Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma

Phuphanich, Surasak; Wheeler, Christopher J.; Rudnick, Jeremy; Mazer, Mia; Wang, HongQian; Nuño, Miriam A; Richardson, Jaime; Fan, Xuemo; Ji, Jianfei; Chu, Ray; Bender, James; Hawkins, Elma S.; Patil, Chirag G.; Black, Keith L.; Yu, John S.

doi:10.1007/s00262-012-1319-0

Cited by 334 publications

(265 citation statements)

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“…In an animal study conducted by Xu et al 104 in 2009, a dendritic cell vaccine was created against tumor-associated antigens specific to CSCs. The results showed that such 77 who used vaccines that targeted tumor antigens highly specific to CSCs. The vaccine developed was nontoxic, and for the 16 patients who received it, the median progression-free survival (PFS) time was 16.9 months and the median OS time was 38.4 months.…”

Section: Ongoing and Previous Clinical Trialsmentioning

confidence: 92%

The role of cancer stem cells in glioblastoma

Sundar

Hsieh

Manjila

et al. 2014

FOC

114

105

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G lioblastoma (GBM) is the most common primary malignant brain tumor. It is extremely aggressive, with a median overall survival (OS) of less than 15 months after diagnosis even with maximal therapy. 95 Survival rates are dismal, ranging from 26% to 33% for 2-year survival and less than 5% for 5-year survival. 49,53,96 The standard first-line treatment includes resection, if possible, followed by concurrent radio-and chemotherapy, typically temozolomide (TMZ), and then 6-12 months of adjuvant TMZ. 38,68 Despite treatment, recurrence is nearly universal. 96 Glioblastoma demonstrates a great deal of phenotypic, morphological, and cellular heterogeneity and is thought to contain a population of self-renewing cancer stem cells (CSCs) that contributes to tumorigenesis and treatment resistance. Both intratumoral heterogeneity and the presence of these CSCs may contribute to the treatment-resistant nature of GBM and its propensity to recur in patients. 15,70 History and DefinitionThe concept of CSCs originated in 1994 with the observation that a fraction of cells in human acute myeloid leukemia can self-renew and reconstitute both the leukemic cell hierarchy and the clinical disease state in vivo after xenotransplantation. 1,11,49,99 These self-renewing cells were later discovered to exist in various solid tumors as well, including those of the breast, colon, lung, brain, and liver. 1,20,71,81,92 The CSC hypothesis proposes that individual tumors comprise a cellular hierarchy. Cancer stem cells reside at the apex of the hierarchy and possess the ability to self-renew and to divide to give rise to the variety of cells that populate a tumor. As tumor cells differentiate, their ability to self-renew is reduced and they lose their "stemness." The hierarchy is dynamic with respect to cell type (CSCs, non-CSCs) and is maintained by the balance between self-renewal and differentiation. 43,107 Viewed in this light, tumors can be thought of as aberrant organs comprising heterogeneous cell types derived from CSCs rather than simply an accumulation of diverse neoplastic clones.Researchers who made the initial attempts to define CSCs described a qualitatively distinct population of pathological cells that was able to self-renew and ir- Recurrence in glioblastoma is nearly universal, and its prognosis remains dismal despite significant advances in treatment over the past decade. Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of cancer stem cells that contributes to tumor propagation, maintenance, and treatment resistance. Cancer stem cells are functionally defined by their ability to self-renew and to differentiate, and they constitute the diverse hierarchy of cells composing a tumor. When xenografted into an appropriate host, they are capable of tumorigenesis. Given the critical role of cancer stem cells in the pathogenesis of glioblastoma, research into their molecular and phenotypic characteristics is a therapeutic priority. In this review, the authors discuss...

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Section: Ongoing and Previous Clinical Trialsmentioning

confidence: 92%

The role of cancer stem cells in glioblastoma

Sundar

Hsieh

Manjila

et al. 2014

FOC

114

105

View full text Add to dashboard Cite

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“…These strategies were evaluated in early-phase clinical trials in newly-diagnosed GBM (111)(112)(113)(114). DC vaccine loaded with autologous tumor lysate was examined in a phase I clinical trial with 56 patients with relapsed GBM, resulting in a median PFS of 3 months and median OS of 9.6 months, with 2-year OS of 14.8% (115).…”

Section: Immunotherapy Of Gbmmentioning

confidence: 99%

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

et al. 2017

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Abstract. Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single antiangiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed.Glioblastoma multiforme (GBM) belongs to the largest group of primary central nervous system (CNS) tumors, so-called gliomas, which are formed from supporting glial cells in the brain parenchyma (1, 2). GBM represents the most common and most malignant tumor in this class, with an incidence of 3-4/100,000/year (3, 4). GBM is an extremely invasive and difficult to treat tumor, characterized by intense and aberrant vascularization and high resistance to radiotherapy (RT) and chemotherapy (CHT). The current standard of care for patients with newly-diagnosed GBM comprises of neurosurgery and subsequent concomitant chemoradiotherapy by fractionated external-beam RT and systemic temozolomide followed by systemic temozolomide in the adjuvant setting (5). There are only very limited possibilities for the treatment of subsequent recurrences, generally with minimal clinical efficacy (6). Despite intensive multimodal treatment strategies, the median survival of patients with GBM is still 12.1-14.6 months and only 3-5% of patients survive longer than 3 years (7).Enormous progress has been made in the genetics and epigenetics of GBM during the past decade. The Cancer 21Τhis article is freely accessible online.Correspondence to: Jiri Polivka, Department of Neurology, Faculty Hospital Plzen, alej Svobody 80, 304 60, Plzen, Czech Republic. E-mail: polivka@fnplzen.cz Key Words: Glioblastoma multiforme, GBM, targeted therapy, immunotherapy, immune checkpoint inhibitors, PD1 inhibition, CTLA4 inhibition, clinical trials, personalized medicine, review. ANTICANCER RESEARCH 37: 21-34 (2017) [8][9][10][11][12]. The most important genetic...

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“…More recently, dendritic cell immunotherapy using multiple epitopes has also been reported in the treatment of brain tumors. 45 Finally, we should consider how we apply immune checkpoint inhibitors in the field of lung cancer. Combination with chemotherapy, molecular-targeted therapy, and other vaccine therapies could be promising choices.…”

Section: Future Perspectivesmentioning

confidence: 99%