A Diversity Covering (DiCo) Plasmodium vivax apical membrane antigen-1 vaccine adjuvanted with RFASE/RSL10 yields high levels of growth-inhibitory antibodies.

Plasmodium vivax malaria is increasingly recognized as a major global health problem and the socio-economic impact of P.vivax-induced burden is huge. Vaccine development against P. vivax malaria has been hampered by the lack of an in vitro culture system and poor access to P. vivax sporozoites. The recent generation of Plasmodium falciparum parasites that express a functional P. vivax AMA1 molecule has provided a platform for in vitro evaluation of PvAMA1 as a potential blood stage vaccine. Three so-called PvAMA1 Diversity Covering (DiCo) proteins were designed to assess their potential to induce a functional and broad humoral immune response to the polymorphic PvAMA1 molecule. Rabbits were immunized with the mixture of three, Pichia-produced, PvAMA1 DiCo proteins, as well as with 2 naturally occurring PvAMA1 alleles. For these three groups, the experimental adjuvant raffinose fatty acid sulfate ester (RFASE) was used, while in a fourth group the purified main mono-esterified constituent (RSL10) of this adjuvant was used. Animals immunized with the mixture of the three PvAMA1 DiCo proteins in RFASE showed high anti-PvAMA1 antibody titers against three naturally occurring PvAMA1variants while also high growth-inhibitory capacity was observed against P. falciparum parasites expressing PvAMA1. This supports further clinical development of the PvAMA1 DiCo mixture as a potential malaria vaccine. However, as the single allele PvAMA1 SalI-group showed similar characteristics in antibody titer and inhibition levels as the PvAMA1 DiCo mixture-group, this raises the question whether a mixture is really necessary to overcome the polymorphism in the vaccine candidate. RFASE induced strong humoral responses, as did the animals immunized with the purified component, RSL10. This suggests that RSL10 is the active ingredient. However, one of the RSL10-immunized animal showed a delayed response, necessitating further research into the clinical development of RSL10.

Effect of ibrutinib on CCR7 expression and functionality in chronic lymphocytic leukemia and its implication for the activity of CAP-100, a novel therapeutic anti-CCR7 antibody.

CAP-100 is a novel therapeutic antibody directed against the ligand binding site of human CCR7. This chemokine receptor is overexpressed in chronic lymphocytic leukemia (CLL) and orchestrates the homing of CLL cells into the lymph node. Previous studies, on a very limited number of samples, hypothesized that the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib might induce loss of surface CCR7 levels in CLL cells. CAP-100 will be evaluated in clinical trials as a therapy for relapse/refractory CLL patients, who have received at least two systemic therapies (NCT04704323). As nowadays many relapse/refractory CLL patients will have received ibrutinib as a prior therapy, we aimed to investigate in a large cohort of CLL patients the impact of this BTKi on CCR7 expression and functionality as well as on the therapeutic activity of CAP-100. Our data confirm that ibrutinib moderately down-regulates the very high expression of CCR7 in CLL cells but has no apparent effect on CCR7-induced chemotaxis. Moreover, CLL cells are perfectly targetable by CAP-100 which led to a complete inhibition of CCR7-mediated migration and induced strong target cell killing through antibody-dependent cell-mediated cytotoxicity, irrespective of previous or contemporary ibrutinib administration. Together, these results validate the therapeutic utility of CAP-100 as a next-line single-agent therapy for CLL patients who failed to ibrutinib and confirm that CAP-100 and ibrutinib have complementary non-overlapping mechanisms of action, potentially allowing for combination therapy.

Targeting cancer homing into the lymph node with a novel anti-CCR7 therapeutic antibody: the paradigm of CLL.

Lymph node (LN) is a key tissue in the pathophysiology of mature blood cancers, especially for chronic lymphocytic leukemia (CLL). Within the multiple de-regulated pathways affecting CLL homeostasis, the CC-chemokine receptor 7 (CCR7) grants homing of CLL cells into the LN where protective environments foster tumor progression. To cover the lack of specific therapies targeting the CCR7-dependence of CLL to enter into the LN, and aiming to displace the disease from LN, we generated CAP-100, an antibody that specifically binds to hCCR7 and neutralizes its ligand-binding site and signaling. In various in vitro and in vivo preclinical models CAP-100 strongly inhibited CCR7-induced migration, extravasation, homing, and survival in CLL samples. Moreover, it triggered potent tumor cell killing, mediated by host immune mechanisms, and was effective in xenograft models of high-risk disease. Additionally, CAP-100 showed a favorable toxicity profile on relevant hematopoietic subsets. Our results validated CAP-100 as a novel therapeutic tool to prevent the access of CLL cells, and other neoplasia with nodal-dependence, into the LN niches, thus hitting a central hub in the pathogenesis of cancer. The first-in-human clinical trial (NCT04704323), which will evaluate this novel therapeutic approach in CLL patients, is pending.

Antifungal Prophylaxis After Lung Transplantation: Where Are We Now?

BACKGROUND: Lung transplantation is an important treatment option for various end-stage lung diseases. However, survival remains limited due to graft rejection and infections. Despite that fungal infections are frequent and carry a bad prognosis, there is currently no consensus on efficacy, optimal drug, route, or duration of antifungal prophylaxis. This narrative review summarizes current strategies for antifungal prophylaxis after lung transplantation. METHODS: English language articles in Embase, Pubmed, UptoDate, and bibliographies were used to assess the efficacy and safety of available antifungal agents for prophylaxis in adult lung transplant recipients. RESULTS: Overall, there are limited high-quality data. Universal prophylaxis is more widely used and may be preferable over targeted prophylaxis. Both formulations of inhaled amphotericin B and systemic azoles are effective at reducing fungal infection rates, yet with their own specific advantages and disadvantages. The benefit of combination regimens has yet to be proven. Considering the post-transplant timing of the onset of fungal infections, postoperative prophylaxis during the first postoperative months seems indicated for most patients. CONCLUSIONS: Based on existing literature, universal antifungal prophylaxis with inhaled amphotericin B and systemic voriconazole for at least 3-6 mo after lung transplantation may be advisable, with a slight preference for amphotericin B because of its better safety profile.