Cancer Immunotherapy

immunology project and need the explanation and answer to help me learn.

cancer and immune system relationship
Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department Faculty of science Zoology Department /> Page 1 of 49 Cancer immunotherapy “Harnessing the immune system to fight and treat cancer” Prepared by Amr Abd- El-Salam Shaher El-Deen 4th level special zoology 2022 Under supervision Dr. Mona Hegazi
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Page 3 of 49 Table of Contents Abstract …………………………………………………………………………………………………… 5 Introduction …………………………………………………………………………………………….. 5 background review ……………………………………………………………………………………… 6 The Definition of Cancer: ……………………………………………………………………………. 8 Cancer vs. Normal Cells: What Are the Differences? …………………………………… 9 What Causes Cancer? ………………………………………………………………………………..10 Cancer-Producing Genes ……………………………………………………………………………11 Understanding the Immune System: …………………………………………………………..13 Cancer Immunoediting: Immunosurveillance, Equilibrium, and Escape ….16 Fundamentals of Immunotherapy ……………………………………………………………19 Cancer Immunotherapy Types ………………………………………………………………..20 Monoclonal Antibodies (mAbs) ……………………………………………………………….20 Antibody Function and Structure ………………………………………………………………22 Effector Mechanisms of Targeted mAbs …………………………………………………….24 Mechanisms of Resistance ………………………………………………………………………….30 Immune Checkpoint Inhibitors ……………………………………………………………….35 Biological Function of PD1/PDL1 in Tumor Immunity ……………………………….36 Mechanism of Action and Treatment of PD1/PDL1 Inhibitors …………………38 Peptides/Polysaccharides and Small Molecules Target Treatment ………………38 Peptide-Based PD1/PDL1 Inhibitors ………………………………………………………….39 Aptamer Therapy ………………………………………………………………………………………39 Antibody Therapy ……………………………………………………………………………………..42 Mechanism of Drug Resistance in PD1/PDL1 Inhibitor Therapy ………………..43 Oncolytic Virus Therapy …………………………………………………………………………44 Conclusion ……………………………………………………………………………………………..46
Page 4 of 49 ACKNOWLEDGMENTS ……………………………………………………………………….47 References ………………………………………………………………………………………………48
Page 5 of 49 Abstract Cancer is currently the world’s greatest health threat. It is the most common causes of morbidity and mortality around the world. However, there are many types of cancer treatment, such as surgery combined with chemotherapy and/or radiation therapy, immunotherapy, targeted therapy, and hormone therapy. One of the most promising treatments and is Cancer immunotherapy (also known as immuno-oncology) is the process of stimulating the immune system in order to treat cancer and enhance the potential of the immune system to fight disease. It is a growing subspecialty of oncology and an application of cancer immunology’s fundamental study. Introduction Cancer, the dreaded disease, is currently the world’s greatest health threat. In developing countries, it is the most common cause of death. Did you know there are over a hundred different varieties of cancer and that they can affect any part of the body? Some cancers can also be avoided. On a global scale, cancer is a serious public health issue. Cancer incidence is predicted to rise in the coming decades, with more than 20 million new cancer cases expected annually by 2025, according to global demographic factors. In 2012, GLOBOCAN data estimated 14.1 million new cancer cases and 8.2 million cancer deaths (Zugazagoitia et al.). There are many types of cancer treatment. The types of treatment you receive will be determined by the type of cancer you have and how far it has progressed. Some cancer patients will just require one treatment. Most people, on the other hand,
Page 6 of 49 receive a mix of therapies, such as surgery combined with chemotherapy and/or radiation therapy. Immunotherapy, targeted therapy, and hormone therapy are all options (National Cancer Institute, 2021). The body’s immune system is responsible of identifying between self and non-self, therefore protecting the body from diseases of both exogenous and endogenous origin. The immune system, which is made up of white blood cells and lymph system organs and tissues such as the thymus, spleen, tonsils, lymph nodes, lymph vessels, and bone marrow, detects and eliminates a variety of threats in order to maintain homeostasis. An understanding of cancer cells and immune system interaction is required to know how immunotherapy has become a foundation of cancer therapy. Immunotherapies, unlike chemotherapy, which kills cancer cells through cytotoxic characteristics, use the host immune system to attack tumor cells. This article will review this interaction as well as provide a historical review of immunotherapy for cancer treatment (Abbott and Ustoyev, 2019). background review Physicians have known for over two centuries that the immune system can play a role in cancer prevention. A Parisian physician injected pus into the leg of a patient with advanced breast cancer in 1774, and observed that the cancer improved as the infection increased (Davis, 2000). Wilhelm Busch published the first report of an intentional erysipelas infection of a cancer patient in 1868, with remarkable tumor regression (Oiseth and Aziz, 2017). In 1891 William Cooley injected bacteria into a group of cancer patients, and several of them showed tumor regression (Oiseth and Aziz, 2017).
