Dendritic Cell-mediated Immunotherapy Research Articles

Elastic Nanovaccine Enhances Dendritic Cell‐Mediated Tumor Immunotherapy (Small 32/2022)

Elastic Nanovaccines In article number 2201108, Zhaogang Teng, Heng Dong, Yongbin Mou, and co-workers report a soft mesoporous organosilica-based nanovaccine (SMONV) and demonstrate that elastic SMONV evokes robust antitumor immune cascades, including lymphatic drainage, antigen internalization and cross-presentation, and tumor-specific T-cell immune responses. Treg-mediated immunosuppression is inhibited after immunization with SMONV. Furthermore, combined administration of anti-PD-L1 antibodies induces tumor regression. The paper provides insight into nanoparticle elasticity and dendritic cell-mediated immunotherapy.

Abstract 2129: Effects of talactoferrin on lung adenoma prevention in A/J mice

Abstract Talactoferrin is a promising non-toxic solid tumor cancer agent which has met with some success in the treatment of early stage lung cancer clinically in humans. It is well tolerated and early phase clinical trials with this agent demonstrated efficacy and immune stimulation as an oral dendritic cell-mediated immunotherapy agent. We felt the nature of this agent would be suitable in the chemoprevention setting in experimental lung carcinogenesis in a B[A]P mouse model. We utilized 120 seven week old female A/J mice. All groups received Benzo[a]pyrene by oral gavage in three doses of 3mg/kg body weight over the course of one week. Animals were then randomized into 5 groups of 24 mice per group based on weight. Experimental diets, talactoferrin (Agennix Inc., Indianapolis, IN) at 1.40 and 0.42% of diet, were started one week or eight weeks after last dose of B[a]P. Animals were continued on the feeding schedule, weighed weekly, and monitored for weight loss, attenuation, rough hair coat, or other signs of ill health. The study was concluded 16 weeks after administration of B[a]P. The agent was well tolerated for the duration of the experiment and there was no observable toxicity. The average number of adenomas per animal was 14.04 ± 0.9315 (N=24) in the control group, 18.14 ± 1.448 (N=22) in the early low dose group, 16.70 ± 1.295 (N=23) in the late low dose group, 15.09 ± 1.408 (N=23) in the early high dose group and 14.46 ± 1.213 (N=24) in the late high dose group. We conclude talactoferrin is well tolerated in the A/J mouse model. We also conclude talactoferrin did not inhibit carcinogenesis in A/J mice at a dose range of 420mg/kg/day to 1400mg/kg/day. Citation Format: Donna Seabloom, Arthur Galbraith, Anna Haynes, Jenny Antonides, Alisha Fujita, Beverly R. Wuertz, Vernon Steele, Frank Ondrey, Lee Wattenberg. Effects of talactoferrin on lung adenoma prevention in A/J mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2129. doi:10.1158/1538-7445.AM2014-2129

Oncolytic viruses induce tumor cell death and antitumor immune memory in the GL261 orthotopic mouse glioma model

Introduction and Aim: Glioblastoma Multiforme is a WHO grade IV neoplasm and is the most frequent primary brain tumor in adults. In spite of current multimodal treatment the prognosis remains poor, with a median overall survival of 14.6 months and a mortality rate of 88% within 3 years. At time of relapse (which is universal), the prognosis is particularly dismal with reports of 100% mortality within 1.5 years. In view of these discouraging results, (pre)clinical research is focused on long-term and tumor-specific treatments, such as oncolytic virotherapy. Not only do oncolytic viruses have the potential to lower tumor volume and viability considerably, they might also alter the local microenvironment within the tumor, to subsequently induce a better immune control through immunotherapeutic approaches. Here we investigate the efficacy of the oncolytic Reovirus Type 3 Dearing, Parvovirus H-1 and Newcastle disease virus (NDV) Hitchner B1 strains in the orthotopic murine GL261 glioma model. Materials and Methods: monolayers of GL261 cells and healthy astrocytes were inoculated with Reovirus, Parvovirus or NDV at different multiplicities of infection, ranging from 0,05 to 10 plague forming units/cells. 72 hours later, cell death was measured via MTT assays. C57/BL6 and Rag2-/- mice were challenged with GL261 cells orthotopically and treated intratumorally with NDV on day 3 or day 7 after tumor induction. Animals were followed for symptoms and survival. Long-term surviving animals were rechallenged with GL261 cells after 100 days. Results: We demonstrated in vitro that Reovirus, Parvovirus and NDV exhibit strong cytotoxicity towards the GL261 cell line. In vivo we showed that local injection of NDV was feasible and significantly prolonged survival of treated animals versus untreated controls. Furthermore, 45% of treated animals survived long-term versus none in the control group. Similar survival data were obtained whether NDV was injected at time of minimal disease or at time of bulky tumor. Tumor rechallenge in long-term surviving animals resulted in 80% survival, suggesting immunization in most mice after NDV therapy. In immunodeficient Rag2-/- animals, NDV failed to prolong survival after glioma challenge, further substantiating the notion that the anticancer effects of NDV can be tracked not only to direct viral oncolysis, but also to an additional immune component. Conclusion: For the first time, we describe that NDV has therapeutic activity against GL261 tumor cells, evidenced in an orthotopic mouse model. NDV therapy significantly improves median survival and induces an antitumor memory response in treated animals. This is a highly innovative finding and ongoing work is focused on further elucidating the immune component in successful oncolytic virotherapy. Furthermore, this model will allow us to study the potential synergism between NDV therapy and dendritic cell mediated immunotherapy, which thus far has not been studied in the field of glioma research

