ALECSAT

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ALECSAT (Autologous Lymphoid Effector Cells Specific Against Tumor cells) 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. [1]

Contents

Method

Blood samples containing the required precursors for CD4+ helper T-cell, CD8+ cytotoxic T-cell, and natural killer (NK) cell are extracted from the patient and activated before being re-administered to the patient to induce anti-tumor activity. [2] These cells are activated in a process called “in vitro immunization”, which allows for selection and expansion of T-cells of varying specificity and has been validated in patients with advanced melanoma skin cancer. [3]

In order to have efficient eradication of cancer cells, the immune system cells should be able to both populate in the secondary lymphoid organs for a long-lasting effect and target a shared variety of tumor cells as opposed to one, specific cancer cell. In the ALECSAT method, several different cells are activated to accomplish this. Cytotoxic T lymphocytes (CTL) are activated to target the cells that present proteins characteristic of tumor cells [4] Some tumor cells, however, do not present an antigen due to lack of a major histocompatibility complex (MHC) and therefore cannot be recognized by the CTLs. The cells that do not present an antigen are targeted by activated NK cells, leaving little opportunity for any cancer cells to escape. CTLs and NK cells are both effector cells so helper T-cells (Th) are also prepared in order to create memory cells for long term resistance toward tumor cells. T helper 1 (TH1) cells, when injected with overexpressed tumor antigens, have been shown to enhance migration of antigen-presenting cells (APCs) into the draining lymph node in mice, further enhancing immune response through activation of CTLs. [5]

Tumor antigens are typically cancer/testis antigens. Chemically inducing this antigen in T-cells by DNA demethylation allows the immune system to recognize a wide range of tumors. This method of activation may be used for the preparation of anti-tumor vaccines or for ex vivo activation of the cytotoxic T-cells which can then be followed by the expansion of T-cells through normal, mature dendritic cells. The latter method is utilized for ALECSAT to treat cancer by adoptive T-cell immunotherapy. [6]

Process

Refer to the adjacent diagram for a depiction the ALECSAT protocol of immunization that occurs over a period of 26 days:

The first step is the isolation of the blood into lymphocytes and monocytes. The lymphocytes are frozen and the monocytes are differentiated into dendritic cells. After 6 days, the lymphocytes are mixed with dendritic cells and incubated for eight days. This process creates CD4+ enriched lymphocytes. After this, the lymphocytes are treated for three days in order to induce the expression of CGL antigen. Next, another set of frozen lymphocytes are mixed with the CD4+ expressing CGL antigens and incubated for 11 days. After that, dendritic cells are added to the lymphocytes to induce further lymphocyte proliferation. Lastly, after seven days of culture, the cells are prepared for injection. This whole process takes a total of 26 days. [7]

ALECSAT Protocol ALECSAT Protocol.png
ALECSAT Protocol

Research

Research on adoptive transfer in melanoma patients laid the groundwork for companies focusing on adoptive transfer research in other types of cancer. Research carried out at the Department of Tumour Cell Biology in Copenhagen has shown that CTL clones targeting specific melanoma tumor associated antigens (gp100 and MART-1) can successfully proliferate if melanoma cell lines are carefully preselected. [8] At the same department, the SCID mouse model was demonstrated as “an excellent model system” for studying interaction between tumors and CTLs. Using this model, eradication of a human melanoma tumor by in vitro generating CTL clone was accomplished. [9] In a study run at the University de la Sante, the adoptive transfer of cloned T cells in “in vitro immunization” caused increased frequencies of cancer fighting T cells in 18 out of 35 melanoma patients. [10]

Related Research Articles

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 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 is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

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 their T cell receptors (TCRs). APCs process antigens and present them to T-cells.

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<span class="mw-page-title-main">Tumor antigen</span> Antigenic substance produced in tumor cells

Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful tumor markers in identifying tumor cells with diagnostic tests and are potential candidates for use in cancer therapy. The field of cancer immunology studies such topics.