Page 7 of 49 Pierre van der Bruggen, C. Traversari, P. Chomez, et al. published the first report of a human tumor antigen recognized by T-cells in 1991(Oiseth and Aziz, 2017). Dana Leach, Matthew Krummel, and James Allison showed in 1996 that CTLA-4 blocking antibodies could treat cancers in animal models (Oiseth and Aziz, 2017). V. Shankaran, alongside L.J. Old, R. Schreiber, et al., reported in 2001 that Rag2 -/- immunodeficient mice with no B or T cells show higher vulnerability to spontaneous and carcinogen-induced tumors (Oiseth and Aziz, 2017). The FDA approved the first autologous cell-based cancer vaccine (sipuleucel-T) for the treatment of metastatic, asymptomatic stage IV prostate cancer in 2010 (Oiseth and Aziz, 2017). W. Qasim, H. Zhan, S. Samarasinghe et al. reported the first successful use of gene-edited T-cells for the treatment of CD19+ hematologic malignancies in humans in 2010 (Oiseth and Aziz, 2017). Anti-CTLA-4 (ipilimumab) was licensed by the FDA in 2011 as the first inhibitory checkpoint inhibitor (ICI) for the treatment of stage IV melanoma (Oiseth and Aziz, 2017). in the year 2016 Anti-PD-1 (pembrolizumab) is a second class of ICIs that has been approved for the treatment of melanoma. The inhibitory receptor programmed cell death protein 1 (PD-1) is expressed on some tumor cells and induces immune system downregulation by lowering T-cell function. Because anti-PD-1 monoclonal antibodies block the PD-1 receptor, T cells are no longer suppressed, and the immune response against the tumor is activated (Oiseth and Aziz, 2017).
Page 8 of 49 Fig (1): show Anti-PD-1 Antibodies in vivo The Definition of Cancer: Cancer is a disease in which cells in the body grow out of control and spread to other parts of the body. Cancer can begin in any of the billions of cells that make up the human body. Human cells normally grow and multiply (via a process known as cell division) to generate new cells as needed by the body. Cells die as they become old or injured, and new cells replace them. This normal process can sometimes break down, resulting in abnormal or damaged cells growing and multiplying when they shouldn’t. Tumors, which are masses of tissue, can grow from these cells. Tumors may or may not be malignant (benign) (National Cancer Institute, 2021). Cancerous tumors can infiltrate adjacent tissues and spread to other parts of the body, resulting in the formation of new tumors (a process called metastasis). Cancerous tumors may also be called malignant tumors. Many cancers form solid tumors, but cancers of the blood, such as leukemia, generally do not (National Cancer Institute, 2021).
Page 9 of 49 Benign tumors do not penetrate or spread into adjacent tissues. Benign tumors rarely reappear after being removed, although malignant tumors do. However, benign tumors can grow to be extremely enormous. Some, such as benign brain tumors, can produce serious symptoms or even be fatal (National Cancer Institute, 2021). Cancer vs. Normal Cells: What Are the Differences? For contrast, cancer cells develop even when no signals instruct them to do so. Signals like these cause normal cells to grow. Signals that tell cells to stop dividing or die are ignored (a process known as programmed cell death, or apoptosis). spread to other parts of the body by invading neighboring areas. When normal cells come into contact with other cells, they stop growing, and most normal cells do not travel around the body. tell blood vessels to expand in the direction of malignancies These blood veins provide oxygen and nourishment to tumors while also removing waste items. They conceal themselves from the immune system. Damaged or aberrant cells are generally eliminated by the immune system. deceive the immune system into assisting cancer cells in their continued survival and growth. Some cancer cells, for example, persuade immune cells to defend rather than fight the tumor. They have various chromosome alterations, such as chromosome duplications and deletions. The number of chromosomes in some cancer cells is double what it should be. rely on nutrients in a different way than normal cells. Furthermore, unlike most normal
Page 10 of 49 cells, some cancer cells generate energy from nutrients in a unique way. This allows cancer cells to multiply at a faster rate. Cancer cells often rely on abnormal activities so heavily that they can’t survive without them. This has led to the development of medicines that target the aberrant characteristics of cancer cells. Some cancer treatments, for example, stop blood vessels from growing toward tumor, thereby starving the tumors of nourishment (National Cancer Institute, 2021). What Causes Cancer? Cancer is a genetic disease, meaning it is caused by mutations in genes that control how our cells work, particularly how they divide and grow. Cancer-causing genetic alterations can arise as a result of mistakes that occur during cell division or DNA damage produced by dangerous substances in the environment, including as chemicals in cigarette smoke and UV rays from the sun. or they were passed down to us from our parents. The body normally eliminates cells with damaged DNA before they turn cancerous. But the body’s ability to do so goes down as we age. This is part of the reason why there is a higher risk of cancer later in life. Each person’s cancer is made up of a unique set of genetic alterations. Additional alterations will occur as the malignancy progresses. Different cells within the same tumor may have different genetic alterations (National Cancer Institute, 2021). Fig (3): Cancer is caused by certain changes to genes, the basic physical units Fig (2): showing the difference between normal cell and cancer cell morphologically.
