immune memory and protection against arising genetic variants.
We recently evaluated a ...peptide-based SARS-CoV-2 T cell activator termed CoVac-1 in a first-in-human trial in healthy adults. Here, we report on long-term safety and efficacy data of CoVac-1 until month 12.
CoVac-1 is well tolerated without long-term immune-related side effects and induces long-lasting anti-viral T cell responses in 100% of study participants, with potent expandability of clusters of differentiation (CD4
) and CD8
T cells targeting multiple different CoVac-1 T cell epitopes. T cell responses were associated with stronger injection site reaction. Beyond induction of T cell immunity, 89% of subjects developed CoVac-1-specific immunoglobulin G antibodies which associated with the intensity of the T cell response, indicating that CoVac-1-specific CD4
T cells support the induction of B-cell responses. Vaccination with approved COVID-19 vaccines boosted CoVac-1-specific T cell responses. Overall, a low SARS-CoV-2 infection rate (8.3%) was observed.
Together, a single application of CoVac-1 elicits long-lived and broad SARS-CoV-2-specific T cell immunity, which further supports the current evaluation of our T cell activator in patients with congenital or acquired B-cell defects.
(1)
Laparoscopic staging is essential in gastric cancer (GC) to rule out peritoneal metastasis (PM). Hypericin, a plant-derived fluorescent compound, has been suggested to improve laparoscopic ...visualization of PM from GC. This prospective, single-arm, open-label clinical trial aimed to assess the feasibility and safety of oral hypericin administration as well as the suitability of fluorescence-guided laparoscopy (FGL) for improving the sensitivity and specificity of staging in GC patients (EudraCT-Number: 2015-005277-21; clinicaltrials.gov identifier: NCT-02840331). (2)
GC patients received Laif
900, an approved hypericin-containing phytopharmaceutical, once orally two to four hours before white light and ultraviolet light laparoscopy. The peritoneal cancer index was evaluated, biopsies taken and hypericin concentrations in serum and peritoneal tissue were determined by mass spectrometry. (3)
Between 2017 and 2021, out of 63 patients screened for eligibility, 50 patients were enrolled and treated per protocol. The study intervention was shown to be feasible and safe in all patients. Standard laparoscopy revealed suspicious lesions in 27 patients (54%), among whom 16 (59%) were diagnosed with PM. FGL identified suspicious areas in 25 patients (50%), among whom PM was confirmed in 13 cases (52%). Although hypericin concentrations in serum reached up to 5.64 ng/mL, no hypericin was detectable in peritoneal tissue biopsies. (4)
FGL in patients with GC was shown to be feasible but futile in this study. Sufficient levels of hypericin should be ensured in target tissue prior to reassessing FGL with hypericin.
Prospective evaluation of intestinal ultrasound (IUS) for disease monitoring of patients with ulcerative colitis (UC) in routine medical practice.
TRansabdominal Ultrasonography of the bowel in ...Subjects with IBD To monitor disease activity with UC (TRUST&UC) was a prospective, observational study at 42 German inflammatory bowel disease-specialised centres representing different care levels. Patients with a diagnosis of a proctosigmoiditis, left-sided colitis or pancolitis currently in clinical relapse (defined as Short Clinical Colitis Activity Index ≥5) were enrolled consecutively. Disease activity and vascularisation within the affected bowel wall areas were assessed by duplex/Colour Doppler ultrasonography.
At baseline, 88.5% (n=224) of the patients had an increased bowel wall thickness (BWT) in the descending or sigmoid colon. Even within the first 2 weeks of the study, the percentage of patients with an increased BWT in the sigmoid or descending colon decreased significantly (sigmoid colon 89.3%-38.6%; descending colon 83.0%-42.9%; p<0.001 each) and remained low at week 6 and 12 (sigmoid colon 35.4% and 32.0%; descending colon 43.4% and 37.6%; p<0.001 each). Normalisation of BWT and clinical response after 12 weeks of treatment showed a high correlation (90.5% of patients with normalised BWT had symptomatic response vs 9.5% without symptomatic response; p<0.001).
IUS may be preferred in general practice in a point-of-care setting for monitoring the disease course and for assessing short-term treatment response. Our findings give rise to the assumption that monitoring BWT alone has the potential to predict the therapeutic response, which has to be verified in future studies.
