MHV-68 producing mIFN␣1 is severely attenuated in vivo and effectively protects mice against challenge with wt MHV-68

Corrigendum Corrigendum to "MHV-68 producing mIFN␣1 is severely attenuated in vivo and effectively protects mice against challenge with wt MHV-68" [Vaccine 29 (2011) In this study, we focused on the effects of interferon-␣ (IFN-␣) on both the lytic and latent phase of MHV-68 infection, as exerted by the constitutive release of IFN-␣1 by a clone of MHV-68 genetically modified to produce this cytokine (MHV-68mIFN␣1). Although the MHV-68mIFN␣1 recombinant virus exhibited in vitro replication features indistinguishable from those of the wild type MHV-68, its pathological properties were severely attenuated in vivo in immunocompetent mice and not in mice rendered genetically unresponsive to type I IFN, suggesting that a stronger immune response was primed in the presence of the cytokine. Notably, MHV-68mIFN␣1 attenuation did not result in a reduced level of longterm spleen latency establishment. These results prompted us to evaluate the efficacy of MHV-68mIFN␣1 in a prophylactic vaccination regimen aimed at inhibiting the symptoms of acute virus infection and the establishment of long-term latency after MHV-68 challenge. Our results show that mice vaccinated with MHV-68mIFN␣1, administered as a live-attenuated or partially inactivated (by Psoralen and UV treatment) vaccine, were protected against the challenge with wt MHV-68 from all phases of infection. The ability of MHV-68mIFN␣1 to produce IFN-␣ at the site of the infection, thus efficiently stimulating the immune system in case of virus reactivation from latency, makes this recombinant virus a safer live-attenuated vaccine as compared to the previously reported latency-deficient clones

Chimeric Antigen Receptor Immunotherapy for Solid Tumors: Choosing the Right Ingredients for the Perfect Recipe

Chimeric antigen receptor T cell therapies are revolutionizing the clinical practice of hematological tumors, whereas minimal progresses have been achieved in the solid tumor arena. Multiple reasons have been ascribed to this slower pace: The higher heterogeneity, the hurdles of defining reliable tumor antigens to target, and the broad repertoire of immune escape strategies developed by solid tumors are considered among the major ones. Currently, several CAR therapies are being investigated in preclinical and early clinical trials against solid tumors differing in the type of construct, the cells that are engineered, and the additional signals included with the CAR constructs to overcome solid tumor barriers. Additionally, novel approaches in development aim at overcoming some of the limitations that emerged with the approved therapies, such as large-scale manufacturing, duration of manufacturing, and logistical issues. In this review, we analyze the advantages and challenges of the different approaches under development, balancing the scientific evidences supporting specific choices with the manufacturing and regulatory issues that are essential for their further clinical development

MHV-68 producing mIFNα1 is severely attenuated in vivo and effectively protects mice against challenge with wt MHV-68.

Human gammaherpesviruses such as Epstein-Barr virus (EBV) cause lifelong infections and associated diseases, by virtue of their ability to establish latent infection. Many studies performed in the past years in murine herpesvirus 68 (MHV-68) model of infection suggested that the limited immunity generated against isolated viral components by subunit vaccines cannot counteract the multiple immune evasion strategies operated by gammaherpesviruses. Indeed, a significant inhibition of long-term latency establishment could be observed in mice vaccinated with strains of genetically modified MHV-68 defective in reactivation or establishment of latency. In this study, we focused on the effects of interferon-α (IFN-α) on both the lytic and latent phase of MHV-68 infection, as exerted by the constitutive release of IFN-α1 by a clone of MHV-68 genetically modified to produce this cytokine (MHV-68mIFNα1). Although the MHV-68mIFNα1 recombinant virus exhibited in vitro replication features indistinguishable from those of the wild type MHV-68, its pathological properties were severely attenuated in vivo in immunocompetent mice and not in mice rendered genetically unresponsive to type I IFN, suggesting that a stronger immune response was primed in the presence of the cytokine. Notably, MHV-68mIFNα1 attenuation did not result in a reduced level of long-term spleen latency establishment. These results prompted us to evaluate the efficacy of MHV-68mIFNα1 in a prophylactic vaccination regimen aimed at inhibiting the symptoms of acute virus infection and the establishment of long-term latency after MHV-68 challenge. Our results show that mice vaccinated with MHV-68mIFNα1, administered as a live-attenuated or partially inactivated (by Psoralen and UV treatment) vaccine, were protected against the challenge with wt MHV-68 from all phases of infection. The ability of MHV-68mIFNα1 to produce IFN-α at the site of the infection, thus efficiently stimulating the immune system in case of virus reactivation from latency, makes this recombinant virus a safer live-attenuated vaccine as compared to the previously reported latency-deficient clones. © 2011 Elsevier Ltd

Clinical and antitumor immune responses In Relapsed/Refractory Follicular Lymphoma patients after intranodal injections of IFNα-Dendritic Cells and Rituximab

This study was aimed at evaluating the feasibility, safety, immunological and clinical responses in patients with Follicular lymphoma (FL) treated with monocyte-derived dendritic cells generated in the presence of interferon-alpha and GM-CSF (IFN-DC) in combination with low doses of Rituximab (R).Firstly, we analyzed in vitro and in vivo the immunological properties of IFN-DC against FL. Thus, we performed a phase I trial in 8 refractory and relapsed FL patients based on sequential intranodal injections of low-dose of R and unloaded IFN-DC and report the safety, clinical and immunological results of the enrolled patients.Preclinical studies indicated that IFN-DC can synergize with R leading to increased cytotoxicity and T cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37% and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11-47). Notably, following the combined therapy all patients showed induction/enhancement of T cell responses by CD107 degranulation or IFN-g ELISPOT assay against patient-specific tumor IGHV sequences.These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in cancer patients