Page 11 of 49 of inheritance. Genes are arranged in long strands of tightly packed DNA called chromosomes. Fig (4): what causes genetic changes. Cancer-Producing Genes Proto-oncogenes, tumor suppressor genes, and DNA repair genes are all affected by the genetic alterations that contribute to cancer. These changes are commonly referred to as cancer’s “drivers”. Proto-oncogenes play a role in normal cell division and proliferation. These genes can become cancer-causing genes (or oncogenes) if they are mutated in specific ways or are more active than usual, allowing cells to grow and survive when they shouldn’t. Tumor suppressor genes are also involved in cell division and growth control. Certain mutations in tumor suppressor genes can cause cells to divide uncontrollably. DNA repair genes are responsible for repairing damaged DNA. Cells with mutations in these genes are more likely to generate
Page 12 of 49 mutations in other genes and chromosome alterations, such as chromosome duplications and deletions. These alterations may lead the cells to become malignant if they occur together. Scientists have found that certain mutations are frequent in many types of cancer as they learn more about the molecular changes that lead to cancer. Now there are several cancer medicines available that target gene alterations detected in cancer (National Cancer Institute, 2021 Fig (5): A DNA change can cause genes involved in normal cell growth to become oncogenes. Unlike normal genes, oncogenes cannot be turned off, so they cause uncontrolled cell growth. Fig (6): Tumor suppressor genes prevent cancer in normal cells by slowing or preventing cell proliferation. Tumor suppressor genes can be inactivated by DNA alterations, which can lead to uncontrolled cell proliferation and cancer.
Page 13 of 49 Understanding the Immune System: Innate and acquired or adaptive immunity are two aspects of the immune system that work together to execute immune surveillance and identify self from non-self. Innate immunity is present from birth and stimulates a non-specific immune response in the presence of non-self-materials by releasing cytokines. The body’s first line of defense is made up of physical barriers like skin and mucous membranes, physiologic barriers like temperature and pH, and more complicated, but still non-specific elements like neutrophils, mast and dendritic cells, and macrophages Innate immune responses are fast and unaffected by antigens. Cytokines play a key role in innate immunity, mediating a variety of immunological processes. The non-specific innate immune system’s components work together to produce a generalized immune response to remove antigens. If this response is insufficient, the adaptive or acquired immune system produces a more targeted response. In contrast to innate immunity, adaptive or acquired immunity is particular and time-dependent, responding to a variety of stimuli and developing over time by exposure to non-self-materials. Antibody generation by B cells and the action of antigen-presenting cells on helper T cells, which stimulate cytotoxic T cells, are all part of adaptive immunity. To destroy non-self-matter, cytotoxic T cells target markers on non-self-cells. Immune memory formation is the final stage of the adaptive immune response. This process is divided into four parts, the first of which is specificity, which refers to the fact that diverse antigens elicit a specific response to a specific antigen. The process of activated immune cells migrating to specific target areas in the body is referred to as trafficking in the second stage. Adaptability follows, allowing for increased immune response through antigen spread. When a tumor-specific T cell is activated to initiate lysis of tumor cells, antigen-presenting cells pick up cell
Page 14 of 49 fragments and antigens, causing the immune system to become activated. The establishment of immunological memory is a key aspect of adaptive immunity vs innate immunity. This memory permits the immune system to detect an antigen it has previously seen, resulting in a more immediate and powerful immunological response when the antigen is reintroduced. These types of immunity work together to protect us from non-self-substances that enter our bodies, such as bacteria. How can the immune system recognize, fight, and eventually destroy malignant cells if cancer is made up of “self” cells and tissues? This is due to the fact that cancer cells differ from “normal” self-cells in terms of biochemical make-up, antigenic structure, and biologic behavior. So, how do cancer cells avoid the immune system and develop uncontrolled until they become a health hazard? (Abbott and Ustoyev, 2019).