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

Cancer immunology is an interdisciplinary branch of biology 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.

<span class="mw-page-title-main">Tumor-infiltrating lymphocytes</span>

Tumor-infiltrating lymphocytes (TIL) are white blood cells that have left the bloodstream and migrated towards a tumor. They include T cells and B cells and are part of the larger category of ‘tumor-infiltrating immune cells’ which consist of both mononuclear and polymorphonuclear immune cells, in variable proportions. Their abundance varies with tumor type and stage and in some cases relates to disease prognosis.

Cancer immunoprevention is the prevention of cancer onset with immunological means such as vaccines, immunostimulators or antibodies. Cancer immunoprevention is conceptually different from cancer immunotherapy, which aims at stimulating immunity in patients only after tumor onset, however the same immunological means can be used both in immunoprevention and in immunotherapy.

Immunotransplant is a maneuver used to make vaccines more powerful. It refers to the process of infusing vaccine-primed T lymphocytes into lymphodepleted recipients for the purpose of enhancing the proliferation and function of those T cells and increasing immune protection induced by that vaccine.

Adoptive cell transfer (ACT) is the transfer of cells into a patient. The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune functionality and characteristics. In autologous cancer immunotherapy, T cells are extracted from the patient, genetically modified and cultured in vitro and returned to the same patient. Comparatively, allogeneic therapies involve cells isolated and expanded from a donor separate from the patient receiving the cells.

Autologous immune enhancement therapy (AIET) is a treatment method in which immune cells are taken out from the patient's body which are cultured and processed to activate them until their resistance to cancer is strengthened and then the cells are put back in the body. The cells, antibodies, and organs of the immune system work to protect and defend the body against not only tumor cells but also 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:

Cytokine-induced killer cells (CIK) cells are a group of immune effector cells featuring a mixed T- and natural killer (NK) cell-like phenotype. They are generated by ex vivo incubation of human peripheral blood mononuclear cells (PBMC) or cord blood mononuclear cells with interferon-gamma (IFN-γ), anti-CD3 antibody, recombinant human interleukin (IL)-1 and recombinant human interleukin (IL)-2.

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Cancer/testis (CT) antigens are a group of proteins united by their importance in development and in cancer immunotherapy. In general, expression of these proteins is restricted to male germ cells in the adult animal. However, in cancer these developmental antigens are often re-expressed and can serve as a locus of immune activation. Thus, they are often classified as tumor antigens. The expression of CT antigens in various malignancies is heterogeneous and often correlates with tumor progression. CT antigens have been described in melanoma, liver cancer, lung cancer, bladder cancer, and pediatric tumors such as neuroblastoma. Gametogenesis offers an important role for many of these antigens in the differentiation, migration, and cell division of primordial germ cells, spermatogonia spermatocytes and spermatids. Because of their tumor-restricted expression and strong in vivo immunogenicity, CT antigens are identified as ideal targets for tumor specific immunotherapeutic approaches and prompted the development of several clinical trials of CT antigens-based vaccine therapy. CT antigens have been found to have at least 70 families so far, including about 140 members, most of which are expressed during spermatogenesis. Their expression are mainly regulated by epigenetic events, specifically, DNA methylation.

<span class="mw-page-title-main">Tumor antigens recognized by T lymphocytes</span>

T lymphocytes are cells of the immune system that attack and destroy virus-infected cells, tumor cells and cells from transplanted organs. This occurs because each T cell is endowed with a highly specific receptor that can bind to an antigen present at the surface of another cell. The T cell receptor binds to a complex formed by a surface protein named "MHC" and a small peptide of about 9 amino-acids, which is located in a groove of the MHC molecule. This peptide can originate from a protein that remains within the cell. Whereas each T cell recognizes a single antigen, collectively the T cells are endowed with a large diversity of receptors targeted at a wide variety of antigens. T cells originate in the thymus. There a process named central tolerance eliminates the T cells that have a receptor recognizing an antigen present on normal cells of the organism. This enables the T cells to eliminate cells with "foreign" or "abnormal" antigens without harming the normal cells.

