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Immunotherapy in Treating Human Cancer
The immune system of our body is a complex network of tissues, cells, and organs that act mutually to protect our body from unknown foreign trespassers. It recognizes the harmful particles entering the body and facilitates the destruction of those particles in order to shield the body system from any ailment. Due to any complexity or disturbance often the immune system targets the wrong particle considering it as a dangerous particle and this anomaly of the immune system may result in various autoimmune diseases like arthritis, allergies, malignancies, and AIDS (Understanding the immune system how it works, 2003, pp. 1).
The immune system has the amazing capability of recognizing the millions of harmful cells, and in response, it produces multiple secretions or compatible cells that assist in destroying the each of the foreign element. An intricate and energetic communications network is involved in this process where a massive collection of the sets and subsets of the cells gather and communicate to transport the information (Understanding the immune system how it works, 2003, pp. 2-3).
There are various radiations, chemicals, viruses, and genetic factors that may lead to the activation or development of oncogenes leading to the production of different proteins triggering the excessive cell division and growth. Other important genes involved in cancer are the tumor suppressor genes that are normal genes, and their absence, inactivation or mutation due to any unknown reason may contribute to cancer. When normal cells become cancerous, the antigens present on their surfaces also change. The altered cells start producing a new peptide TSTA (Tumour Specific Transplantation Antigen) that mutates the class-1 MHC molecule. The production of oncofetal antigen on mutated cell surface leads to the inappropriate or overexpression of TATAs (Tumour Associated Transplantation Antigens). In chemically or viral induced tumor growth c-DNA of tumor cells replicate making more similar copies, and each tumor possesses similar antigens. In this case, the immune system of the body considers it as foreign antigens resulting in the defensive immune response with the help of NK cells, macrophages, B cells and T cells. In NK cells mediated response, Fc receptor binds to ADCC (Antibody‐dependent cell‐mediated cytotoxicity) while macrophages start eliciting ADCC and stimulate TNF-α (Understanding the immune system how it works, 2003, pp. 36).
Lymphocytes also play a key role in immune response through releasing IL-2 and IFN-γ. In response to active immune system cancer cells also react through releasing immunosuppressive cytokines and altering TGF-β, IL-10 and VEGF (vascular endothelial growth factor). Tumor antigens also escape immune response through either hiding from antibodies or shedding themselves from the cancer cell surface initially (Stromnes et al., 2015; Ahmadzadeh et al., 2015; Rosenberg and Restifo, 2015).
Nowadays the scientists are developing personalized biological modifiers containing lymphocytes and lymphokines against these particular antigens that are administered to the patient to strengthen the immune responses as well as to target the compatible cancer cells. These tailored antibodies can also be attached to other toxins, drugs and radioactive materials so that they can help in direct tracking or killing of the cancer cells (Understanding the immune system how it works, 2003, pp. 36).
According to Dieci et al. (2016), the immunoediting procedure acts in three primary steps as seen in the case of breast cancer (BC) namely, elimination, equilibrium, and escape. Elimination phase involves the detection and destruction of the evolving cell and in the case of failed elimination, an equilibrium stage is maintained in the remaining tumor cells. In escape phase the immune recognition is decreased due to immunosuppressive condition is developed by the tumor microenvironment (Dieci et al., 2016, pp.9-19). It is observed that numerous modulators and effectors are implicated in the homeostasis or equilibrium of tumor-mediated immune reactions. Several cells like CD4+, CD8+ Th1, and NK cells support a tumor-suppressive reaction while other cells like CD4+ Th2, FOXP3+ T-regulatory, and dendritic cells support a pro-tumorigenic retort (Dieci et al., 2016, pp.9-19). Similarly, Schmidt highlighted the use of the immune system components to fight BC as an immense comeback with the probability of BC vaccine (Schmidt, 2015, pp.105-107). Moreover, antibody-mediated drugs are claimed to provide some more free years to women who are at risk of BC (Eisenstein, 2015, pp.110-112).
