Dendritic cell-based cancer vaccine

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The dendritic cell-based cancer vaccine is an innovation in therapeutic strategy for cancer patients.

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Dendritic cells (DCs) are antigen presenting cells for the induction of antigen specific T cell response. [1] DC-based immunotherapy is safe and can promote antitumor immune responses and prolonged survival of cancer patients. [2]

Human DC subsets

Immature dendritic cells

Non-activated (immature) DCs are usually located in the peripheral non-lymphoid tissues and they can present self-antigens to T cells, that leads to immune tolerance either through T cell deletion or through the differentiation of regulatory T cells. [3]

Mature dendritic cells

Mature DCs have ability to present antigens in the lymphoid tissues, and to prime, activate, and expand immune effector cells with unique functions and cytokine profiles. [4]

Myeloid dendritic cells (cDCs)

Myeloid or conventional DCs (cDCs) are derived from myeloid progenitor cells in the bone marrow and are characterized by expression of CD11c. [5] cDCs can be subdivided into 3 groups: monocyte-derived DCs, CD1a- interstitial DCs, and CD1a+ Langerhans cells. [6]

Plasmacytoid dendritic cells (pDCs)

Plasmacytoid dendritic cells (pDCs) differentiate from lymphoid progenitor cells in the lymphoid tissues. [7] They express CD123 and product high levels of type I interferon. [8] pDCs also contribute to inflammatory responses in the steady state and in pathology. During inflammatory response, inflammatory DCs (iDCs) are generated from monocytes. [9]

Function of cancer therapeutic vaccines

The main goal of the therapeutic vaccines is to elicit cellular immunity. [10] They should prime naïve T cell, and induce transition from chronically activated non-protective CD8+ T cells to healthy CD8+ T cells that can produce cytotoxic T lymphocytes (CTLs), which recognize and eliminate cancer cells by recognizing specific antigens. This process also creates long-lived memory CD8+ T cells that will act to prevent relapse. [11] The most critical step in vaccination is the effective presentation of cancer antigens to T cells, and because of DCs are the most efficient antigen presenting cells, they are the promising option for improvement of therapeutic vaccines. [12]

Methods for exploiting dendritic cells in cancer therapeutic vaccines

DC-based immunotherapy approach can be employed in two ways:

Direct targeting/stimulating of the DCs in vivo to accentuate their anticancer phenotype

Many trials evaluating in vivo DC stimulation with synthetic peptides failed because of inability of effective stimulation of CD4+ cellular responses and stimulation of Th2 type cytokines. [13] The solution showing clinical responses was pre-treatment with single-dose cyclophosphamide as well as vaccination with tumor associated antigens (TAAs) and granulocyte macrophage colony stimulating factor (GM-CSF). [14]

Stimulation of the DCs ex vivo and infusing them back into the host for carrying out anticancer effector function

In this way, DCs’ precursors are isolated from the patient through leukapheresis and after maturation/stimulation of these precursors ex vivo, fully mature DCs are injected back into the patient. [15] There are different ways applied to generate cancer cells-specific DCs. We can used specific TAAs, tumor lysates, created DC-cancer cell fusions, electroporation/transfection of DCs with total cancer cell-mRNA or tumor derived exosomes (TDEs) by the stimulation. There is also the possibility of additional co-stimulating with cytokine “cocktails” to assure strong maturation. [14]

Dendritic cell vaccine against brain tumor

The most well-known source of antigens used for vaccines in Glioblastoma (Aggressive type of brain tumor) investigations were whole tumor lysate, CMV antigen RNA and tumor associated peptides for instance EGFRvIII. The initial studies showed that patients developed immune responses as measured by Interferon-gamma expression in the peripheral blood, systemic cytokine responses, or CD8+ antigen specific T cell expansion. Clinical response rates were not as vigorous as the immune response rates. Overall survival (OS) and progression free survival (PFS) varied in different studies but were enhanced compared to historical controls. [16]

Dendritic cell vaccine against COVID-19

Autologous dendritic cells previously loaded ex-vivo with SARS-CoV-2 spike protein. Subjects eligible for treatment will be those who at baseline, are not actively infected with SARS-CoV-2, have no evidence of prior infection with SARS-CoV-2 based on serologic testing, and give informed consent for a vaccination with AV-COVID-19. The patient population will include the elderly and others at higher risk for poor outcomes after COVID-19 infection. For this reason, individuals will not be excluded solely on the basis of age, body mass index, history of hypertension, diabetes, cancer, or autoimmune disease.[ citation needed ]

Sipuleucel-T

Sipuleucel-T is the first DCs- based cancer vaccine for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC), approved by the US Food and Drug Administration (FDA) . [17] [18] It is an active cellular immunotherapy, which involves obtaining antigen-presenting autologous dendritic cells from the patient following a leukapheresis procedure. [19] The cells are incubated ex vivo in the presence of a recombinant fusion protein PA2024 containing a prostate antigen, prostate acid phosphatase and GM-CSF, an immune-cell activator. The cells are then returned to the patient to generate an immune response. [20] [21]

