T‐cell modulation by cyclophosphamide for tumour therapy

The power of T cells for cancer treatment has been demonstrated by the success of co‐inhibitory receptor blockade and adoptive T‐cell immunotherapies. These treatments are highly successful for certain cancers, but are often personalized, expensive and associated with harmful side effects. Other T‐cell‐modulating drugs may provide additional means of improving immune responses to tumours without these disadvantages. Conventional chemotherapeutic drugs are traditionally used to target cancers directly; however, it is clear that some also have significant immune‐modulating effects that can be harnessed to target tumours. Cyclophosphamide is one such drug; used at lower doses than in mainstream chemotherapy, it can perturb immune homeostasis, tipping the balance towards generation of anti‐tumour T‐cell responses and control of cancer growth. This review discusses its growing reputation as an immune‐modulator whose multiple effects synergize with the microbiota to tip the balance towards tumour immunity offering widespread benefits as a safe, and relatively inexpensive component of cancer immunotherapy

Antitumor effect of murine dendritic and tumor cells transduced with IL-2 gene Antitumor effect of murine dendritic and tumor cells transduced with IL-2 gene

Interleukin (IL-) 2 acts on a number of types of immune cells promoting their effector functions. To replace&lt;br /&gt;systemic administration of recombinant form of this cytokine, various genetically modified cells have been used in&lt;br /&gt;different preclinical models for tumor growth inhibition. In this study, dendritic or tumor cells transduced with retroviral&lt;br /&gt;vector carrying IL-2 gene (JAWS II/IL-2, X63/IL-2, MC38/IL-2 cells) alone or combined with tumor antigenstimulated&lt;br /&gt;dendritic cells (JAWS II/TAg) were exploited to treat colon carcinoma MC38-bearing mice. After the&lt;br /&gt;peritumoral injection of vaccine cells, the tumor growth delay and the increase in the number of tumor infiltrating&lt;br /&gt;CD4+ and CD8+ T lymphocytes were noted. A considerable increase in CD4+ cell influx into tumor tissue was observed&lt;br /&gt;when JAWS II/IL-2 cells or JAWS II/TAg with syngeneic MC38/IL-2 cells were applied. The increase in&lt;br /&gt;intensity of CD8+ cell infiltration was associated with immune reaction triggered by the same combination of applied&lt;br /&gt;cells or JAWS II/TAg with allogeneic X63/IL-2 cells. The effect observed in vivo was accompanied by MC38/0 cell&lt;br /&gt;specific cytotoxic activity of spleen cells in vitro. Thus, the application of vaccines, including IL-2-secreting cells of&lt;br /&gt;various origins, was able to induce different antitumor responses polarized by exogenous IL-2 and the encountered&lt;br /&gt;tumor antigen.<br>Interleukin (IL-) 2 acts on a number of types of immune cells promoting their effector functions. To replace&lt;br /&gt;systemic administration of recombinant form of this cytokine, various genetically modified cells have been used in&lt;br /&gt;different preclinical models for tumor growth inhibition. In this study, dendritic or tumor cells transduced with retroviral&lt;br /&gt;vector carrying IL-2 gene (JAWS II/IL-2, X63/IL-2, MC38/IL-2 cells) alone or combined with tumor antigenstimulated&lt;br /&gt;dendritic cells (JAWS II/TAg) were exploited to treat colon carcinoma MC38-bearing mice. After the&lt;br /&gt;peritumoral injection of vaccine cells, the tumor growth delay and the increase in the number of tumor infiltrating&lt;br /&gt;CD4+ and CD8+ T lymphocytes were noted. A considerable increase in CD4+ cell influx into tumor tissue was observed&lt;br /&gt;when JAWS II/IL-2 cells or JAWS II/TAg with syngeneic MC38/IL-2 cells were applied. The increase in&lt;br /&gt;intensity of CD8+ cell infiltration was associated with immune reaction triggered by the same combination of applied&lt;br /&gt;cells or JAWS II/TAg with allogeneic X63/IL-2 cells. The effect observed in vivo was accompanied by MC38/0 cell&lt;br /&gt;specific cytotoxic activity of spleen cells in vitro. Thus, the application of vaccines, including IL-2-secreting cells of&lt;br /&gt;various origins, was able to induce different antitumor responses polarized by exogenous IL-2 and the encountered&lt;br /&gt;tumor antigen

T4 phage and its head surface proteins do not stimulate inflammatory mediator production.

Viruses are potent activators of the signal pathways leading to increased cytokine or ROS production. The effects exerted on the immune system are usually mediated by viral proteins. Complementary to the progress in phage therapy practice, advancement of knowledge about the influence of bacteriophages on mammalian immunity is necessary. Particularly, the potential ability of phage proteins to act like other viral stimulators of the immune system may have strong practical implications for the safety and efficacy of bacteriophage therapy. Here we present studies on the effect of T4 phage and its head proteins on production of inflammatory mediators and inflammation-related factors: IL-1α, IL-1β, IL-2, IL-6, IL-10, IL-12 p40/p70, IFN-γ, TNF-α, MCP-1, MIG, RANTES, GCSF, GM-CSF and reactive oxygen species (ROS). Plasma cytokine profiles in an in vivo mouse model and in human blood cells treated with gp23*, gp24*, Hoc and Soc were evaluated by cytokine antibody arrays. Cytokine production and expression of CD40, CD80, CD86 and MHC class II molecules were also investigated in mouse bone marrow-derived dendritic cells treated with whole T4 phage particle or the same capsid proteins. The influence of T4 and gp23*, gp24*, Hoc and Soc on reactive oxygen species generation was examined in blood cells using luminol-dependent chemiluminescence assay. In all performed assays, the T4 bacteriophage and its capsid proteins gp23*, gp24*, Hoc and Soc did not affect production of inflammatory-related cytokines or ROS. These observations are of importance for any medical or veterinary application of bacteriophages

Mouse Cytokine Antibody Array map.

<p>Mouse Cytokine Antibody Array map.</p

Kinetics of ROS formation by PMNs stimulated by gp23*, gp24*, Hoc, and Soc.

<p>(A) gp23*, (B) gp24*, (C) Hoc, (D) Soc. Alb – albumin.</p

Cytokine profiles in mice and in human blood treated with phage proteins.

<p>(A) Cytokine profiles in mice stimulated with gp23*, gp24*, Hoc, PBS, albumin (alb), (B) Cytokine profiles in mice stimulated with Soc, PBS, albumin (alb), (C) Cytokine profiles in human whole blood stimulated with gp23*, gp24*, Hoc, Soc, PBS, albumin (alb).</p

Human Cytokine Antibody Array map.

<p>Human Cytokine Antibody Array map.</p

Kinetics of ROS formation by PMNs and PBMCs stimulated by T4 phage.

<p>(A) PMNs, (B) PBMCs.</p