Survivin and PSMA Loaded Dendritic Cell Vaccine for the Treatment of Prostate Cancer

Abstract

Key words dendritic cell vaccine; prostate cancer; autologous cellular immunotherapy; prostate specific membrane antigen; Survivin Immunotherapy has recently emerged as a promising treatment modality for management of advanced hormone-refractory prostate cancer (HRPC), in light of new advances in discovery of cancer-specific antigens (tumor-associated antigen (TAA)), and adoptive cellular targeting. Dendritic cell (DC) based adoptive immunotherapy is one such treatment. Dendritic cells are the professional antigen presenting cells that efficiently activate T lymphocytes by presenting antigen to naïve major histocompatibility complex I restricted CD8+ cells and to major histocompatibility complex II restricted CD4+ cells. Dendritic cells generated from autologous monocytes (CD14+ cells) concentrated by aphaeresis, using a culture medium enriched with granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4, or IL-13 1-4) and pulsed ex vivo with TAA have been found to elicit a potent T-cell-mediated immune response and also protect against further tumour challenges. [5][6][7][8] Results from various clinical studies indicate that DC-based therapy can lead to significant therapeutic benefit in cancer patients without any significant toxic side effects. [9][10][11][12] In 2010, the U.S. Food and Drugs Administration (FDA) approved Sipuleucel-T, an autologous dendritic cell vaccine for the treatment of HRPC, this has paved way for a new category of autologous cellular immunotherapy for management of prostate cancer.Prostate specific membrane antigen (PSMA) is a type II membrane protein with folate hydrolase activity expressed primarily in prostate epithelium and a limited number of other cell types. This well-defined prostate expression is significantly elevated in prostate cancer, especially in advanced stages, [12][13][14] furthermore, PSMA immunoreactivity is absent to moderate in most hyperplastic and benign tissues. These features make PSMA an excellent target for prostate cancer immunotherapy. Several PSMA-based vaccines have been developed and clinical trials indicate that these immunotherapy approaches can be safely administered and can induce immune responses in patients with advanced carcinoma of prostate. 15,16) Survivin is a member of the family of inhibitors of apoptosis which is involved in cell cycle progression and control of apoptosis.17) It is over-expressed in a number of human cancers [18][19][20][21] and is often associated with poor prognosis. [22][23][24] Because of its frequent over-expression in many cancer types, survivin constitutes an interesting tumour-associated antigen (TAA) target for T cell based immunotherapy. 21,25,26) Because of its nodal properties, and over-expression in virtually every human tumour, survivin has been intensely pursued as a drug target for novel cancer therapeutics. [27][28][29] Various studies suggest that a combination of TAA might be more efficient in dendritic cell based cancer immunotherapy than using a single TAA.These observations prom...

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer

“…It is unclear why pancreatic cancer is poorly amenable to current immune-based therapies, but the ability to bolster an endogenous tumor-reactive T cell response may be critical to advance treatment outcome. Anti-tumor immune responses can be achieved by DC vaccines in a number of cancers, including melanoma [45–47], hepatocellular carcinoma [48], glioblastoma [49], castration-resistant prostate cancer [50, 51], renal cell carcinoma [52], acute myeloid leukemia (AML) [53], non-small cell lung cancer [54], pancreatic cancer [55, 56], and in various infectious diseases including hepatitis C virus [57] and HIV infection [58]. …”

Trial watch: Dendritic cell-based anticancer immunotherapy

“…1) involved autologous DCs exposed to autologous tumor-derived RNA, 196 tumor-cell lysates, [197][198][199][200][201][202][203] autologous tumor stem cell lysates, 204 self-renewing and proliferating autologous tumor cells, 205 allogeneic cancer cell line lysates, [206][207][208] TAAs or TAA-derived peptides [209][210][211][212][213][214][215][216][217][218] or a combination thereof. 219 Most clinical studies based on the latter approach preferred melanoma-associated differentiation antigens including premelanosome protein (PMEL; also known as gp100), antigens belonging to the melanoma antigen gene (MAGE) family, tyrosinase (TYR) and Melan-A (MLANA; also known as MART1) (Fig.…”

“…230 Regarding the distribution across different cancer types ( Fig. 1), patients harboring melanoma were most commonly enrolled in these trials, 186,196,198,205,213,221,223,227,[231][232][233][234] followed by patients with prostate cancer, 206,208,212,215 glioma or glioblastoma (GBM), 185,197,202,219 hepatocellular carcinoma, 204,211,220 non-small cell lung carcinoma (NSCLC), 207,214,230 renal cell carcinoma (RCC), 201,203 esophageal carcinoma, 216,226 and pancreatic ductal adenocarcinoma, 209,217 among others. Of note, only two trials included a wide range of advanced solid tumors refractory to previous treatments.…”

The therapeutic and diagnostic potential of the prostate specific membrane antigen/glutamate carboxypeptidase II (PSMA/GCPII) in cancer and neurological disease

“…Xi et al, 2015) The median overall survival of patients in the DC vaccine group improved by 11 months compared with were transduced with Ad-tPSMA, Ad-m4-1BBL and Ad-tPSMA-m4-1BBL (Youlin et al, 2013). Highest level of T-cell cytotoxicity in RM-1 cells (~60%) was seen in the group transduced with Ad-tPSMA-m4-1BBL.…”