Page 15 of 49 Innate Adaptive/Acquired Specificity • Nonspecific • Always present • All foreign pathogens trigger an immune response. • General defense • Specific • Requires activation • Direct response to triggering pathogen • Specific defense Response time Immediate reaction Delayed reaction Memory Absent (Same response with repeated exposure to same pathogens) Present • Antibody development • Provides retained immunity to repeated exposure to same pathogens Cell components Macrophages Dendritic cells Phagocytes Neutrophils Natural killer cells T lymphocytes B lymphocytes Table 1: Innate and adaptive/acquired immunity
Page 16 of 49 Cancer Immunoediting: Immunosurveillance, Equilibrium, and Escape Normal body cells’ development, maturation, and death are all controlled by genes. Each cell undergoes approximately 20,000 DNA-damaging events every day, which are regularly repaired by DNA repair pathways. Apoptosis, or programmed cell death, is used to inhibit the multiplication of cells that are no longer needed or pose a threat. Uncontrolled proliferation of altered or abnormal cells that spread throughout the body and infiltrate healthy tissue is a hallmark of cancer cells. Sustained proliferation, evasion of growth suppressors, cell death resistance, replicative immortality, angiogenesis, metastasis, altered metabolism, and finally evasion of immune destruction are the eight steps that lead to cancer formation and progression. For decades, scientists have investigated how to avoid immunological destruction. Paul Erlich hypothesized in 1909 that cancers may be managed by the immune system. The hypothesis of cancer immunosurveillance was first introduced by Thomas and Burnet in 1957, and it indicated that lymphocytes operate as guards, recognizing and killing cells that have undergone mutations and differ from normal host cells. In 1957, there was a dearth of evidence and technology to perform experiments to create supporting data, therefore research into the link between cancer cells and the immune system was delayed once more. Studies on the occurrence of cancer in patients with immune suppression due to disease, such as HIV and AIDS, or in post-allogeneic transplant patients on chronic immune suppression medication gave data to support the presence and importance of immunosurveillance. From the mid-1970s to the 1980s, there was a renewed interest in cancer immunosurveillance research. Natural killer (NK) cells were found at the
Page 17 of 49 time, and scientists were excited until they couldn’t come up with a precise definition and understanding of them. Because cancer cells differ biochemically from normal self-cells, it is now known that cancer cells can be detected and recognized by the immune system. Immunoediting is a dynamic period in which immune cells initially eliminate tumor cells before later allowing cancer cells to evade immune system elimination through various mechanisms. Because it involves all phases of cancer and immune system interaction beyond immunosurveillance, the term “immunoediting” has become common. There are three stages to the immunoediting hypothesis (Fig. 7). The first phase is elimination, which refers to the period during which intensive immunosurveillance is performed. Immunosurveillance allows the immune system to identify and kill cells that are not typically repaired by the natural genetic DNA repair pathways and become malignant or potentially malignant. Cancer cells are destroyed by innate immunity, which is triggered by tumor antigens, dendritic cells, and the formation of tumor-specific CD4+ and CD8+ T lymphocytes. Immunosurveillance is commonly regarded as the stage of tumor development that is undetectable and early. The second phase, equilibrium, follows elimination, during which tumor cells that were not eliminated by the immune system during elimination are not destroyed but are unable to progress. Tumor cells and the immune system continue to coexist. This phase is regarded to be the longest of the three, and it could extend for years. Escape or evasion is the third phase of immunoediting. Due to a lack of control and removal by the immune system, cancer
Page 18 of 49 cells can thrive and spread during the escape phase. During scape, the immune system becomes overloaded and can no longer control the spread and growth of cancerous cells. Malignant cells can avoid immune system elimination through a variety of ways, including immune system suppression by the tumor cell itself or genetic alterations that allow immune suppression. One such method is the capability of cancer cells to express immune checkpoint molecules similar to those found on normal cells on their surfaces, suppressing T cells at immune checkpoints and evading immune system attack. This ability to avoid immune response is once again seen as a characteristic of cancer pathogenesis. So, how can immunotherapy help with cancer treatment? (Abbott and Ustoyev, 2019). Fig (7): Immunoediting and Cancer Surveillance (Reprinted with permission from Schreiber, Old, and Smyth. Science 2011; 331:1565-1570.
