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Dendritic vaccines

Exploiting the most potent APC of the immune system

Dendritic cells (DCs) can stimulate antigen-specific T cell responses and are the most potent antigen-presenting cell (APC) of the human immune system, active in both the innate and adaptive immune responses1-4.

Human DCs are divided into three subsets5:

 

  1. Plasmacytoid DCs (pDCs) are characterized by the expression of CD123 and they express the transcription factors IRF4+/IRF8+. pDCs contribute to inflammatory responses in pathology and in the steady state. They produce high levels of interferon (IFN) type I upon infection, in turn activating natural killer (NK) cells and B cells. They are found in lymph nodes and peripheral blood.
  2. Myeloid or Conventional DC1 (cDC1) are characterized by the expression of CD141 and they are IRF4–/IRF8+. They produce IL2 to activate CD8+ T cells and to promote T helper type 1 (Th1) and natural killer cells. They are found in human blood and tissues.
  3. Myeloid or Conventional DC2 (cDC2) are characterized by the expression of CD1c and they are IRF4+/IRF8low. They are cross-presenting cells, producing IL12 to activate Th1, Th2, Th17 and Th22 and regulatory T cells. They are found in human blood, tissues and lymphoid organs.
Dendritic cells are involved in both innate and adaptive immune responses, which ultimately lead to tumor cell death.

DCs are an interesting cell type to focus on for cell-based immunotherapeutic approaches in the form of dendritic cell-based vaccines (or simply, dendritic vaccines) as they induce antigen-specific immune responses by stimulating a variety of cells from both the innate and adaptive immune systems, eliciting a series of responses causing tumor cells to die.

Using DCs for anti-cancer vaccine therapies

All strategies aim to modify the activity and mode of action of DCs in either the innate or adaptive immune responses to cancer cells. Dendritic vaccines consist of DCs loaded with tumor peptides, mRNA, DNA, viral vectors, or tumor cell lysates of various kinds6. The treatment strategy is one of several types of approaches to exercise the anti-tumor effect7:

  1. Tumor-associated antigens (TAAs)
  2. Defined antigens
  3. Neo-antigen-targeted approaches
  4. Whole tumor preparations

Several dendritic vaccines against different types of cancer are in development, and the Sipuleucel-T vaccine against a subset of castration-resistant prostate cancer (CRPC) was approved by the US Federal Drug Association (FDA) in 20118,9. In 2017, the Indian Central Drugs Standard Control Organization (CDSCO) approved the APCEDEN® for four cancer indications10.

Challenges in DC vaccine generation and manufacturing

The generation of efficient allogeneic dendritic vaccines is very difficult. Translation of experimental results into the clinic are hampered by the difficulties in reproducing results in vivo11. This is in part due to inadequate targeting of suppressive factors in the tumor microenvironment or insufficient recruitment of patients with adequate baseline immune function12; and due to a lack in understanding of how the vaccine strategies interact with other treatment regimens e.g. chemotherapy or radiotherapy.

On the technical side of these therapies, there are manufacturing challenges and a lack of standardization of procedures for dendritic vaccines. Critical issues for successful vaccination involve optimization of procedures for harvesting, isolating, maturing, and formulating the antigen loading and administration of dendritic vaccines13. There is also the question of scaling up production capacity from a few products useful in autologous therapies to formulating many thousands of treatment doses for allogeneic therapies.

DCs are isolated from a blood sample, cultured, formulated into a vaccine, tested, and administered to the patient.

A GMP/21 CFR part 11-ready cell counting solution for dendritic vaccines

Throughout dendritic vaccine therapy development and manufacturing, cell counting and viability assessments are crucial. The NucleoCounter® NC-202™ is a GMP/21 CFR Part 11-ready automated cell counter to use from the earliest R&D experiments, through Process Development, Manufacturing, Validation and Quality Control (QC). This means you will not waste time on laborious technical SOP and protocol transfers but can focus on cultivating the most effective cells for an optimal patient outcome.

The NC-202™ is the automated cell counter of choice because it provides robust results, whereby R&D, manufacturers and QC labs can collaborate throughout the formulation, production, and quality control stages with ease. The instrument is validated against a standard, meaning all instruments count the same, no matter where in the world they, or the operator, are located. Therefore, the NC-202™ does not require any calibration or other daily maintenance, meaning it is easy to access and ready for use when needed.

Furthermore, the NC-202™ uses the Via2-Cassette™, a closed system for sample handling, which ensures that no user or pipetting errors interfere with data generation. The Via2-Cassette™ is very safe since there is no manual handling of or exposure to dyes.

Documents

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References

  1. LH Stockwin, D McGonagle, IG Martin et al.: Dendritic cells: Immunological sentinels with a central role in health and disease. Immunol Cell Biol. 2000; 78(2): 91–102.
  2. I Mellman: Dendritic Cells: Master Regulators of the Immune Response. Cancer Immunol Res. 2013. 1(3): 145-149.
  3. M Dalod, R Chelbi, B Malissen, et al.: Dendritic cell maturation: functional specialization through signaling specificity and transcriptional programming. EMBO J. 2014; 33(10): 1104–1116.
  4. K McKenna, A-S Beignon, and N Bhardwaj: Plasmacytoid Dendritic Cells: Linking Innate and Adaptive Immunity. J Virol. 2005; 79(1): 17–27.
  5. M Collin, V Bigley: Human dendritic cell subsets: an update. Immunology. 2018; 154(1): 3-20.
  6. AM Dudek, S Martin, AD Garg et al.: Immature, Semi-Mature, and Fully Mature Dendritic Cells: Toward a DC-Cancer Cells Interface That Augments Anticancer Immunity. Front Immunol. 2013; 4: 438.
  7. B Mastelic-Gavillet, K Balint, C Boudousquie et al.: Personalized Dendritic Cell Vaccines—Recent Breakthroughs and Encouraging Clinical Results. Front. Immunol. 2019; 10: 766.
  8. E Anassi and UA Ndefo: Sipuleucel-T (Provenge) Injection: The First Immunotherapy Aget (Vaccine) for Hormone-Refractory Prostate Cancer. Pharmacy & Therapeutics. 2011; 36(4): 197-202.
  9. AE Hammerstrom, DH Cauley, BJ Atkinson et al.: Cancer Immunotherapy: Sipuleucel-T and Beyond. Pharmacotherapy. 2011; 31(8): 813–828.
  10. C Kumar, S Kohli, S Chiliveru et al.: A retrospective analysis comparing APCEDEN ® dendritic cell immunotherapy with best supportive care in refractory cancer. Immunotherapy. 2017; 9(11): 889-897.
  11. MJ Cannon, MS Block, LC Morehead et al.: The evolving clinical landscape for dendritic cell vaccines and cancer immunotherapy. Immunother. 2019; 11(2): 75-79.
  12. MC Pinder-Schenck, SJ Antonia: Chapter 19 – Genetically Modified Dendritic Cell Vaccines for Solid Tumors. Gene Therapy of Cancer (Third Edition). 2014, 273-282.
  13. M Lozano, J Cid, D Benitez-Ribas et al.: Technical Challenges in the Manufacture of Dendritic Cell Cancer Therapies. European Oncology and Haematology. 2019; 15(1): 22–8.