Cancer is a complex heterogeneous disease characterized by a combination of genetic and epigenetic changes that facilitate immortality. The diverse genetic and phenotypic characterization of cancer along with metastasis poses many therapeutic challenges. Recent advances in cancer immunotherapy have revolutionized the field of oncology in terms of patient care, survival, and quality of life.
For decades, the role of immunotherapy in cancer has remained underappreciated due to the lack of appropriate analytic techniques and due to the disabled host immune function against the tumor.
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How does the immune system detect cancer cells?
Cancer cells express surface proteins that may be specific or overexpressed. These molecules are tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs). TAAs are not tumor-specific and are usually overexpressed in tumor cells but can be expressed in normal cells too.
The caveat to using TAAs is the resulting autoimmunity against normal tissue expressing that antigen. On the other hand, TSAs arise as a result of somatic point mutations in the cancer cells. Therefore, TSAs are not expressed in normal cells and are highly immunogenic as they are not subject to immune tolerance.
Cancer cells have an innate ability to evade immune attack by- 1) secreting immunosuppressive substances, 2) expressing self-antigen in the context of Major Histocompatibility Class I (MHC I) on their surface which is recognized by the host immune system as “self” or a non-threatening signal, 3) down-regulating surface expression of TSA’s or TAAs when expressed with MHC1 and 4) evading immune cell invasion via the tumor microenvironment, comprising the cancer cells and surrounding stroma, forming a protective barrier.
Therefore, the primary role of immunotherapy in cancer is to overcome the immune escape mechanisms of cancer cells by specifically targeting tumor cells, exploiting the most efficient immune cells that can elicit a robust, long-lasting response, and finally to avoid cancer recurrence.
Types of cancer immunotherapies
Adoptive T cell transfer (ACT)
ACT involves reinfusion of genetically modified autologous patient lymphocytes to mediate antitumor, antiviral, or anti-inflammatory effects. In theory, ACT should circumvent the burden of overcoming tolerance to tumor antigens and produce an overload of high avidity effector T cells.
Three different forms of ACT are tumor-infiltrating lymphocytes (TILs), T cell receptor (TCR) T cells, and chimeric antigen receptors (CAR) T cells.
TILs therapy involves the adoptive transfer of mixtures of CD8+ and CD4+ T cells from resected metastatic tumor deposits. These cells are harvested and expanded ex vivo in a cocktail of cytokines. The goal of TIL therapy is to repair the function of the tumor-specific T cells caused by the immune-suppressive tumor microenvironment. TIL therapy has shown long-lasting clinical responses in patients with metastatic melanoma and other cancers.
TCR involves the expression of α and β chains of T cell receptors (TCR) that confer the engineered T cell with antigen-specificity of the transferred TCR. This therapy seems to be efficient in patients with tumor cells with the cognate human leukocyte antigen allele and expressing the target antigen recognized by the TCR. One disadvantage of the high avidity TCR therapy is significant secondary destruction of the host’s normal cells expressing the same target antigen.
The CAR T cells therapy involves the patient’s T cells being transfected with a construct encoding an antibody against the tumor surface antigen, fused to the T cell signaling domains. This procedure avoids immunization, and it involves the infusion of large quantities of modified T cells to overcome immune suppression. CAR T therapy is used for the treatment of refractory pre-B cell acute lymphoblastic leukemia and diffuse large B cell lymphoma and multiple myeloma.
Checkpoint inhibition
Checkpoint inhibition involves the blockade of immune-inhibitory pathways activated by cancer cells. CTLA-4 is an inhibitory receptor that down-regulates the initial stages of T cell activation. Therefore, anti-CTLA-4 in cancer therapy enhances pre-existing anticancer T cell responses and potentially triggers new ones. Melanoma patients with metastatic disease treated with anti-CTLA-4 antibody therapy showed a prolongation of overall survival.
PD1 is another inhibitory receptor expressed by antigen-stimulated T cells which inhibits T cell proliferation, cytokine release, and cytotoxicity. PD-L1 and PD-L2 and two ligands of PD1. The PD1-PD-L1 axis blockade has yielded promising results in a variety of cancer types including melanoma, lung, colon, head, and neck, and gastric cancers, and renal cell carcinoma.
Vaccines
Cancer vaccines help boost the host’s immune system to defend against cancer.
Prophylactic Cancer Vaccines prevent cancer in individuals who may be at high risk of developing cancer due to genetic predisposition or environmental factors. The vaccines target infections that may lead to the development of cancer. Examples: Human Papilloma Virus (HPV) which causes cervical cancer and Hepatitis B virus (HBV)infection which causes liver cancer.
Therapeutic vaccines treat existing tumors. Dendritic cells (DC) based vaccines are a popular form of therapy. DC vaccines are a) Ex vivo in which DCs may be loaded with antigen by culturing DCs obtained from patients with a tumor-specific antigen and an adjuvant to induce DC maturation. These cells are transfused back into the patient. b) In vivo where DCs may be induced to take up tumor antigen in vivo. The resulting antitumor responses are robust and long-lasting.
DC-based vaccines are being tested in cancers such as prostate, colorectal, kidney, breast cancer, melanoma, leukemia, lymphoma, and others.
Conclusion
The role of cancer immunotherapy has been very promising in the treatment of a few cancers. However, there are still numerous malignancies, in which immunotherapy alone has not achieved desirable response rates. Complementary therapies that reverse the immunosuppression in the tumor microenvironment and unleash the full potential of neoantigen-based vaccine will need to be explored.
Perhaps a mixed treatment option or Polytherapy with chemotherapeutic or another immunotherapeutic drug could be the solution. Studies have shown a possible synergistic effect between a cancer vaccine and checkpoint blockade. Furthermore, the dual blockade of both CTLA-4 and PD-1 pathways seem to have an additive response, allowing for more effective T cell activation, which is further augmented with a vaccine. Therefore, such combinatorial treatment approaches will be the aim for future cancer therapy.
Sources:
- Esfahani, K., Roudaia, L., Buhlaiga, N., Del Rincon, S.V., Papneja, N. and Miller, W.H. (2020). A review of cancer immunotherapy: from the past, to the present, to the future. Current Oncology, [online] 27(Suppl 2), pp.S87–S97.
- Farkona, S., Diamandis, E.P. and Blasutig, I.M. (2016). Cancer immunotherapy: the beginning of the end of cancer? BMC Medicine, 14(1).
- Kokate, R. (2017). A systematic overview of cancer immunotherapy: an emerging therapy. Pharmacy & Pharmacology International Journal, [online] Volume 5(Issue 2). Available at: https://medcraveonline.com/.
- Martin-Liberal, J., Ochoa de Olza, M., Hierro, C., Gros, A., Rodon, J. and Tabernero, J. (2017). The expanding role of immunotherapy. Cancer Treatment Reviews, 54(54), pp.74–86.
- Velcheti, V. and Schalper, K. (2016). Basic Overview of Current Immunotherapy Approaches in Cancer. American Society of Clinical Oncology Educational Book, 36(36), pp.298–308.
Further Reading