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<span class="mw-page-title-main">Cellular adoptive immunotherapy</span> Cellular adoptive immunotherapy

Cellular adoptive immunotherapy is a type of immunotherapy. Immune cells such as T-cells are usually isolated from patients for expansion or engineering purposes and reinfused back into patients to fight diseases using their own immune system. A major application of cellular adoptive therapy is cancer treatment, as the immune system plays a vital role in the development and growth of cancer. The primary types of cellular adoptive immunotherapies are T cell therapies. Other therapies include CAR-T therapy, CAR-NK therapy, macrophage-based immunotherapy and dendritic cell therapy.

References

  1. "About Us". CytoVac. Archived from the original on 8 June 2010. Retrieved 4 April 2013.
  2. "Welcome". CytoVac. Archived from the original on 25 February 2013. Retrieved 4 April 2013.
  3. "Technology". CytoVac. Archived from the original on 8 June 2010. Retrieved 4 April 2013.
  4. .Crommelin, D. J. A; Sindelar, R. D.; Meibohm, B. (2008). Pharmaceutical Biotechnology (3 ed.). New York, NY: informa healthcare. pp. 423–424.
  5. Chamoto, K.; Wakita D.; Narita Y.; Zhang Y.; Noguchi D.; Ohnishi H.; Iguchi T.; Sakai T.; Ikeda H.; Nishimura T. (February 2006). "An essential role of antigen-presenting cell/T-helper type 1 cell-cell interactions in draining lymph node during complete eradication of class II-negative tumor tissue by T-helper type 1 cell therapy". Cancer Res. 66 (3): 1809–1817. doi:10.1158/0008-5472.CAN-05-2246. PMID   16452242.
  6. DKpatent 20100092498,Alexei Kirkin, Karine Dzhandzhugazyan,"Anti-Tumour Vaccine Derived from Normal Chemically Modified Cells",published 2010-04-15, assigned to Cytovac A/S
  7. Kirken, Alexei (April 10, 2013). A new epigenetic approach to immunotherapy and its use for treatment of late stage glioblastoma and prostate cancer patients (Speech). ALECSAT Technology Seminar 2013. CytoVac, Hørsholm, DK.
  8. Kirken, A.F.; Thor Straten, P.; Hansen, M.R.; Barfod, A.; Dzhandzhugazyan, K.N.; Zeuthen, J. (1999). "Establishment of gp100 and MART-1/Melan-A-specific CTL clones using in vitro immunization against a preselected highly immunogenic melanoma cell clone". Cancer Immunol. 48 (5): 239–246. doi:10.1007/s002620050571. PMID   10478640. S2CID   12270616.
  9. Stenholm, A.C.O.; Kirkin, A.F.; Zeuthen, J (1998). "In vivo eradication of an established human melanoma by an in vitro generated autologous cytotoxic T cell clone: a SCID mouse model". Int. J. Cancer. 77 (3): 476–480. doi: 10.1002/(SICI)1097-0215(19980729)77:3<476::AID-IJC27>3.0.CO;2-4 . PMID   9663614.
  10. Vignard, V.; Lemercier, B.; Lim, A.; Pandolfino, M.C.; Guilloux, Y.; Khammari, A.; Rabu, C.; Echasserieau, K.; Lang, F.; Gougeon, M.L.; Dreno, B.; Jotereau, F.; Labarriere, N. (October 2005). "Adoptive transfer of tumor-reactive Melan-A-specific CTL clones in melanoma patients is followed by increased frequencies of additional Melan-A-specific T cells". The Journal of Immunology. 175 (7): 4797–4805. doi: 10.4049/jimmunol.175.7.4797 . PMID   16177129. S2CID   212507.