Page 19 of 49 Fundamentals of Immunotherapy Immunotherapy is defined as the application of materials to enhance and/or restore the immune system’s ability to prevent and fight disease. Immunotherapy aims to balance the immune system in order to kill cancer cells while avoiding unregulated autoimmune inflammatory responses, which can lead to immunotherapies’ therapeutic limits. Innate immunity is restricted to the production of cytokines that recruit immune cells to initiate a non-specific immune response. Because of its ability to target non-self-antigens, the adaptive immune system plays a considerably larger role in the immunological response to cancer cells. Vaccinations, monoclonal antibodies, and checkpoint inhibitors have all been produced as a result of this understanding. Each immunotherapy aims to improve immune function and is classified according to numerous mechanisms of action. Active and passive immunotherapies are the two types of immunotherapies that are used. The direct stimulation of an immune response, immunological memory, and long-term response is known as active immunotherapy. Active immunotherapies include, for example, oncolytic vaccinations. Monoclonal antibodies and other passive immunotherapies induce specific but generally short-lived responses, requiring their administration on a regular basis. Finally, immunotherapy can cause a delay in clinical and radiologic response. This is due to the time required for an immune response to occur, followed by the time required for T cells to destroy the tumor. Immunotherapy benefits include maintained immune action following medication termination, which may lead to continuing anticancer effects and prolonged overall survival due to immunological memory qualities. Some research suggests that tumors that respond to immunotherapy initially may become resistant over time.
Page 20 of 49 Immunotherapy resistance is still being studied in clinical trials (Abbott and Ustoyev, 2019). Cancer Immunotherapy Types Cancer is treated with many methods of immunotherapy. Here are a few examples: Monoclonal Antibodies (mAbs) In their work on animal models of diphtheria, Behring and Shibasaburo defined antibodies as a neutralizing substance discovered in blood for the first time in 1890. Several significant scientific advancements would pave the road for the use of antibodies as a cancer therapy throughout the next century. Heidelberger and Avery defined antibodies as proteins that identify certain antigens, and Astrid Fagraeus established that antibodies are produced by plasma B cells of the adaptive immune system in 1947. Then Sir Gustav Nossal demonstrated that a single B cell clone generates only one particular antibody, proving the clonal selection theory. Monoclonal antibodies (mAbs) are antibodies produced by clones of a single B cell, each of which binds to a distinct epitope of an antigen. Schwaber discovered methods for producing monoclonal antibodies using human–mouse hybrid cells in 1973, and Köhler and Milstein exploited them to create human-derived hybridomas, which have since become a cornerstone in the large-scale manufacturing of therapeutic antibodies. The use of mAbs to treat cancer began shortly after the discovery of hybridomas. In nude mice, anti-melanoma mAbs were demonstrated to inhibit the growth of human melanomas, and the first human trial of mAb treatment for cancer was performed in a lymphoma patient in 1980. Unfortunately, early therapeutic monoclonal antibodies were immunogenic in humans and poor inducers
Page 21 of 49 of immunity in patients due to their murine origins, limiting their clinical applicability. To overcome these limitations, approaches to humanize antibodies emerged in the late 1980s. Using transgenic mice or in vitro yeast or phage display systems, researchers were able to create “fully human” antibodies. mAbs have become a significant strategy in the treatment of cancer as a result of these antibody engineering developments (Zahavi and Weiner, 2020). Fig (8): The antibody synthesis method is shown in this illustration of transgenic antibody technology: Targeted gene deletion was used to generate mice homozygous for the required deletions, which functionally inactivated mouse immunoglobulin
Page 22 of 49 gene loci in embryonic stem (ES) cells. The XenoMouse strain was created by crossing transgenic mice (carrying both human and mouse antibodies) with mice incapable of making mouse immunoglobin. B cells from immunized XenoMouse are combined with myeloma cells to create hybridomas that produce human mAbs. (Parray et al, 2020). Antibodies are unique in that they can destroy tumor cells directly while also activating the host immune system to create long-lasting antitumor effector responses. The ability of antibodies to produce powerful anti-tumor responses while reducing toxicity and side effects is due to the combination of a complex mode of action with target specificity, which distinguishes mAb therapy from therapies like chemotherapy. We