Patients with psoriatic arthritis (PsA) often develop joint symptoms years after their initial diagnosis of psoriasis disease; therefore, dermatologists should test for and detect PsA early. In this ...study, we focused on patients with psoriasis with both nail and joint disease being treated with tumor necrosis factor-α inhibitors by dermatologists. We performed a noninterventional, prospective, multicenter, and open-label study to evaluate the effectiveness of adalimumab, etanercept, or infliximab over 24 months of continuous therapy in patients with moderate to severe plaque-type psoriasis (Pso) and PsA. Disease assessments with the Psoriasis Area and Severity Index, Nail Psoriasis Severity Index (NAPSI), joint assessment, Dermatology Life Quality Index (DLQI), and Health Assessment Questionnaire (HAQ) instruments were performed every 3 months for the first year and twice annually thereafter. The cohort included 100 patients with Pso, nail psoriasis, and PsA. A significant reduction of NAPSI was observed 3 months after therapy initiation compared with the baseline (mean ± SD, 22.9 ± 17.8 vs. 33.8 ± 21.4; p < 0.001). Similarly, the mean ± SD number of both tender and swollen joints decreased significantly within the first 3 months of treatment, from 10.8 ± 11.5 to 6.4 ± 10.3 (p < 0.001) and from 6.4 ± 9.5 to 3.1 ± 7.2 (p < 0.001), respectively. Additionally, the distal interphalangeal joint involvement improved throughout the observation time, and DLQI and HAQ scores decreased. Improvements in control of skin, nail, and joint symptoms were seen, as well as in patients’ quality of life and functionality. Dermatologists have an important role not only in PsA diagnosis but also in PsA long-term care.
Mistletoe extracts are widely used in complementary and alternative cancer therapy in Europe. The extracts possess cytotoxic, as well as immunostimulatory effects. However, some investigators have ...suggested that low doses of mistletoe extracts could also induce tumor growth. The mistletoe extracts Helixor A, Helixor M and Helixor P were investigated for growth inhibitory and stimulatory effects in a panel of 38 human tumor cell lines in vitro. Mistletoe lectin I (ML-1), adriamycin and interleukin-6 (IL-6) were used as reference compounds. All three mistletoe preparations showed cytotoxic activity T/C (Test/Control) < 30%: Helixor P was the most potent, followed by Helixor M and Helixor A with IC50 (50% inhibitory concentration) values of 68.4, 114 and 133 microg/ml, respectively. The IC50 values of ML-1 and adriamycin were 0.026 and 0.069 microg/ml. None of the human tumor cell lines in the panel showed growth stimulation (T/C (Test/Control) > 125%) by the mistletoe extracts or ML-1, apart from two exceptions in the colon carcinoma cell line HCC-2998, in which Helixor M and ML-1 showed a marginal stimulation (TIC 128% and 131%, respectively) at one concentration only. Further investigations into the latter effect of Helixor M and ML-1 in the HCC-2998 line using five different proliferation assays, modified cell culture conditions and the identical production charge of mistletoe extract, as well as a new one, did not confirm the previous observation. It was concluded that the marginal stimulation found in the earlier experiments was a statistical coincidence. Helixor mistletoe preparations and ML-1 have cytotoxic activity and do not stimulate tumor cell proliferation in vitro which is in accordance with previous scientifically based observations on aqueous mistletoe extracts.
Purpose: To assess the association of patient, lesion, and procedure variables, including calcification, with late lumen loss (LLL) after use of drug-eluting balloon (DEB) therapy in patients with ...femoropopliteal arterial disease. Methods: In this retrospective study, 91 patients (mean age 72.0±8.62 years; 50 men) were analyzed at 6 months after DEB treatment. Lesions were located in the superficial femoral artery (SFA, n=68) and popliteal artery (n=23). Lesion calcification was graded by a core laboratory using 2 published scoring indices: the peripheral artery calcification scoring system and a grading system based on circumference (arc) and length of calcium. Results: The median LLL after 6 months was 0.2 mm (interquartile range −0.5, 1.14) overall and varied significantly across lesions with differing severity of calcification (p=0.042). However, LLL did not differ based on calcium location (intimal, medial, or mixed) or calcium length (p=0.351 and p=0.258, respectively). Additional predictors of LLL after DEB treatment included diabetes (p=0.034), coronary artery disease (p=0.024), and prior intervention (p=0.013). Interestingly, the severity of residual stenosis after the intervention did not have any impact on the LLL during follow-up (Spearman r = −0.238). Conclusion: Severity of lesion calcification is associated with LLL after treatment with DEB. One possible approach to overcome this limitation might be plaque modification or removal prior to DEB usage. Nevertheless, clinical data that support this hypothesis are currently lacking.
T cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T cell epitopes derived from various viral proteins
, combined ...with the Toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG, aiming to induce profound SARS-CoV-2 T cell immunity to combat COVID-19. Here we conducted a phase I open-label trial, recruiting 36 participants aged 18-80 years, who received a single subcutaneous CoVac-1 vaccination. The primary end point was safety analysed until day 56. Immunogenicity in terms of CoVac-1-induced T cell response was analysed as the main secondary end point until day 28 and in the follow-up until month 3. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study participants, whereas systemic reactogenicity was absent or mild. SARS-CoV-2-specific T cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T helper 1 CD4
and CD8
T cells. CoVac-1-induced IFNγ T cell responses persisted in the follow-up analyses and surpassed those detected after SARS-CoV-2 infection as well as after vaccination with approved vaccines. Furthermore, vaccine-induced T cell responses were unaffected by current SARS-CoV-2 variants of concern. Together, CoVac-1 showed a favourable safety profile and induced broad, potent and variant of concern-independent T cell responses, supporting the presently ongoing evaluation in a phase II trial for patients with B cell or antibody deficiency.
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