Talactoferrin alfa versus placebo in patients with refractory advanced non-small-cell lung cancer (FORTIS-M trial)

BackgroundTalactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC). Patients and methodsAn FORTIS-M trial was an international, multicenter, randomized, double-blind comparison of talactoferrin (1.5g p.o. BID) versus placebo BID, in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens. Treatment was administered for a maximum of five 14-week cycles. The primary efficacy end point was overall survival (OS); secondary end points included 6- and 12-month survival, progression-free survival (PFS), and disease control rate (DCR). ResultsSeven hundred and forty-two patients were randomly assigned (2:1) to talactoferrin (497) or placebo (245). The median OS in the intent-to-treat (ITT) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [hazard ratio (HR), 1.04; 95% CI, 0.873–1.24; P = 0.6602]. The 6-month survival rates were 59.9% (95% CI, 53.4% to 65.8%) and 55.7% (95% CI, 51.1% to 59.9%), respectively. The 12-month survival rates were 32.2% (95% CI, 26.3% to 38.2%) and 30.9% (95% CI, 26.8% to 35%), respectively. The median PFS rates were 1.64 months and 1.68 months, respectively (HR, 0.99; 95% CI, 0.835–1.16; P = 0.8073). The DCRs were 38.4 and 37.6%, respectively [stratified odds ratio (OR), 0.96; 95% CI, 0.698–1.33; P = 0.8336]. The safety profiles were comparable between arms. ConclusionsThere was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens.

LBA34 - Fortis-M, a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Oral Talactoferrin Alfa with Best Supportive Care in Patients with Advanced Non-Small Cell Lung Cancer Following Two or More Prior Regimens- by the Fortis-M Study Group

ABSTRACT Background Talactoferrin alfa (TLF) is an oral Dendritic Cell Mediated Immunotherapy (DCMI). Based on positive results in two randomized phase II trials in NSCLC, we conducted a phase III study of TLF versus placebo for advanced NSCLC following ≥2 prior systemic therapy regimens (NCT00707304). Methods Inclusion criteria were: age >18 years; failed ≥2 prior systemic regimens (received 1 platinum-based regimen); presence of measureable disease; ECOG performance status 0-2; and life expectancy >12 weeks. Patients were randomly assigned (2:1) to receive TLF (1.5 g oral solution) or placebo BID, each with best supportive care, for a maximum of five 14-week cycles (12 weeks on/2 weeks off). The primary endpoint was overall survival (OS). Secondary endpoints included 6-month and 1-year survival rates, progression-free survival (PFS), objective response rate, and objective disease control rate (DCR), complete or partial response or stable disease). The primary endpoint was analyzed using a stratified log rank test with a 2-sided significance level of 0.05. Results A total of 742 patients (TLF = 497, placebo =245) were enrolled between November 2008 and March 2011 at 163 centers worldwide. Median age was 62 years for TLF and 63 years for placebo; 90% of patients in each group had Stage IV disease; and 56.5% of TLF patients and 58.4% of placebo patients had received ≥3 prior regimens. The median OS for TLF was 7.49 months versus 7.66 months for placebo (HR 1.04, P = 0.6602); and the respective values for PFS were 1.68 and 1.64 months (HR 0.99, P = 0.8829). The DCR was 37.6% for TLF and 38.4% for placebo (P = 0.8336). 87.3% of patients in the TLF arm experienced an adverse event (AEs), 86.0% in the placebo arm; 36.4% of patients had Grade 3-4 AEs in the TLF arm, 35.5% in the placebo arm; and those for serious AEs were 43.7% and 41.7%. Discontinuations due to AEs occurred for 14.5% of TLF patients vs 15.7% for placebo. Conclusions TLF plus best supportive care did not extend OS or PFS vs placebo plus best supportive care in patients with advanced NSCLC. Oral TLF had a safety profile comparable to that for placebo. Disclosure S.S. Ramalingam: I have served on advisory board meetings for Agennix and have received honorarium. J. Crawford: Author has served on advisory board meetings to Agennix and has received honorarium. A. Chang: Author has served on advisory board meetings to Agennix and has received honorarium. C. Manegold: Author has served on advisory board meetings to Agennix and has received honorarium. R. Perez-Soler: Author has served on advisory board meetings to Agennix and has received honorarium. J. Douillard: Author has served on advisory board meetings to Agennix and has received honorarium. N. Thatcher: Author has served on advisory board meetings to Agennix and has received honorarium. F. Barlesi: Author has served on advisory board meetings to Agennix and has received honorarium. Y. Wang: Co-author is an employee and stockholder of Agennix P. Pultar: Co-author is an employee and stockholder in Agennix. J. Zhu: Co-author is an employee and stockholder of Agennix R. Malik: Author is an employee of Agennix and owns stock and stock options with Agennix. All other authors have declared no conflicts of interest.