Related Research Articles

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

A cancer vaccine, or oncovaccine, is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as therapeutic cancer vaccines or tumor antigen vaccines. Some of the vaccines are "autologous", being prepared from samples taken from the patient, and are specific to that patient.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

Plasmacytoid dendritic cells (pDCs) are a rare type of immune cell that are known to secrete large quantities of type 1 interferon (IFNs) in response to a viral infection. They circulate in the blood and are found in peripheral lymphoid organs. They develop from bone marrow hematopoietic stem cells and constitute < 0.4% of peripheral blood mononuclear cells (PBMC). Other than conducting antiviral mechanisms, pDCs are considered to be key in linking the innate and adaptive immune systems. However, pDCs are also responsible for participating in and exacerbating certain autoimmune diseases like lupus. pDCs that undergo malignant transformation cause a rare hematologic disorder, blastic plasmacytoid dendritic cell neoplasm.

<span class="mw-page-title-main">FMS-like tyrosine kinase 3 ligand</span> Protein-coding gene in the species Homo sapiens

Fms-related tyrosine kinase 3 ligand (FLT3LG) is a protein which in humans is encoded by the FLT3LG gene.

<span class="mw-page-title-main">Cancer immunology</span> Study of the role of the immune system in cancer

Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

Vaccine therapy is a type of treatment that uses a substance or group of substances to stimulate the immune system to destroy a tumor or infectious microorganisms such as bacteria or viruses.

Active immunotherapy is a type of immunotherapy that aims to stimulate the host's immune system or a specific immune response to a disease or pathogen and is most commonly used in cancer treatments. Active immunotherapy is also used for treatment of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, prion disease, and multiple sclerosis. Active immunotherapies induce an immune response through direct immune system stimulation, while immunotherapies that administer antibodies directly to the system are classified as passive immunotherapies. Active immunotherapies can elicit generic and specific immune responses depending on the goal of the treatment. The categories of active immunotherapy divide into:

Neuvenge, Lapuleucel-T, is a therapeutic cancer vaccine (TCV) in development by Dendreon (DNDN). It uses the "immunotherapy platform approach" first successfully demonstrated on the U.S. Food and Drug Administration (FDA)-approved TCV Provenge. It was first tested on breast cancer patients with tumors expressing HER2/neu, and is now scheduled to be tested on bladder cancer patients.

Gustav Gaudernack is a scientist working in the development of cancer vaccines and cancer immunotherapy. He has developed various strategies in immunological treatment of cancer. He is involved in several ongoing cellular and immuno-gene therapeutic clinical trials and his research group has put major efforts into the development of various T cell-based immunotherapeutic strategies.

ALECSAT technology is a novel method of epigenetic cancer immunotherapy being used by the company CytoVac. It uses a patient's own immune system to target tumor cells in prostate cancer, glioblastomas, and potentially pancreatic cancer. ALECSAT research, directed by Alexei Kirken and Karine Dzhandzhugazyan, has led to several clinical trials.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage.

Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.

<span class="mw-page-title-main">Bacterial therapy</span>

Bacterial therapy is the therapeutic use of bacteria to treat diseases. Bacterial therapeutics are living medicines, and may be wild type bacteria or bacteria that have been genetically engineered to possess therapeutic properties that is injected into a patient. Other examples of living medicines include cellular therapeutics, activators of anti-tumor immunity, or synergizing with existing tools and approaches. and phage therapeutics, or as delivery vehicles for treatment, diagnosis, or imaging, complementing or synergizing with existing tools and approaches.

Whole-cell vaccines are a type of vaccine that has been prepared in the laboratory from entire cells. Such vaccines simultaneously contain multiple antigens to activate the immune system. They induce antigen-specific T-cell responses.

