Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients

Mitchell, Duane A.; Batich, Kristen A.; Gunn, Michael D.; Huang, Mou Tuan; Sánchez-Pérez, Luis; Nair, Smita K.; Congdon, Kendra L.; Reap, Elizabeth A.; Archer, Gary E.; Desjardins, Annick; Friedman, Allan H.; Herndon, James E.; Coan, April; McLendon, Roger E.; Reardon, David A.; Vredenburgh, James J.; Bigner, Darell D.; Sampson, John H.

doi:10.1038/nature14320

Cited by 466 publications

(420 citation statements)

References 26 publications

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“…Finally, we looked at a number of inflammatory chemokines and chemokine receptors that are crucial for DC and T-cell recruitment to tumors. 27–30 CCR5, CCL4, and CXCR3 were highly expressed in HPV+ HNSCC compared to HPV- tumors and normal samples, while CCL3 expression was elevated in HPV+ HNSCC compared to normal samples (Supplementary Figure 3). Overall, these results indicate a higher level of DC involvement in HPV+ than in HPV- HNSCC, with higher levels of effector cytokines that could be responsible for the elevated levels of T-cell infiltration of these samples.…”

Section: Resultsmentioning

confidence: 99%

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

et al. 2018

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Cancers progress when the immune system fails to identify and eliminate malignant cells. Recognition of this, combined with advances in tumor immunology, has allowed development of therapies that induce effective anti-tumor immune responses. For incompletely-understood reasons, effective responses to immunotherapy occur in some patients and not others. Head and neck squamous cell carcinomas (HNSCC) are a common cancer type that can be divided into two subsets based on human papillomavirus (HPV) status. HPV status is a strong predictor of positive clinical outcome. Expression of exogenous viral antigens by HPV+, but not HPV-, HNSCC allows direct comparison of the immune status (immune cell presence and characteristics) between these two otherwise anatomically-similar tumors. Using TCGA data, we compared the immune landscape between HPV+ and HPV- treatment-naïve HNSCC. As compared to HPV- samples, HPV+ HNSCC exhibited a strong Th1 response characterized by increased infiltration with multiple types of immune cells and expression of their effector molecules. HPV+ HNSCC also expressed higher levels of CD39 and multiple T-cell exhaustion markers including LAG3, PD1, TIGIT, and TIM3 compared to HPV- HNSCC. Importantly, patients with higher expression of these exhaustion markers–indicative of a T-cell-inflamed tumor–correlated with markedly improved survival in HPV+, but not HPV-, HNSCC. Thus, profound differences exist between the immune landscape of HPV+ and HPV- HNSCC. These results suggest that immune checkpoint inhibitor therapy is a promising treatment strategy for HPV+ HNSCC, and that expression of immune checkpoint molecules could serve as a predictive biomarker of patient outcome in HPV+ HNSCC.

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Section: Resultsmentioning

confidence: 99%

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

et al. 2018

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“…In a clinical trial, GBM patients were randomized to receive standard therapy with pp65 DC vaccine alone or pp65 DC vaccine combined with a tetanus diphtheria toxoid (Td) booster vaccine. 57 The group that received the combination vaccination had significantly more DCs migrate to the draining lymph nodes due to an upregulation of CCL3. This increased migration correlated with significant improvement in overall survival (> 36.6 months versus 18.5 months).…”

Section: As Immunotherapeutic Targetmentioning

confidence: 97%

The role of CMV in glioblastoma and implications for immunotherapeutic strategies

et al. 2018

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Controversy surrounds the role of cytomegalovirus (CMV) in glioblastoma (GBM). However, several studies have shown that CMV nucleic acids and proteins are present within GBM tumor tissue. CMV has been implicated in GBM pathogenesis by affecting tumor stem cell factors, angiogenesis and immune pathways. Anti-viral therapy has not been found to definitively improve outcomes for patients with GBM. Several studies have leveraged CMV by targeting CMV antigens using ex-vivo expanded T cells or dendritic cell vaccines. The initial results from these studies are promising and larger studies are underway.

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“…Mitchell and group reported results of a randomized trial for adults with newly diagnosed glioblastoma who were treated with DC vaccine loaded with Cytomegalovirus phosphoprotein 65 (pp65) with or without pre-treatment with tetanus toxoid (Td). 50 They found that pretreated patients had increased migration of DC to vaccine draining lymph nodes as well as increased interferon-g production in post-vaccine ELISPOT assays. In addition, they showed significantly improved progression free survival, with 3 patients alive and disease free at 3 y post-vaccine.…”

Section: Adjuvant For DC Vaccinesmentioning

confidence: 99%

“…Other recently published work has focused on the use of novel adjuvants from natural sources, [46][47][48][49] known recall antigens, 50 tumor derived immunogenic proteins, 51 or proprietary costimulatory mixtures. 52,53 In one study of naturally occurring plant polysaccharides used in ancient Chinese medicine, intraperitoneal injections of extracts from Antrodia cinnamomea were shown to enhance DC activation in vivo, with increased T H 1 T cells as well as increased native CD11c C DC's in tumor draining lymph nodes.…”

Section: Adjuvant For DC Vaccinesmentioning

confidence: 99%

Dendritic cell vaccines: A review of recent developments and their potential pediatric application

Elster

Krishnadas

Lucas

2016

Human Vaccines & Immunotherapeutics

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For many cancers the use of conventional chemotherapy has been maximized, and further intensification of chemotherapy generally results in excess toxicity with little long-term benefit for cure. Many tumors become resistant to chemotherapy, making the investigation of novel approaches such as immunotherapy of interest. Because the tumor microenvironment is known to promote immune tolerance and down regulate the body's natural defense mechanisms, modulating the immune system with the use of dendritic cell (DC) therapy is an attractive approach. Thousands of patients with diverse tumor types have been treated with DC vaccines. While antigen specific immune responses have been reported, the duration and magnitude of these responses are typically weak, and objective clinical responses have been limited. DC vaccine generation and administration is a multi-step process with opportunities for improvement in source of DC for vaccine, selection of target antigen, and boosting effector cell response via administration of vaccine adjuvant or concomitant pharmacologic immunomodulation. In this review we will discuss recent developments in each of these areas and highlight elements that could be moved into pediatric clinical trials.

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Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients

Abstract: Reprints and permissions information is available at www.nature.com/reprints.

Cited by 466 publications

References 26 publications

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

The role of CMV in glioblastoma and implications for immunotherapeutic strategies

Dendritic cell vaccines: A review of recent developments and their potential pediatric application

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