Potentiation of the immunotherapeutic effect of autologous dendritic cells by pretreating hepatocellular carcinoma with low-dose radiation

To determine whether exposing hepatocellular carcinoma (HCC) to low dose radiation increases the efficacy of dendritic cell-mediated immunotherapy for HCC. Tumour specimens collected from 20 recruited patients with HCC were cultured in primary culture (half successfully) and then exposed to low-dose radiation (0.5 Gy). Immature DCs derived from peripheral blood monocytes of patients were pulsed with autologous HCC cell lysates and matured with a cytokine cocktail. Autologous tumour lysate-pulsed DCs (TLP-DCs) were used to stimulate mixed lymphocytes, which were then tested for inhibitory effect on the growth of HCC cells. Surface markers of immunogenicity on primary HCC cells, MHC, and Fas were investigated before and after low-dose irradiation. Exposing HCC cells to low-dose (0.5 Gy) radiation enhanced the immunotherapeutic effect of TLP-DC-stimulated lymphocytes. Growth inhibition increased from 50.6+/-7.5% without irradiation to 74.3+/-4.3% with radiation. The expression of MHC class ll and Fas was upregulated after irradiating HCC cells. Exposing tumour cells to a low dose of radiation can enhance the immunotherapeutic effect of the autologous tumor lysate-pulsed DC vaccine.

Deletion of the virion host shutoff protein (vhs) from herpes simplex virus (HSV) relieves the viral block to dendritic cell activation: potential of vhs- HSV vectors for dendritic cell-mediated immunotherapy.

Herpes simplex virus (HSV) infects dendritic cells (DC) efficiently but with minimal replication. HSV, therefore, appears to have evolved the ability to enter DC even though they are nonpermissive for virus growth. This provides a potential utility for HSV in delivering genes to DC for vaccination purposes and also suggests that the life cycle of HSV usually includes the infection of DC. However, DC infected with HSV usually lose the ability to become activated following infection (M. Salio, M. Cella, M. Suter, and A. Lanzavecchia, Eur. J. Immunol. 29:3245-3253, 1999; M. Kruse, O. Rosorius, F. Kratzer, G. Stelz, C. Kuhnt, G. Schuler, J. Hauber, and A. Steinkasserer, J. Virol. 74:7127-7136, 2000). We report that for DC to retain the ability to become activated following HSV infection, the virion host shutoff protein (vhs) must be deleted. vhs usually functions to destabilize mRNA in favor of the production of HSV proteins in permissive cells. We have found that it also plays a key role in the inactivation of DC and is therefore likely to be important for immune evasion by the virus. Here, vhs would be anticipated to prevent DC activation in the early stages of infection of an individual with HSV, reducing the induction of cellular immune responses and thus preventing virus clearance during repeated cycles of virus latency and reactivation. Based on this information, replication-incompetent HSV vectors with vhs deleted which allow activation of DC and the induction of specific T-cell responses to delivered antigens have been constructed. These responses are greater than if DC are loaded with antigen by incubation with recombinant protein.

Immunization with dendritic cells pulsed with tumor extract increases survival of mice bearing intracranial gliomas.

The purpose of this study is to investigate the efficacy of dendritic cell-mediated immunotherapy against intracranial gliomas. Cloned DC2.4 dendritic cells originating from C57BL/6 mice were pulsed with glioma GL261 cell extracts and administered i.p. to C57BL/6 mice with intracranial GL261 gliomas. The survival of mice with and without pulsed dendritic cells was monitored after intracranial implantation of the GL261 glioma cells. Fluorescence activated cell sorting (FACS) analysis showed that DC2.4 cells express high levels of MHC class I and class II molecules, costimulatory molecules B7-1 and B7-2, and the cell adhesion molecule ICAM-1. Antigen-presenting capabilities in these dendritic cells were initially characterized in vitro by a mixed lymphocyte reaction, showing that Balb/c CD4+ and CD8+ T cells were able to generate allogeneic responses to DC2.4 cells. Tumor extract-pulsed DC2.4 dendritic cells were then used for the treatment of C57BL/6 mice with syngeneic GL261 gliomas. Animals with intracranial GL261 gliomas and vaccinated i.p. with pulsed DC2.4 dendritic cells exhibited significantly enhanced survival, relative to animals treated with saline or non-pulsed DC2.4 cells alone. In addition, cured animals showed an increased delayed-type hypersensitivity response to GL261 cells and survived when rechallenged with intracranial GL261 gliomas. In summary these results indicate that dendritic cells pulsed with tumor extract can enhance immune responses to tumor antigen and therefore represent a potential immunotherapeutic approach for treating patients with intracranial gliomas.