Influenza virus vector iNS1 expressing bovine papillomavirus 1 (BPV1) antigens efficiently induces tumour regression in equine sarcoid patients

Bovine papillomaviruses types 1 and 2 (BPV1, BPV2) commonly induce skin tumours termed sarcoids in horses and other equids. Sarcoids seriously compromise the health and welfare of affected individuals due to their propensity to resist treatment and reoccur in a more severe form. We have developed influenza (Flu) A and B virus vectors that harbour a truncated NS1 gene (iNS) assuring interferon induction and co-express shuffled BPV1 E6 and E7 antigens for sarcoid immunotherapy. In a safety trial involving 12 healthy horses, intradermal administration of iNSA/E6E7equ and iNSB/E6E7equ was well tolerated, with the only transient side effect being mild fever in four horses. Repeated screening of secretions and faeces by RT-PCR and plaque assay revealed no virus shedding, thus also confirming biological safety. In a patient trial involving 29 horses bearing BPV1-induced single or multiple sarcoids, at least one lesion per horse was intratumourally injected and then boosted with iNSA/E6E7equ and/or iNSB/E6E7equ. The treatment induced a systemic antitumour response as reflected by the synchronous regression of injected and non-injected lesions. Irrespective of vaccination schemes, complete tumour regression was achieved in 10/29 horses. In 10/29 horses, regression is still ongoing (May 2021). Intriguingly, scrapings collected from former tumour sites in two patients tested negative by BPV1 PCR. Nine severely affected individuals with a history of unsuccessful therapeutic attempts did not (6/29) or only transiently (3/29) respond to the treatment. INSA/E6E7equ and iNSB/E6E7equ proved safe and effective in significantly reducing the tumour burden even in severe cases.

Treatment with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine in AML Patients Shows MRD Conversion and Improved Survival

Background. Persistence of measurable residual disease (MRD) is a poor prognostic factor and predicts relapse in acute myeloid leukemia (AML). In a phase I study, the allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown safety and humoral and cellular immune responses (A.A. van de Loosdrecht, et al. Cancer Immunol. Immunother. 2018;67:1505). In the current phase II study, (Clintrials.gov: NCT03697707) we report on progress and evaluation of MRD conversion, as primary endpoint, relapse free and overall survival. Methods. AML-patients, ineligible at screening for HSCT, who are in first complete remission (CR1) but with MRD receive 4 biweekly doses of 25e6 or 50e6 cells per vaccination (cells/vc) followed by 2 doses of 10e6 cells/vc as boosts at week 14 and 18. MRD is assessed at 4 timepoints (baseline, week 14, 20 and 32) by flow cytometry and/or molecular analyses. Primary endpoints are the effect of vaccination on MRD status and safety and tolerability of the two vaccination schedules. Secondary endpoints include relapse free, overall survival and immunological response evaluation. Results. As of 28 th July 2021, 19 patients have been enrolled, of which 10 patients have been given at least 4 vaccinations with 25e6 cells/vc and 9 with 50e6 cells/vc. No serious adverse events (AE) or severe AE (grade 3 or higher) related to DCP-001 have been reported. AE's related to DCP-001 are mainly injection site reactions, occurring within 48 hours after intradermal administration. In the 25e6 cells/vc cohort all patients have completed the treatment phase up to week 32, allowing full assessment of MRD response. Three patients have converted to MRD negative, 4 patients relapsed (followed by HSCT for 1 patient), 3 patients remained MRD positive, of which 2 patients underwent HSCT immediately after completion of the full dosing schedule. In this cohort 2 patients eventually died during follow up. Treatment is still ongoing in the 50e6 dose cohort, with thus far one additional MRD conversion reported and two relapses, 3 patients with stable MRD levels, and 3 have no MRD data available yet. Median follow-up of patients in the 25e6 cells/vc cohort was 288 days (range 148 - 546). Median RFS and OS have not yet been reached, but estimated RFS and OS at 12 months is calculated at 57% and 79%, respectively (Figure 1). MRD converted patients after DCP-001 vaccination, showed improved survival, compared to patients without MRD conversion (Figure 2). All 4 patients who converted to MRD negative are still in CR and alive (FU median 423.5 days (range 140 - 546). Immunological monitoring of patients is currently being performed. As previously reported (abstract #168, ASH2020), 3 of 4 evaluable patients show at least 1 or more responses against tumor-associated antigens known to be present in DCP-001 in IFNy ELISPOT assay. Conclusion/discussion. Four patients have shown MRD conversion (3 in the 25e6 dose cohort, and 1 in the 50e6 dose cohort). Six patients remained in complete remission with stable or declining levels of MRD, 6 patients relapsed and for 3 patients no MRD data is available yet. Median RFS and OS have not yet been reached. MRD conversion showed improved relapse free and overall survival. Treatment with DCP-001 is very well tolerated, with limited side effects mainly related to intradermal administration. Immunological analyses for specific tumor-associated antigen responses and general immune profiling are currently being performed. Preliminary data from this study shows that the relapse vaccine DCP-001 is a promising treatment for patients with AML in complete remission but with residual disease aiming to deepen responses and prolong survival. Its excellent safety profile allows for future combination therapy. Figure 1 Figure 1. Disclosures Van de Loosdrecht: Novartis: Consultancy; Alexion: Consultancy; Roche: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. Cloos: Takeda: Research Funding; Novartis: Consultancy, Other, Research Funding; Navigate: Patents & Royalties; Merus: Other, Research Funding; Janssen: Research Funding; Helsinn: Other; Genentech: Research Funding; DC-One: Other, Research Funding; Astellas: Speakers Bureau. Platzbecker: AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria; Takeda: Honoraria. Holderried: Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; MSD: Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Therakos: Other: Travel support; Abbvie: Other: Travel support; Medac: Other: Travel support; Eurocept Pharmaceuticals: Other: Travel support; Janssen: Other: Travel support; Daiichi Sankyo: Other: travel support. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. van Zeeburg: Immunicum AB: Current Employment; Kiadis: Ended employment in the past 24 months. Rovers: Immunicum AB: Current Employment. Gjertsen: KinN Therapeutics: Current holder of stock options in a privately-held company; Alden Cancer Therapy: Current holder of stock options in a privately-held company; Pfizer Inc.: Consultancy; BerGenBio: Consultancy; Novartis: Consultancy.

