Cancer and neoplastic lesions are affecting our lives every day. Nearly 40% of the world’s population is affected by cancer, irrespective of age, gender, and ethnicity. Cancer not only has a physical manifestation, but psychological influences are equally detrimental. However, medical advancement and clinical research have proven to combat this life-threatening disease.
Current Treatment Regimens
Cancer is the accumulation of abnormally proliferating cells that form an abnormally growing
mass called a tumor. The cancer cells in a tumor grow and divide rapidly and are no more
under regulation by the normal signaling mechanism. There are mainly two types of cancer.
It can either be benign, in which cancer cells remain within the confinement of the area of
origin e.g. skin wart, or it can be malignant, meaning that the unregulated cells invade the
surrounding structures and eventually spread throughout the body via the circulatory or
lymphatic system. Eventually, it leads to compression of the vital structures and compromise
in their functions.
Currently, anticancer medications have a wide range of side effects that include the
induction of other types of cancer itself. Some of the treatment options include:
Chemotherapy
Chemotherapy is the use of anticancer drugs to kill or halt the proliferation of cancer cells.
Generally, chemotherapy is administered orally or intravenously. In some patients, the
chemotherapeutic agent is given intrathecally i.e. injected into the CSF (cerebrospinal fluid)
that bathes the brain and spinal cord. This is done after performing a lumbar puncture and
injecting chemotherapeutic drugs, such as methotrexate. The course is usually repeated
every 3 weeks.
Radiotherapy
Compared to chemotherapy that attacks all the cells of the body, including the healthy ones,
radiotherapy is a localized treatment regimen. High ionizing-energy radiation is emitted to
destroy the cells that have an increased proliferation rate. Radiotherapy can either be given
to cure the disease (therapeutic) or to improve the sign and symptoms encountered during
disease course (palliative).
Stem cell or bone marrow transplantation
With this intervention, Bone marrow is taken from the patients’ family or whoever that bears
the same bone marrow and is transplanted into the diseased person. The survival rates vary
with different factors, but the cost and affordability remain the major concern in this
treatment modality.
Hope for Cancer Patients Comes Through Clinical Research
Continuous clinical researches have been undergoing in the field of medical oncology to
develop drugs that can target the malignant cells specifically without having any effect on
healthy or normal cells. The development of such drugs and their subsequent approval by
the FDA has given a leap forward with the advancement in immune therapy.
The immune therapy, also known as biological therapy, works by modulating or sensitizing
the body’s own immune cells to attack the cancer cells. In fact, deceiving the immune
system is one of the hallmarks of cancer proliferation. In recent years, immunotherapy is at
the center stage of research and clinical studies due to promising results.
Immune therapy can be broadly classified into:
1. Immune Checkpoint Inhibitors
Immune checkpoints are the part of the immune system that keeps the T-cells proliferation in
check. Normally, the activation of T-cells is a two-step process in which the recognition of
ligand-bound antigen-presenting cells by the lymphocytes and the subsequent inhibition of
cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptors results in proliferation of T-cells and
mounting of an immune response. Cancer cells can exploit these checkpoints by either
expressing the proteins on their cell surface (such as CD-24) which acts as “Do not eat me”
signal and thus deceiving APCs and immune cells. The production of CTLA-4 by the tumor
cells inhibits the T-cells activation and thus handicaps the immune system.
With the discovery of these checkpoints and their mechanism of action in tumor progression,
antibodies directed against CTLA-4 receptors are one of the first immune therapy drugs to
improve cancer outcomes. Ipilimumab belongs to this category of drugs and was approved
for the treatment of metastatic melanoma in 2001 by the FDA.
Other targeted therapies against Programmed-cell Death (PD-1) receptors. PD-1 receptors
are located on the surface of immune cells including T-cells, B-cells, NK cells, and Dendritic
cells. The activation of PD-1 receptors by PD-1 ligands () results in the inactivation of these
cells and contributes to T-cell anergy. The expression of PD-1L on the cell surface of tumors
leads to apoptosis and functional exhaustion of T-cells, leading to immune evasion and
the unchecked growth of malignant cells. Nivolumab, pembrolizumab, and cemiplimab target
PD-1 receptors whereas atezolizumab, avelumab, and durvalumab are the antibodies that
destroy PD-1L, as has been assessed through clinical research, and are currently approved
by the FDA for the treatment of various types of cancers, while other drugs of this
superfamily are undergoing clinical research for their clinical benefits.
1. T-Cell Transfer Therapy
This is another form of cancer immunotherapy that makes use of genetic engineering to
modify T-cell receptors. It is subdivided into:
CAR T-cell therapy
Cancer cells, like other cells in the body, have certain ligands expressed. The T-cells are
isolated from the patient by leukapheresis and are transfected by the virus genome to
incorporate Chimeric Antigen Receptors (CAR) on their surface that can recognize the
cancer-specific antigens. After the in vitro expansion of CAR T-cells, thy are infused back
into the patient for the targeted killing to cancer cells.
