Characterization of Human Tumor-Infiltrating Lymphocytes Expanded in Hollow-Fiber Bioreactors for Immunotherapy of Cancer

Malone, Colin C.; Schiltz, Patric M.; Mackintosh, A D; Beutel, Linda D.; Heinemann, Frank; Dillman, Robert O.

doi:10.1089/108497801753354285

Cited by 40 publications

(33 citation statements)

References 24 publications

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“…Stirred cultures were shown to have equal or better performance compared to static flask cultures, and could be operated at higher cell densities (Collins et al, 1998b). Other bioreactor configurations employed for the cultivation of HPC include flat bed perfusion devices (Jaroscak et al, 2003;Koller et al, 1998;Palsson et al, 1993;Sandstrom et al, 1996Sandstrom et al, , 1995, hollow fiber perfusion devices (de Kreuk et al, 2004;Knazek et al, 1990;Malone et al, 2001;Sardonini and Wu, 1993), rotating wall vessels (Liu et al, 2006), and airlift reactors (Sardonini and Wu, 1993).…”

Section: Discussionmentioning

confidence: 99%

Clinical scale ex vivo manufacture of neutrophils from hematopoietic progenitor cells

Timmins

Palfreyman

Marturana

et al. 2009

Biotech & Bioengineering

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Dose-intensive chemotherapy results in an obligatory period of severe neutropenia during which patients are at high risk of infection. While patient support with donor neutrophils is possible, this option is restricted due to donor availability and logistic complications. To overcome these problems, we explored the possibility of large scale ex vivo manufacture of neutrophils from hematopoietic progenitor cells (HPC). CD34+ HPC isolated from umbilical cord blood (UCB) and mobilized peripheral blood (mPB) were expanded in serum-free medium supplemented with stem cell factor, granulocyte colony stimulating factor, and a thrombopoietin peptide mimetic. After 15 days of cultivation a 5,800-fold expansion in cell number was achieved for UCB, and up to 4,000-fold for mPB, comprising 40% and 60% mature neutrophils respectively. Ex vivo expanded neutrophils exhibited respiratory burst activity similar to that for donor neutrophils, and were capable of killing Candida albicans in vitro. These yields correspond to a more than 10-fold improvement over current methods, and are sufficient for the production of multiple neutrophil transfusion doses per HPC donation. To enable clinical scale manufacture, we adapted our protocol for use in a wave-type bioreactor at a volume of 10 L. This is the first demonstration of a large scale bioprocess suitable for routine manufacture of a mature blood cell product from HPC, and could enable prophylactic neutrophil support for chemotherapy patients.

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Section: Discussionmentioning

confidence: 99%

Clinical scale ex vivo manufacture of neutrophils from hematopoietic progenitor cells

Timmins

Palfreyman

Marturana

et al. 2009

Biotech & Bioengineering

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“…Multiple immunohistochemical studies have described the relationship between immune-cell infiltration and tumour progression or prognosis in several cancers (Naito et al, 1998;Lespagnard et al, 1999;Ishigami et al, 2000a, b;Nakano et al, 2001;Schumacher et al, 2001). These studies have formed the basis for the practical application of immunotherapy (Malone et al, 2001;Valone et al, 2001;Ying et al, 2001;Barnea et al, 2002;Dhodapkar et al, 2002). The clinicopathological significance of infiltrating antitumour immune cells within gallbladder adenocarcinomas, however, has not been clarified.…”

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confidence: 99%

Clinical significance of immune cell infiltration within gallbladder cancer

et al. 2003

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To investigate the pathophysiological significance of infiltrating antitumour immune cells, we evaluated the quantity of immune cell intratumoral infiltration in 110 surgically resected gallbladder specimens by immunohistochemistry. We examined 45 cases of gallbladder cancer and 65 cases of benign gallbladder diseases for CD4 þ T cells, CD8 þ T cells, natural killer cells (NKCs), and dendritic cells (DCs). High levels of CD4 þ T cell, CD8 þ T cell, NKC, and DC infiltration were recognised in 51.1% (23 out of 45), 37.8% (17 out of 45), 33.3% (15 out of 45), and 48.9% (22 out of 45) of cancer specimens, respectively. High numbers of infiltrating CD4 þ and CD8 þ T cells correlated with decreasing tumour invasion, and high numbers of infiltrating DCs correlated with decreasing lymph-node tumour metastasis. Furthermore, increased infiltration of CD4 þ and CD8 þ T cells and DCs exhibited a significant correlation with prolonged survival. NKC infiltration, however, did not correlate with any of the clinicopathological factors examined. Additionally, high levels of infiltration were not identified in specimens from benign diseases, consistent with the cancerspecific activity of CD4 þ and CD8 þ T cells and DCs. In this study, we demonstrate that CD4 þ and CD8 þ tumour-infiltrating lymphocyte and DCs, but not NKCs, are important factors in the accurate prognosis of survival after surgical removal of gallbladder adenocarcinoma.

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“…This 3D system evaluates controlling condition and adjusting experimental variables for optimalization of tumour cell cultures [11]. It has been already established that 3D culture in the HFBR simulates in vivo an environment and recapitulates particularly well the spatial organization of solid tumor [12]. It was shown that breast cancer cells cultured in two dimensional (2D) cultures do not recapitulate the differential structures observed in vivo.…”

Section: Discussionmentioning

confidence: 99%