Dendritic Cell Vaccines

Developing More Effective Tumor Vaccines Using a Commercially Proven Delivery Platform for Efficient Loading of Dendritic Cells

 

Rapidly and efficiently load dendritic cells with proteins or cell lysates using a cGMP-compliant, commercially validated delivery platform that scales from bench to bedside. MaxCyte’s electroporation-based platform efficiently delivers proteins with minimal cell disturbance, high levels of cell viability and no appreciable change in dendritic cell phenotype or T cell activation functions. Easily control the degree of antigen loading for optimum presentation of processed antigen in functionally mature DC, resulting in enhanced T cell activation and anti-tumor efficacy.

  • Proven platform that supports a commercially marketed DC vaccine in Japan
  • 5 – 20 fold higher biological activity compared to lysate co-incubation
  • Efficient antigen delivery enables lower antigen doses
  • Cryopreserve antigen-loaded cells for flexibility in manufacturing operations (1 manufacturing lot often yields 6 doses)
  • Significantly reduces COGS for manufacturing of patient-specific lots
  • Clear regulatory pathway – cGMP compliant and FDA Master File

 

 

Direct Cytosolic Antigen loading of Dendritic Cells

C57BL6 mouse bone-marrow-derived DCs were either co-cultured or electroporated with 0.5 mg/mL FITC-dextran (250kDa). FACS analysis was performed 3 hours after electroporation. Figure adapted from Methods in Molecular Biology, Chapter 9, Vol. 423, 2008.

Electroloaded Human DCs Display Significantly Higher Potency

 

 

DCs were isolated from nine healthy human leukocyte antigen-A2+ donors and loaded with lysate from JCOB cells expressing the influenza matrix protein M1 either by co-incubation or by MaxCyte electroporation. DCs were co-incubated with primary blood lymphocytes following a 48 hour maturation period, and antigen-specific expansion of CD8+ T cells assessed via M1 peptide tetramer staining. Detected M1 tetramer positive CD8+ T cell frequency was 5–20 fold for MaxCyte-loaded versus co-incubation DC vaccine. Figure adapted from Int Immunopharmacol. 15(3):488-97, 2013.

Electroloaded DCs Reduce Metastases in a Therapeutic Model

 

 

DCs electroloaded with LLC lysate reduced lung metastases. LLC cells were administered intravenously (iv) into C57BL6 mice. Isolated C57BL6 DCs were coincubated or electroporated with ± LLC whole–tumor cell lysate and matured. As a control, DCs were then cryopreserved in 2 separate doses each. On day 3 and day 6 post LLC injection, DCs were administered iv (8 mice per group). On day 15 after LLC injection, mice were killed and lungs were dissected and weighed. The no tumor control group reflects normal lung weights of mice that were not challenged with any LLC (the dotted line indicates the mean baseline). Each dot on the graph represents 1 mouse from a group of at least 8 mice. Figure adapted from Journal of Immunotherapy, Volume 28(6), 2005.

Electroloaded DCs Elicit Tumor Cell Killing

 

 

Splenocytes were isolated from C57BL6 mice that had previously received 2 intravenous administrations of syngeneic DCs electroporated with LLC lysate (in vivo priming). These splenocytes were then cocultured in vitro with lysate-loaded DCs at a ratio of 1 DC/10 splenocytes. Splenocytes were restimulated once a week for a total of 3 restimulations with lysate-loaded DCs. As controls, splenocytes were cultured in the absence of any DCs (splenocytes only) or mixed with irrelevant lysate-loaded DCs (liver lysate control). DCs that had been coincubated with LLC lysate were compared with those that had been electroporated with LLC lysate. Primed splenocytes were washed and incubated with 51Cr-labeled intact LLC cells for a standard cell-mediated killing assay. Figure adapted from Journal of Immunotherapy, Volume 28(6), 2005.

Key Scientific Publications

 

  • Development of ‘Enhanced’ Potency Immunotherapy Products using Nonviral Approaches. Pharmaceutical Bioprocessing, Vol. 3(7): 463-470, 2015.
  • A Pilot Study of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination Combined With Sunitinib For Metastatic Renal Cell Carcinoma. Journal for ImmunoTherapy of Cancer, 2:30, 2014.
  • Immunotherapy of Autologous Tumor Lysate-loaded Dendritic Cell Vaccines by a Closed-flow Electroporation System for Solid Tumors. Anticancer Res., 33(7):2971-6, 2013.
  • Clinical Scale Electroloading of Mature Dendritic Cells with Melanoma Whole Tumor Cell Lysate is Superior to Conventional Lysate Co-incubation in Triggering Robust In Vitro Expansion of Functional Antigen-specific CTL. Int Immunopharmacol. 15(3):488-97, 2013.
  • Delivery of Whole Tumor Lysate into Dendritic Cells for Cancer Vaccination Electroporation Protocols: Preclinical and Clinical Gene Medicine. Methods in Molecular Biology, Chapter 9, Vol. 423, 2008.
  • Efficient Responses in a Murine Renal Tumor Model by Electroloading Dendritic Cells With Whole-Tumor Lysate. Journal of Immunotherapy, Volume 28(6), 2005.

 

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