T-cell transfer therapy is currently being used for hematological malignancies and they’re
thought to bring a paradigm shift in the cancer treatment in the near future. FDA has
approved two drugs; Tisagenlecleucel and Axicabtagene ciloleucel for blood cancer
treatment and their role in solid tumors i.e. breast cancer is still a topic of research.
Tumor-Infiltrating Lymphocytes Therapy
Inside the tumor micro-environment, some T-cells have better receptor binding with tumor
cells than the others. One mechanism of the failed immune response to tumor cells is that
not enough receptor interaction has taken place between the immune cells and tumor
antigens. The immune cells better recognize and bind to antigens on repeated interactions
(priming) thereby improving the immune response.
TIL therapy uses these “sensitized” T-cells, cultured in vitro, to target the autologous tumor
cells. TIL has been used for the treatment of melanoma since the last century giving a high
response rate when combined with IL-2.
1. Monoclonal Antibodies
Monoclonal antibodies (mAbs) are the “synthetic” antibodies that target certain surface
proteins of malignant cells resulting in their targeted destruction. They bind to the cancer
cells with specific antigens on their surface and mount an immune response by the body’s
own B and T cells. For example, rituximab is a monoclonal antibody that binds to the cells
expressing CD20 antigens on their surface and stimulates their lymphocyte-mediated
destruction.
Some monoclonal antibodies have antigenic makeup close to the tumor cells, which results
in a cytotoxic response of T-cells that cross-react with cancer cells and decrease their
population. Blinatumomab is an example of such mAbs that binds to both the CD29
receptors on malignant cells and CD3 on T-cells, essentially crosslinking them and resulting
in cytotoxic destruction.
Conclusion
Although nearly 40% of the world’s population is affected by cancer, medical advancement
is being made every day to combat this life-threatening disease. Clinical research is a
necessary part of medical advancement.
Should you need help with conducting your clinical trial, HYGEIA Research will be happy to
help. Please read more about our services HERE.
References
Almåsbak, H., Aarvak, T., & Vemuri, M. C. (2016). CAR T Cell Therapy: A Game
Changer in Cancer Treatment. Journal of immunology research, 2016, 5474602.
doi:10.1155/2016/5474602
Bianchi M. E. (2014). Killing cancer cells, twice with one shot. Cell death and
differentiation, 21(1), 1–2. doi:10.1038/cdd.2013.147
Boyiadzis, M. M., Dhodapkar, M. V., Brentjens, R. J., Kochenderfer, J. N., Neelapu, S.
S., Maus, M. V., … Bishop, M. R. (2018). Chimeric antigen receptor (CAR) T
therapies for the treatment of hematologic malignancies: clinical perspective and
significance. Journal for immunotherapy of cancer, 6(1), 137. doi:10.1186/s40425-
018-0460-5
Flies, D. B., Sandler, B. J., Sznol, M., & Chen, L. (2011). Blockade of the B7-H1/PD-1
pathway for cancer immunotherapy. The Yale journal of biology and medicine, 84(4),
409–421.
Gonzalez, H., Hagerling, C., & Werb, Z. (2018). Roles of the immune system in cancer:
from tumor initiation to metastatic progression. Genes & development, 32(19-20),
1267–1284. doi:10.1101/gad.314617.118
Lipowska-Bhalla, G., Gilham, D. E., Hawkins, R. E., & Rothwell, D. G. (2012). Targeted
immunotherapy of cancer with CAR T cells: achievements and challenges. Cancer
Immunology, Immunotherapy, 61(7), 953-962.
Messerschmidt, J. L., Prendergast, G. C., & Messerschmidt, G. L. (2016). How
Cancers Escape Immune Destruction and Mechanisms of Action for the New
Significantly Active Immune Therapies: Helping Nonimmunologists Decipher Recent
Advances. The oncologist, 21(2), 233–243. doi:10.1634/theoncologist.2015-0282
Kradin, R., Lazarus, D., Dubinett, S., Gifford, J., Grove, B., Kurnick, J., … & Strauss, H.
W. (1989). Tumor-infiltrating lymphocytes and interleukin-2 in the treatment of
advanced cancer. The Lancet, 333(8638), 577-580.
Rosenberg, S. A., Spiess, P., & Lafreniere, R. (1986). A new approach to the adoptive
immunotherapy of cancer with tumor-infiltrating lymphocytes. Science, 233(4770),
1318-1321.
Saint-Jean, M., Knol, A. C., Volteau, C., Quéreux, G., Peuvrel, L., Brocard, A., …
Dréno, B. (2018). Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes in
Advanced Melanoma Patients. Journal of immunology research, 2018, 3530148.
doi:10.1155/2018/3530148
Scott, A. M., Allison, J. P., & Wolchok, J. D. (2012). Monoclonal antibodies in cancer
therapy. Cancer immunity, 12, 14.
Weiner, G. J. (2015). Building better monoclonal antibody-based therapeutics. Nature
Reviews Cancer, 15(6), 361-370.