Monday Article #24: Introduction to immunotherapy for cancer
Cancer is a disease where the cells in our body start to grow abnormally and uncontrollably, and eventually spread to other parts of our body. But why are cancers important to look at?
Perhaps many people already know the answer to this question. Cancer remains to be one of the most worrying diseases and is the leading cause of death worldwide, for it accounts for nearly 10 million deaths in 2020. Cancer is a genetic disease, that is it can be developed due to mutations in our genes that control our cell growth and proliferation. These genetic changes can result from biological, chemical and physical carcinogens. There are more than 100 different types of cancer under a few different categories, including carcinoma, sarcoma, leukaemia, lymphoma, and more. More information on cancer, how they are developed and the different types of cancer can be found in What is Cancer?
It is important to understand the characteristics of cancers as it is crucial to the design of cancer treatment. For instance, cancer cells grow without signals, ignore apoptotic signalling and utilise blood supply to gain access to oxygen and nutrients that are important for cell growth. Most importantly, cancer cells’ ability to trick, suppress or evade our immune system is what determines its continual growth and persistence. Hence, cell-based immunotherapies primarily aim to allow selective immune responses toward cancer cells, with the hope to cure cancer or prolong life considerably. This is done through collective efforts of immune effector cells such as macrophages, lymphocytes, cytotoxic T cells, NK cells, etc that target specifically the foreign antigens expressed on the surface of cancer cells. To note, while cancer immunotherapy has shown to be effective in some cancers, it is often used in combination with conventional cancer treatment, including chemotherapy and radiotherapy. Studies showed that this combination significantly increased survival rate, disease-free period, as well as the efficacy of treatment by 20-30%.
Types of Immunotherapy
Different approaches have been made in order to treat a wide variety of cancers. They can be divided in 5 main classes, namely immune checkpoint blockade (ICB) therapy, lymphocyte-promoting cytokine therapy, chimeric antigen receptor T cells (CAR T cells), cancer vaccine and agonistic antibodies.
Aside from the recognition of MHC antigen, T cell activation requires additional signals, such as co-stimulating signals. Interactions at T cell-antigen presenting cell (APC) interface i.e. checkpoint, therefore hold a pivotal role in dictating the activity of that particular T cell. Activation of T cells involves the turning off of negative signals and the provision of sufficient co-stimulatory signals. In ICB, Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programed cell death protein 1 (PD-1/PD-L1) are commonly blocked to relieve its inhibition to T cell activation. CTLA-4 is a competitive agonist, that is it blocks the binding of CD28 to CD80 and CD86, thereby dampening T cell activation and promoting tumour progression. On the other hand, PD-1 functions by restricting T cell activity at the tumour site. When T cells are activated, the expression of PD-1 is induced. This enables the recognition of abnormal cells by T cells. In return, cancer cells adaptively express PD-L1 that binds to PD-1, leading to the inhibition of T cell activity. Similarly, PD-1 is also expressed in T regulatory cells (Tregs), further suppressing immune responses. The blockage of CTLA-4 and the PD-1 pathway will then allow T cell activation and killing of cancer cells. While they showed excellent therapeutic results, it is often accompanied with systemic autoimmune side effects. This is because they also block the negative regulation of T cells that are potentially autoreactive.
Cytokines hold an important role in innate and adaptive immunity. It is found that interferons can activate natural killer (NK) cells and macrophages by binding to its receptor, as well as activate adaptive immunity via an improvement in antigen-presenting ability through upregulation of major histocompatibility complex (MHC). Interleukins allow the activation and proliferation of CD4+ T cells, CD8+ T cells and NK cells. Further, granulocyte-macrophage colony-stimulatory factor (GM-CSF) increases the processing and presentation of cancer antigens by dendritic cells, that in turn induce cytotoxic T cell activity. Though these cytokines contribute significantly to treating cancer, it has transitory half-life when injected. This means bolus injections in clinical treatment are required, leading to vascular leakage and cytokine release syndrome.
Adoptive T cell therapy involves the modification of varied immune cells, including dendritic cells, NK cells and T cells. T cells’ endogenous ability to identify and kill cancer cells through releasing perforin, granzyme and other cytokines makes it the perfect candidate for adoptive T cell therapy. T cells can be obtained and genetically engineered to express chimeric antigen receptors (CAR), which are artificially developed for the high specificity to cancer antigen. These engineered T cells will then be expanded and injected back into patients. This is done to overcome the downregulated expression of MHC class I in cancer cells, as well as to promote the infiltration of programmed T cells to cancer site. However, CAR-T therapy still faces the challenges of cytokine release syndrome and low and temporary efficacy to solid tumours.
Two types of cancer vaccines are developed: prophylactic and therapeutic vaccination. Among these, prophylactic vaccine is the most effective against cancer, however only applicable to patients who don’t have cancer. Therapeutic vaccine is developed for cancer patients in which it targets unique and distinguishable properties of cancer cells to allow a more sophisticated approach. For instance, prostatic acid phosphatase (PAP) is often overexpressed by prostate cancer cells.
Agonistic antibodies can bind to targeted T cell receptors (TCR), triggering intracellular signalling pathways that ultimately lead to the survival and growth of T cells. Commonly targeted TCRs are the co-stimulatory receptor (CD28) and tumour necrosis factor receptor (TNFR) family. Agonistic antibodies remain at their initial stage of development due to similar reasoning for cytokines in which their dose-dependent toxicities may lead to undesired autoimmune activities.
Implantable and injectable immunotherapy will be discussed in later articles, focusing on the synergic effect by biomaterials and immunotherapy that addresses the aforementioned limitations.
This article is prepared by : Lim Tze Yee