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

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

patients. Dendritic cells (DCs) are

antigen presenting cells An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...

for the induction of antigen specific

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

response. DC-based

immunotherapy 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 immunotherap ...

is safe and can promote antitumor

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

s and prolonged survival of cancer patients.

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 Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by ...

either through T cell deletion or through the differentiation of

regulatory T cell The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosu ...

s or suppressor T cells.

Mature dendritic cells

Mature DCs have ability to present

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...

s in the lymphoid tissues and prime, activate and expand effector immune cells with unique functions and

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

profiles.

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 CD11c, also known as Integrin, alpha X (complement component 3 receptor 4 subunit) (ITGAX), is a gene that encodes for CD11c . CD11c is an integrin alpha X chain protein. Integrins are heterodimeric integral membrane proteins composed of an alph ...

. cDCs can be subdivided into 3 groups: monocyte-derived DCs,

CD1 CD1 (cluster of differentiation 1) is a family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are related to the class I MHC molecules, and are involved in the presentation of lipid antigens to T ...

a- interstitial DCs, and CD1a+

Langerhans cell A Langerhans cell (LC) is a tissue-resident macrophage of the skin. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in the stratum spinosum. They also occur in the ...

Plasmacytoid dendritic cells (pDCs)

Plasmacytoid dendritic cell 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. T ...

s (pDCs) differentiate from

lymphoid progenitor cell __NOTOC__ A lymphoblast is a modified naive lymphocyte with altered cell morphology. It occurs when the lymphocyte is activated by an antigen (from antigen-presenting cells) and increased in volume by nucleus and cytoplasm growth as well as new mRN ...

s in the

lymphoid tissue The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...

s. They express CD123 and product high levels of

type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T cell, T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p2 ...

. pDCs also contribute to inflammatory responses in the steady state and in pathology. During

inflammatory response Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...

, inflammatory DCs (iDCs) are generated from

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

Function of cancer therapeutic vaccines

The main goal of the therapeutic vaccines is to elicit cellular immunity. They should prime naive T cells as well as induce transition from chronically activated non-protective CD8⁺ T cells to healthy CD8⁺ T cells able to produce cytotoxic T lymphocytes (CTLs), that recognise and eliminate cancer cells in an antigen-specific way and also provide long-lived memory CD8⁺ T cells that will act to prevent relapse. 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.

Methods for exploiting dendritic cells in cancer therapeutic vaccines

DC-based immunotherapy approach can be employed in a couple of ways:

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

Most of trials testing ''in vivo'' DCs’ stimulation with synthetic peptides failed because of inability of effective stimulation of CD4⁺ cellular responses and stimulation of Th2 type cytokines. 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).

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. 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.

Dendritic cell vaccine against brain tumor

The most well-known source of antigens used for vaccines in

Glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...

(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.

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.

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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) . It is an active cellular immunotherapy, which involves obtaining antigen-presenting autologous dendritic cells from the patient following a

leukapheresis Leukapheresis () is a laboratory procedure in which white blood cells are separated from a sample of blood. It is a specific type of apheresis, the more general term for separating out one particular constituent of blood and returning the remain ...

procedure. 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.

References

{{reflist Cancer vaccines