References

  1. ↑ Stockwin, Luke H.; McGonagle, Dennis; Martin, Iain G.; Blair, G. Eric (April 2000). "Dendritic cells: Immunological sentinels with a central role in health and disease". Immunology and Cell Biology. 78 (2): 91–102. doi:10.1046/j.1440-1711.2000.00888.x. ISSN   0818-9641. PMC   7159383 . PMID   10762408.
  2. ↑ Datta, Jashodeep; Terhune, Julia H.; Lowenfeld, Lea; Cintolo, Jessica A.; Xu, Shuwen; Roses, Robert E.; Czerniecki, Brian J. (2014-12-12). "Optimizing Dendritic Cell-Based Approaches for Cancer Immunotherapy". The Yale Journal of Biology and Medicine. 87 (4): 491–518. ISSN   0044-0086. PMC   4257036 . PMID   25506283.
  3. ↑ Mellman, Ira (2013-09-01). "Dendritic Cells: Master Regulators of the Immune Response". Cancer Immunology Research. 1 (3): 145–149. doi: 10.1158/2326-6066.CIR-13-0102 . ISSN   2326-6066. PMID   24777676.
  4. ↑ Dalod, Marc; Chelbi, Rabie; Malissen, Bernard; Lawrence, Toby (2014-05-16). "Dendritic cell maturation: functional specialization through signaling specificity and transcriptional programming". The EMBO Journal. 33 (10): 1104–1116. doi:10.1002/embj.201488027. ISSN   0261-4189. PMC   4193918 . PMID   24737868.
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  7. ↑ McKenna, Kelli; Beignon, Anne-Sophie; Bhardwaj, Nina (January 2005). "Plasmacytoid Dendritic Cells: Linking Innate and Adaptive Immunity". Journal of Virology. 79 (1): 17–27. doi:10.1128/JVI.79.1.17-27.2005. ISSN   0022-538X. PMC   538703 . PMID   15596797.
  8. ↑ Swiecki, Melissa; Colonna, Marco (August 2015). "The multifaceted biology of plasmacytoid dendritic cells". Nature Reviews Immunology. 15 (8): 471–485. doi:10.1038/nri3865. ISSN   1474-1733. PMC   4808588 . PMID   26160613.
  9. ↑ Chistiakov, Dimitry A.; Orekhov, Alexander N.; Sobenin, Igor A.; Bobryshev, Yuri V. (2014-07-25). "Plasmacytoid dendritic cells: development, functions, and role in atherosclerotic inflammation". Frontiers in Physiology. 5: 279. doi: 10.3389/fphys.2014.00279 . ISSN   1664-042X. PMC   4110479 . PMID   25120492.
  10. ↑ Guo, Chunqing; Manjili, Masoud H.; Subjeck, John R.; Sarkar, Devanand; Fisher, Paul B.; Wang, Xiang-Yang (2013). Therapeutic Cancer Vaccines: Past, Present and Future. Vol. 119. pp. 421–475. doi:10.1016/B978-0-12-407190-2.00007-1. ISBN   9780124071902. ISSN   0065-230X. PMC   3721379 . PMID   23870514.{{cite book}}: |journal= ignored (help)
  11. ↑ Palucka, Karolina; Banchereau, Jacques (2013-07-25). "Dendritic cell-based cancer therapeutic vaccines". Immunity. 39 (1): 38–48. doi:10.1016/j.immuni.2013.07.004. ISSN   1074-7613. PMC   3788678 . PMID   23890062.
  12. ↑ Anguille, Sébastien; Smits, Evelien L; Lion, Eva; van Tendeloo, Viggo F; Berneman, Zwi N (2014-06-01). "Clinical use of dendritic cells for cancer therapy". The Lancet Oncology. 15 (7): e257–e267. doi:10.1016/S1470-2045(13)70585-0. PMID   24872109.
  13. ↑ Rosenberg, Steven A.; Yang, James C.; Schwartzentruber, Douglas J.; Hwu, Patrick; Marincola, Francesco M.; Topalian, Suzanne L.; Restifo, Nicholas P.; Dudley, Mark E.; Schwarz, Susan L. (March 1998). "Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma". Nature Medicine. 4 (3): 321–327. doi:10.1038/nm0398-321. ISSN   1078-8956. PMC   2064864 . PMID   9500606.
  14. 1 2 Dudek, Aleksandra M.; Martin, Shaun; Garg, Abhishek D.; Agostinis, Patrizia (2013-12-11). "Immature, Semi-Mature, and Fully Mature Dendritic Cells: Toward a DC-Cancer Cells Interface That Augments Anticancer Immunity". Frontiers in Immunology. 4: 438. doi: 10.3389/fimmu.2013.00438 . ISSN   1664-3224. PMC   3858649 . PMID   24376443.
  15. ↑ Palucka, Karolina; Banchereau, Jacques (2012-03-22). "Cancer immunotherapy via dendritic cells". Nature Reviews. Cancer. 12 (4): 265–277. doi:10.1038/nrc3258. ISSN   1474-175X. PMC   3433802 . PMID   22437871.
  16. ↑ Dastmalchi, Farhad; Karachi, Aida; Mitchell, Duane; Rahman, Maryam (2018), "Dendritic Cell Therapy", eLS, American Cancer Society, pp. 1–27, doi:10.1002/9780470015902.a0024243, ISBN   9780470015902, S2CID   155185753
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  18. ↑ Anassi, Enock; Ndefo, Uche Anadu (April 2011). "Sipuleucel-T (Provenge) Injection". Pharmacy and Therapeutics. 36 (4): 197–202. ISSN   1052-1372. PMC   3086121 . PMID   21572775.
  19. ↑ Graff, Julie N; Chamberlain, Erin D (2014-12-18). "Sipuleucel-T in the treatment of prostate cancer: an evidence-based review of its place in therapy". Core Evidence. 10: 1–10. doi: 10.2147/CE.S54712 . ISSN   1555-1741. PMC   4279604 . PMID   25565923.
  20. ↑ Rini, Brian I.; Weinberg, Vivian; Fong, Lawrence; Conry, Shauna; Hershberg, Robert M.; Small, Eric J. (2006-07-01). "Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy". Cancer. 107 (1): 67–74. doi: 10.1002/cncr.21956 . ISSN   0008-543X. PMID   16736512. S2CID   25676266.
  21. ↑ Eager, Robert; Nemunaitis, John (2005-07-01). "GM-CSF Gene-Transduced Tumor Vaccines". Molecular Therapy. 12 (1): 18–27. doi: 10.1016/j.ymthe.2005.02.012 . PMID   15963916.
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