Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination nanochemotherapy for treating patients with MPNSTs

Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor

Background: Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells. Methods: Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1st generation (SCF-CD3ζ, 1st gen) and 2nd generation (SCF-CD28-CD3ζ, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions. Results: We successfully produced the 1st and 2nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1st and 2nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1st and 2nd gen dTc proliferated and produced IFNγ. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1st or 2nd gen human anti-KIT dTc led to significant reductions in tumor growth rates. Conclusions: We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc

Beyond CAR T Cells: Other Cell-Based Immunotherapeutic Strategies Against Cancer

Background: Chimeric antigen receptor (CAR)-modified T cells have successfully harnessed T cell immunity against malignancies, but they are by no means the only cell therapies in development for cancer.Main Text Summary: Systemic immunity is thought to play a key role in combatting neoplastic disease; in this vein, genetic modifications meant to explore other components of T cell immunity are being evaluated. In addition, other immune cells—from both the innate and adaptive compartments—are in various stages of clinical application. In this review, we focus on these non-CAR T cell immunotherapeutic approaches for malignancy. The first section describes engineering T cells to express non-CAR constructs, and the second section describes other gene-modified cells used to target malignancy.Conclusions: CAR T cell therapies have demonstrated the clinical benefits of harnessing our body's own defenses to combat tumor cells. Similar research is being conducted on lesser known modifications and gene-modified immune cells, which we highlight in this review

Designing Magnetically Responsive Biohybrids Composed of Cord Blood-Derived Natural Killer Cells and Iron Oxide Nanoparticles.

We report the generation of magnetically responsive, cord blood-derived natural killer (NK) cells using iron oxide nanoparticles (IONPs). NK cells are a promising immune cell population for cancer cell therapy as they can target and lyse target tumor cells without prior education. However, NK cells cannot home to disease sites based on antigen recognition, instead relying primarily on external stimuli and chemotactic gradients for transport. Hence, we hypothesized that conjugating IONPs onto the surface of NK cells provides an added feature of magnetic homing to the NK cells, improving their therapeutic function. We describe a robust design for conjugating the IONPs onto the surface of NK cells, which maintains their intrinsic phenotype and function. The conferred magnetic-responsiveness is utilized to improve the cytolytic function of the NK cells for target cells in 2D and 3D models. These findings demonstrate the feasibility of improving NK cell homing and therapeutic efficacy with our NK:IONP “biohybrid”

Conjugating Prussian blue nanoparticles onto antigen-specific T cells as a combined nanoimmunotherapy.

AIM: To engineer a novel nanoimmunotherapy comprising Prussian blue nanoparticles (PBNPs) conjugated to antigen-specific cytotoxic T lymphocytes (CTL), which leverages PBNPs for their photothermal therapy (PTT) capabilities and Epstein–Barr virus (EBV) antigen-specific CTL for their ability to traffic to and destroy EBV antigen-expressing target cells. MATERIALS & METHODS: PBNPs and CTL were independently biofunctionalized. Subsequently, PBNPs were conjugated onto CTL using avidin–biotin interactions. The resultant cell-nanoparticle construct (CTL:PBNPs) were analyzed for their physical, phenotypic and functional properties. RESULTS: Both PBNPs and CTL maintained their intrinsic physical, phenotypic and functional properties within the CTL:PBNPs. CONCLUSION: This study highlights the potential of our CTL:PBNPs nanoimmunotherapy as a novel therapeutic for treating virus-associated malignancies such as EBV+ cancers

Engineering the TGFb receptor to enhance the therapeutic potential of natural killer cells as an immunotherapy for neuroblastoma

Purpose: The ability of natural killer (NK) cells to lyse allogeneic targets, without the need for explicit matching or priming, makes them an attractive platform for cell-based immunotherapy. Umbilical cord blood is a practical source for generating banks of such third-party NK cells for off-the-shelf cell therapy applications. NK cells are highly cytolytic, and their potent antitumor effects can be rapidly triggered by a lack of HLA expression on interacting target cells, as is the case for a majority of solid tumors, including neuroblastoma. Neuroblastoma is a leading cause of pediatric cancer–related deaths and an ideal candidate for NK-cell therapy. However, the antitumor efficacy of NK cells is limited by immunosuppressive cytokines in the tumor microenvironment, such as TGFb, which impair NK cell function and survival. Experimental Design: To overcome this, we genetically modified NK cells to express variant TGFb receptors, which couple a mutant TGFb dominant-negative receptor to NK-specific activating domains. We hypothesized that with these engineered receptors, inhibitory TGFb signals are effectively converted to activating signals. Results: Modified NK cells exhibited higher cytotoxic activity against neuroblastoma in a TGFb-rich environment in vitro and superior progression-free survival in vivo, as compared with their unmodified controls. Conclusions: Our results support the development of off-the-shelf gene-modified NK cells, that overcome TGFb-mediated immune evasion, in patients with neuroblastoma and other TGFb-secreting malignancies

Liver metastases induce reversible hepatic B cell dysfunction mediated by Gr-1+CD11b+ myeloid cells.

LM escape immune surveillance, in part, as a result of the expansion of CD11b+MC, which alter the intrahepatic microenvironment to promote tumor tolerance. HBC make up a significant proportion of liver lymphocytes and appear to delay tumor progression; however, their significance in the setting of LM is poorly defined. Therefore, we characterized HBC and HBC/CD11b+MC interactions using a murine model of LM. Tumor-bearing livers showed a trend toward elevated absolute numbers of CD19+ HBC. A significant increase in the frequency of IgM(lo)IgD(hi) mature HBC was observed in mice with LM compared with normal mice. HBC derived from tumor-bearing mice demonstrated increased proliferation in response to TLR and BCR stimulation ex vivo compared with HBC from normal livers. HBC from tumor-bearing livers exhibited significant down-regulation of CD80 and were impaired in inducing CD4(+) T cell proliferation ex vivo. We implicated hepatic CD11b+MC as mediators of CD80 down-modulation on HBC ex vivo via a CD11b-dependent mechanism that required cell-to-cell contact and STAT3 activity. Therefore, CD11b+MC may compromise the ability of HBC to promote T cell activation in the setting of LM as a result of diminished expression of CD80. Cross-talk between CD11b+MC and HBC may be an important component of LM-induced immunosuppression

Composite iron oxide-Prussian blue nanoparticles for magnetically guided T1-weighted magnetic resonance imaging and photothermal therapy of tumors

© 2017 Kale et al. Theranostic nanoparticles offer the potential for mixing and matching disparate diagnostic and therapeutic functionalities within a single nanoparticle for the personalized treatment of diseases. In this article, we present composite iron oxide-gadolinium-containing Prussian blue nanoparticles (Fe3O4@GdPB) as a novel theranostic agent for T1-weighted magnetic resonance imaging (MRI) and photothermal therapy (PTT) of tumors. These particles combine the well-described properties and safety profiles of the constituent Fe3O4 nanoparticles and gadolinium-containing Prussian blue nanoparticles. The Fe3O4@GdPB nanoparticles function both as effective MRI contrast agents and PTT agents as determined by characterizing studies performed in vitro and retain their properties in the presence of cells. Importantly, the Fe3O4@GdPB nanoparticles function as effective MRI contrast agents in vivo by increasing signal: noise ratios in T1-weighted scans of tumors and as effective PTT agents in vivo by decreasing tumor growth rates and increasing survival in an animal model of neuroblastoma. These findings demonstrate the potential of the Fe3O4@GdPB nanoparticles to function as effective theranostic agents