Cancer development is characterized by an abnormal increase in the number of structural differences in cells spread throughout the body. Cancer therapy has progressed from non-specific methods such as surgery, radiotherapy, chemotherapy to specific immunotherapy practices in recent years.
Because non-specific methods damage healthy cells, it is not sufficient to eliminate the disease. For this reason, immunotherapy is one of the essential options in the treatment of cancer as it can directly target the tumor and its microenvironment. Thus, it is possible to have individualized therapy with less toxicity and fewer side effects.
Immunotherapy uses certain parts of a patient’s immune system to target various diseases, including cancer and mainly solid tumors. The primary purpose of cancer immunotherapy is to re-activate the immune system, which is silenced by the tumor cells in various ways, making the tumor cells become glands.
Immunotherapy has several advantages over non-specific cancer therapy methods. Activated and tumor-specific immune cells can reach areas where the surgeon cannot. When the immune system is adequately stimulated, it targets spreading metastases and cancer stem cells.
Because of the specificity, side effects of chemotherapy and radiotherapy can be avoided. The mainly used treatment methods in cancer immunotherapy are cancer vaccines, adoptive cell therapy, cytokines, and monoclonal antibodies.
Cancer vaccines try to influence the immune system cells by creating an attack against the cancer cells. Cancer vaccines are designed to induce tumor-specific or tumor-reactive immunoreactivity in vivo. The most popular category is peptide-based vaccines consisting of immunogenic epitopes, usually from tumor-specific or tumor-associated antigens.
Vaccines are usually administered with other helpers called adjuvants to increase the effectiveness of the immune system. Dendritic cells (DCs) are used as natural adjuvants because of their ability to initiate and support immune responses. Dendritic cell vaccination is performed by two different approaches, direct targeting of antigens to Dendritic cell receptors or ex vivo (out of living cell) production of antigen-loaded Dendritic cells.
In the case of DNA vaccines, plasmids (extra-chromosomal DNA molecule) containing cDNAs (DNA complementary to messenger RNA) encoding tumor antigens are administered to the patient so that the patient begins to express these antigens and provides immunity and T cell response against them. Therapeutic vaccines represent a viable option for active immunotherapy of cancers that aim to treat late-stage disease using a patient’s immune system.
The goal of therapeutic cancer vaccines is to induce anti-tumor T cells by immunizing patients against tumor-associated or tumor-specific antigens. Effective, safe, and enduring cancer treatments constitute significant medical science challenges, with therapeutic cancer vaccines emerging as attractive approaches for provoking long-lasting protective anti-tumor immunity.
Although studies on cancer immunotherapy are continuing, practical applications are still inadequate. One of the essential benefits of these studies is that they are the basis of studies on monoclonal antibodies used in the treatment of cancer.
Adoptive cell therapy
Adoptive cell therapy (ACT) is the process of administering immunologically active cells to the patient for treatment and prevention of the formation of the disease. ACT involves collecting immune cells from the patient’s peripheral blood or the tumor itself, the isolation of cells, the ex vivo replication of tumor-specific immune cells, and the re-infusion of activated T cells to the patient.
T cells used for this purpose are tumor-infiltrating lymphocytes (TILs), T cells engineered to express a cancer-specific T cell receptor (TCR) expression, and T cells for regulated chimeric antigen receptor (CAR) expression, which combines the extracellular portion of the antibody with the signaling mechanism of the TCR. In addition, DCs, which are antigen-presenting cells and highly effective in inducing T-cell immunity, are also used in this approach.
Cytokines are chemicals produced by some immune system cells. Cytokines play an essential role in the production and activity of the immune system cells and blood cells. Although there are many different types, the most commonly used are interleukins, interferons, and granulocyte-macrophage colony-stimulating factors.
As a result of a foreign substance’s entry into the body, B-lymphocytes become active, and antibody production recognizes this foreign substance (antigen). Antibodies recognize the epitope (the part that triggers the immune system) regions on the antigen. If an antibody is produced against a single epitope instead of an entire epitope, this antibody is called a monoclonal antibody (mAb).
Antibody-based immune therapeutics can be specific treatment tools based on the Fv region’s (the trunk of the Y shape antibody) affinity to the target at different concentration levels and the Fc region’s antibody’s ability to engage components of the host immune system.
The cancer immunotherapeutic efficacy of mAbs is based on three main mechanisms. These mechanisms include:
- Inhibition of the factors and receptors that activate the cancer cells’ signal pathways in division and angiogenesis by antibody binding.
- The antibody-dependent cellular cytotoxicity (ADCC) is composed of target monoclonal antibodies formed from either chimeric or fully human antibody components that bind to specific tumor-associated antigens.
- Complement-dependent cytotoxicity (CDC) by complement (helper) activation.
Although monoclonal antibodies have different mechanisms of action, all of these mAbs have become part of the standard treatment protocol combined with chemotherapy and/or radiotherapy.
In the antibody-dependent cellular cytotoxicity mechanism, mAb first binds to antigens on target cells’ surface, such as tumor cells. Then the Fc receptors of immune cells such as macrophages and natural killer (NK) cells recognize cell-bound mAbs. Cross-linking of receptors causes the release of cytotoxic agents. Finally, tumor cells die by apoptosis.
Whereas in the complement-dependent cytotoxicity mechanism, the monoclonal antibody binds to membrane-surface antigens on the target cell. Thus, multiple pathways trigger a complement cascade, where the complement binds to the mAbs.
The binding of complement leads to the induction of a membrane attack complex, and the activated complement system kills the target cell. Many mAbs used in cancer immunotherapy target and bind to an antigen on the cancer cell surface, blocking specific downstream signaling pathways and cell proliferation.
There are two classes of immunotherapeutic monoclonal antibodies, depending on whether they carry drugs or radioactive substances. The first class is self-acting, non-conjugated, naked mAbs are associated with antigens on cancer cells. The second class is mAbs joined together with chemotherapeutic drugs or radioactive particles that act as targets to take these mAbs to cancer cells. Also, there are bispecific antibodies that contain two different mAbs and can bind two different antigens at the same time.
Immunotherapy is a research field of medicine that is evolving rapidly. Although studies on cancer immunotherapy are continuing, practical applications are still inadequate. As cancer biology is better understood, the hypotheses in this area are increasing, and the researches are getting deeper.
The number of approved or developing monoclonal antibodies for cancer therapy has been increasing in recent years. Although mAbs are primarily used in cancer immunotherapy in clinical applications, more successful results are obtained with the combinations of the applications of immunotherapy.
Cancer immunotherapy’s critical success is identifying optimal tumor antigens, developing biomarkers, and the uptake of toxicity issues. As the cellular and molecular components of the tumor-immune system interaction are better understood, more effective immunotherapies will be developed.
Current clinical practice shows us that the maximum effective responses are possible through various anti-tumor mechanisms. Two deductions can be made from previous experiences. The first one is that the “ideal” anticancer drug may be the mechanism that brings together as many mechanisms as possible. Second, antibody technology can provide us with new versatile anti-tumor molecules.