On the use of tissue hydrophilicity test for rheumatism in children

The test for the hydrophilicity of tissues according to McClure, which is reduced to the intradermal administration of 0.2 saline and monitoring the time of resorption of the blister formed in this case, has already been used for rheumatism in children (O. K-Miss), and its acceleration in the acute period has been shown rheumatism up to 15-40 minutes, whereas normally its time ranges from 30 minutes. in infants up to 52 minutes. - at an older age (MS Maslov), The most significant acceleration of it was observed in violent rheumatic arthritis and in severe acute period with severe symptoms of heart failure.

Comparison of avascular lymph node fragment transplantation techniques to optimize lymphangiogenesis in the minipig model

Background Secondary lymphoedema is a challenging pandemic. This condition may arise after oncologic resection of tumor-draining lymph nodes and/or radiation. Plastic-surgical procedures for lymphoedema comprise transplantation of vascularized lymph node flaps, which are, however, technically challenging and difficult to implement on a global level due to the scarcity of microsurgery facilities in some countries. To improve this situation, comparative research in valid animal models is needed. Methods A total of 33 minipigs were subjected to lymphatic resection in the hind limbs. This large animal model was used in a first phase to compare different lymph node fragmentation methods and assess lymphatic regeneration after avascular transplantation. In a second phase, several stimulants were tested for their effect on lymphatic regeneration after fragment transplantation. In a third phase, animals additionally received irradiation of the groin. In this novel animal model, autologous avascular lymph node fragment transplantation was complemented by peripheral injections of vascular endothelial growth factor-C (VEGF-C). Finally, regeneration rates were quantified in relative numbers (percentage) in the irradiated tissue. Results In the first phase, transversal lymph node fragmentation under preservation of the nodal capsule showed the best percentage of regeneration (62.5%). Peripheral intradermal administration of VEGF-C enhanced lymph node fragment regeneration (70.8%) better than injections of tetanus toxoid (41.6%) or Streptococcus suis (62.5%). Lymph node fragment regeneration also occurred in an irradiated porcine model of lymphadenectomy under VEGF-C administration (66.6%). Conclusions The present findings provide a pre-clinical proof-of-concept for a possible simplification strategy for current operative procedures of autologous lymph node transplantation. Level of evidence : Not gradable

Extended Injection Intervals of Gonadotropins by Intradermal Administration in IVF Treatment

Context Gonadotropins can be administered every five days under intradermal injection in in vitro fertilization (IVF) treatment. Objective To explore the effectiveness of intradermal injection of recombinant human FSH (rhFSH) for women undergoing IVF. Materials and Methods Women who received their first time IVF enrolled in this prospective intervention in 2018. All women received a bolus of 900 IU rhFSH intradermally at day 2 of the treatment cycle followed by additional dosage of rhFSH at day 7 and/or day 10. The main outcome measures included the total dose of rhFSH and number of injections required, sequential serum FSH level detected, and number of mature oocytes retrieved. Results Seventy women completed the study. On average, 2.31±0.73 injections and 1662±397 IU of rhFSH were administered. While the baseline FSH level was 5.6±2.2 IU/L, the serum concentrations of FSH after rhFSH administration were 35.3±7.0 on the first day (24 hours) and 10.7±3.7 IU/L on the fifth day (120 hours). A total of 10.5±6.6 mature oocytes were retrieved, resulting in 7.3±5.1 pronuclear embryos; and 1.8±0.6 embryos were transferred to the uterus. Our findings resulted in 72% fertilization, 91% cleavage, 31% implantation, and 36% live birth rates. Although less larger follicles were found, non-inferiority results were noted in the mature oocytes retrieved, good embryos available and clinical pregnancy rate compared to those received conventional daily subcutaneous rhFSH administration. Conclusion Intradermal administration of rhFSH, with less dose of rhFSH and numbers of injection, may achieve the goal of a cost-effective and more patient-friendly regimen.

On Friedberger's and Reis's reaction in typhus

In searching for evidence in favor of the etiological significance of b. proteus vulgaris x19 in typhus and on the assumption that typhus patients must be hypersensitive to this microbe, Prof. Friedberger together with Dr. Reis in 1919 applied subcutaneous (and also intradermal) administration to typhus patients of suspensions of killed bacilli of b. prot. prot. vulgaris x19. Friedberger and Reis expected that when certain doses of this suspension, which were completely indifferent to healthy persons, were administered, typhus patients would react to them in the same manner as, for example, tuberculosis patients react to tuberculin injections.