Sarcoma is derived from mesenchymal neoplasms and has numerous subtypes, accounting for 1% of all adult malignancies and 15% of childhood malignancies. The prognosis of metastatic or recurrent sarcoma remains poor. The current study presents two cases of sarcoma enrolled in a phase I dose escalation trial for solid tumor, who had previously failed all standard therapies. These patients were treated with VG161, an immune-stimulating herpes simplex virus type 1 oncolytic virus with payloads of IL-12, IL-15 and IL-15 receptor α unit, and a programmed cell death 1 (PD-1)/PD-1 ligand 1 blocking peptide. Both cases demonstrated stable disease as the best response, accompanied by a noteworthy prolongation of progression-free survival (11.8 months for chondrosarcoma and 11.9 months for soft tissue sarcoma, respectively) at a dose of 2.5×108 PFU/cycle. In addition, the treatment led to the activation of anti-cancer immunity, as evident from cytokine, lymphocyte subset and related pathway analyses of peripheral blood and/or tumor biopsy samples. These promising results suggest that VG161 monotherapy holds promise as an effective treatment for sarcoma and warrants further investigation through clinical trials. The two reported patients were part of a phase I clinical trial conducted and registered on the Australian New Zealand Clinical Trials Registry in Australia (registration no. ACTRN12620000244909; registration date, 26 February, 2020).
Copyright: © 2024 Qiu et al.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic highlights the importance of determining the breadth and durability of humoral immunity to SARS-CoV-2 mRNA vaccination. Herein, we characterize the humoral response in 27 naive and 40 recovered vaccinees. SARS-CoV-2-specific antibody and memory B cell (MBC) responses are durable up to 6 months, although antibody half-lives are shorter for naive recipients. The magnitude of the humoral responses to vaccination strongly correlates with responses to initial SARS-CoV-2 infection. Neutralization titers are lower against SARS-CoV-2 variants in both recovered and naive vaccinees, with titers more reduced in naive recipients. While the receptor-binding domain (RBD) is the main neutralizing target of circulating antibodies, Moderna-vaccinated naives show a lesser reliance on RBDs, with >25% neutralization remaining after depletion of RBD-binding antibodies. Overall, we observe that vaccination induces higher peak titers and improves durability in recovered compared with naive vaccinees. These findings have broad implications for current vaccine strategies deployed against the SARS-CoV-2 pandemic.© 2022 The Author(s).

Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs and NAbs prevent new rounds of viral infection, but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (ADCC) in vitro resulted in arming of effector cells in vivo, yet led to viral-decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominant mechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function can contribute to the overall antiviral activity, making them distinct from standard ARVs.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi is one of the most important neglected parasitic diseases in the Americas. Vaccines represent an attractive complementary strategy for the control of T. cruzi infection and pre-clinical studies in mice demonstrated that trypomastigote surface antigen (TSA-1) and the flagellar calcium-binding (Tc24) parasite antigens are promising candidates for vaccine development. We performed here the first evaluation of the safety and immunogenicity of two recombinant vaccine antigens (named TSA1-C4 and Tc24-C4) in naïve non-human primates. Three rhesus macaques received 3 doses of each recombinant protein, formulated with E6020 (Eisai Co., Ltd.), a novel Toll-like receptor-4 agonist, in a stable emulsion. All parameters from blood chemistry and blood cell counts were stable over the course of the study and unaffected by the vaccine. A specific IgG response against both antigens was detectable after the first vaccine dose, and increased with the second dose. After three vaccine doses, stimulation of PBMCs with a peptide pool derived from TSA1-C4 resulted in the induction of TSA1-C4-specific TNFα-, IL-2- and IFNγ-producing CD4+ in one or two animals while stimulation with a peptide pool derived from Tc24-C4 only activated IFNγ-producing CD4+T cells in one animal. In two animals there was also activation of TSA1-C4-specific IL2-producing CD8+ T cells. This is the first report of the immunogenicity of T. cruzi-derived recombinant antigens formulated as an emulsion with a TLR4 agonist in a non-human primate model. Our results strongly support the need for further evaluation of the preventive efficacy of this type of vaccine in non-human primates and explore the effect of the vaccine in a therapeutic model of naturally-infected Chagasic non-human primates, which would strengthen the rationale for the clinical development as a human vaccine against Chagas disease.Copyright © 2020 Elsevier Ltd. All rights reserved.

Immune checkpoint inhibitors have revolutionized cancer treatment. However, many cancers are resistant to ICIs, and the targeting of additional inhibitory signals is crucial for limiting tumor evasion. The production of adenosine via the sequential activity of CD39 and CD73 ectoenzymes participates to the generation of an immunosuppressive tumor microenvironment. In order to disrupt the adenosine pathway, we generated two antibodies, IPH5201 and IPH5301, targeting human membrane-associated and soluble forms of CD39 and CD73, respectively, and efficiently blocking the hydrolysis of immunogenic ATP into immunosuppressive adenosine. These antibodies promoted antitumor immunity by stimulating dendritic cells and macrophages and by restoring the activation of T cells isolated from cancer patients. In a human CD39 knockin mouse preclinical model, IPH5201 increased the anti-tumor activity of the ATP-inducing chemotherapeutic drug oxaliplatin. These results support the use of anti-CD39 and anti-CD73 monoclonal antibodies and their combination with immune checkpoint inhibitors and chemotherapies in cancer.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.