Ahmadzadeh et al. (2015) recognized a human leukocyte antigen named C*08:02–restricted T cell receptor from CD8+ cells targeting a particular (KRASG12D) point mutation which is common in many human carcinomas. This revelation led to the use of such immunogenic mutations of GI cancer patients for fabricating the highly customized immunotherapies (Ahmadzadeh et al., 2015, pp.1387-1390).
Moreover, it is found that E6-specific TCR gene-engineered T cells have a capability of attacking the HPV-16+ which offer a valuable insight into the development of new cellular therapy. This approach will facilitate the development of immunotherapies against HPV-16+ malignancies that include oropharyngeal, cervical, vulvar, anal, penile and vaginal cancers (Draper et al., 2015, pp. 4431-4439). Adoptively transmitted TIL or tumor-infiltrating T lymphocytes are found capable of deteriorating the metastatic melanoma and can identify the mutated epitopes of tumors. This finding offers the potential basis of scheming the customized immunotherapies for advanced stage cancer patients (Cohen et al., 2015, pp.3981-3991).
A similar approach was described by Feldman and coworkers where they portrayed successful administration of Interleukin-2, a T-cell growth factor for treating the metastatic melanoma and renal cell cancer (Feldman et al., 2015, pp. 626-639). A study highlighted that the immunotherapy using analogously designed CD8+ T cells integrated with specific TCR possess the lysing capability for PDA and other cancer cells (Stromnes et al., 2015, pp.638-652). Adoptive cell therapy (ACT) is an advanced and tailored cancer therapy which is based on the introduction of cancer-bearing immune cell hosts that also possess anticancer activity (Rosenberg and Restifo, 2015, pp.62-68).
References
Ahmadzadeh, M., Lu, Tran, E., Y.C., Gros, A., Turcotte, S., Robbins, P.F., Gartner, J.J., Zheng, Z., Li, Y.F., Ray, S. and Wunderlich, J.R., 2015. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science, 350(6266), pp.1387-1390.
Cohen, C.J., Gartner, J.J., Horovitz-Fried, M., Shamalov, K., Trebska-McGowan, K., Bliskovsky, V.V., Parkhurst, M.R., Ankri, C., Prickett, T.D., Crystal, J.S. and Li, Y.F., 2015. Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. The Journal of clinical investigation, 125(10), pp.3981-3991.
Dieci, M.V., Griguolo, G., Miglietta, F. and Guarneri, V., 2016. The immune system and hormone-receptor positive breast cancer: Is it really a dead end?. Cancer treatment reviews, 46, pp.9-19.
Draper, L.M., Kwong, M.L.M., Gros, A., Stevanović, S., Tran, E., Kerkar, S., Raffeld, M., Rosenberg, S.A. and Hinrichs, C.S., 2015. Targeting of HPV-16+ epithelial cancer cells by TCR gene engineered T cells directed against E6. Clinical Cancer Research, 21(19), pp.4431-4439.
Eisenstein, M., 2015. Medicine: eyes on the target. Nature, 527(7578), pp.S110-S112.
Feldman, S.A., Assadipour, Y., Kriley, I., Goff, S.L. and Rosenberg, S.A., 2015, August. Adoptive cell therapy—tumor-infiltrating lymphocytes, T-cell receptors, and chimeric antigen receptors. In Seminars in oncology (Vol. 42, No. 4, pp. 626-639). Elsevier.
Rosenberg, S.A. and Restifo, N.P., 2015. Adoptive cell transfer as personalized immunotherapy for human cancer. Science, 348(6230), pp.62-68.
Schmidt, C., 2015. Immunology: Another shot at cancer. Nature, 527(7578), pp.S105-S107.
Stromnes, I.M., Schmitt, T.M., Hulbert, A., Brockenbrough, J.S., Nguyen, H.N., Cuevas, C., Dotson, A.M., Tan, X., Hotes, J.L., Greenberg, P.D. and Hingorani, S.R., 2015. T cells engineered against a native antigen can surmount immunologic and physical barriers to treat pancreatic ductal adenocarcinoma. Cancer cell, 28(5), pp.638-652.
Understanding the immune system how it works, 2003. US Department of Health and Human Services, NIH Publication.