review the structure, mechanisms of action, and mechanisms of resistance of monoclonal antibodies to better understand how they work as cancer therapies (Zahavi and Weiner, 2020). Antibody Function and Structure Antibodies are large glycoproteins that belong to the immunoglobulin (Ig) superfamily. They identify foreign antigens, neutralize them, and activate an immune response. Their primary structure is a Y-shaped arrangement of two heavy and two light chains. The fragment antigen-binding (Fab) region of the antibody is located at each tip of the Y and is responsible for antigen recognition. At the base of the Y structure, the fragment crystallizable (Fc) region mediates interactions between the antibody and other immune system members. Fc receptors (FcRs) on a variety of immune cells identify the Fc regions of antibodies. Antibodies are divided into five types based on the kind of heavy chain: IgA, IgD, IgE, IgG, and IgM. Because IgGs interact with their associated type of FcR, FcR, found on natural killer
Page 23 of 49 (NK) cells, neutrophils, monocytes, dendritic cells, and eosinophils to mediate specialized functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity, IgG is the most commonly used form in antibody therapy (CDC). The IgG class can further be subdivided based on the ability of the Fc region to facilitate those functions: IgG1 and IgG3 are able to elicit ADCC and CDC, while IgG2 and IgG4 cannot. Monoclonal antibodies represent a clonal version of a specified antibody isotype that is targeted to a unique antigen epitope (Zahavi and Weiner, 2020). Fig (9): illustrates the structure of antibody
Page 24 of 49 Effector Mechanisms of Targeted mAbs Antibodies directed against antigens that are either unique to tumor cells or overexpressed by them can kill tumor cells through a number of mechanisms (Figure 9). Blocking growth factor receptor signaling is the key direct method by which many antibodies cause tumor cell death. When mAbs attach to their target growth factor receptors and modify their activation state or inhibit ligand binding, pro-tumor growth and survival signaling is disrupted. Many tumors, for example, overexpress the epidermal growth factor receptor (EGFR), and EGFR activation leads to tumor cell proliferation, migration, and invasion. Cetuximab, an anti-EGFR monoclonal antibody, causes tumor cells to die by preventing ligand binding and receptor dimerization. Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor that is overexpressed in many cancers but primarily ovarian and breast carcinomas. It is distinct from EGFR in that it has no known ligand and instead hetero-dimerizes with other growth factor receptors to enhance their activation. Antibodies targeting HER2 therefore achieve signaling perturbation by inhibiting hetero-dimerization and internalization. Trastuzumab was the first FDA approved anti-HER2 mAb and remains a vital component of treatments for HER2-amplified breast cancer. Indirect mechanisms of action of mAbs require the engagement of components of the host immune system and are CDC, antibody-dependent cellular phagocytosis (ADCP), and ADCC. Most targeted mAbs are able to activate the complement system. For instance, rituximab depends in part on CDC for its in vivo efficacy. In a preclinical model, rituximab anti-tumor effects were completely abolished by knockout of the complement cascade component C1q. The importance of CDC in mAb therapy is further supported by the fact that genetic polymorphisms in the C1qA gene correlate with clinical response to rituximab in patients with
Page 25 of 49 follicular lymphoma. Likewise, optimization of CDC via antibody engineering can enhance anti-tumor activity. For example, the anti-CD20 mAb ofatumumab, which mediates amplified CDC, demonstrated greater efficacy than rituximab in a clinical trial of chronic lymphocytic leukemia (CLL) patients. ADCP occurs when FcγRI expressed on cells such as macrophages binds to IgG1 or IgG3 mAbs that have opsonized a tumor cell. There have been very limited studies of ADCP; however, there is some evidence that ADCP plays an important role in destruction of circulating tumor cells following mAb therapy. First described in 1965 by Erna Möeller, ADCC has since been established as an immune mechanism where target cells become opsonized by antibodies which then recruits effector cells to induce target cell death by non-phagocytic mechanisms. Antibodies act as bridges between by binding to antigens on the target cell surface via their Fab portions and linking the effector cells via their Fc portions. While IgG, IgA, and IgE can all mediate ADCC, IgG1 is the most relevant subclass for anti-cancer therapeutic antibodies. Effector cells must express FcR that will bind the antibody in order to facilitate ADCC. Each class of antibody has a corresponding class of FcR such as FcγR, which binds IgG, and FcαR, which binds IgA. FcγR is the most relevant class to ADCC of tumor cells and encompasses both the activating FcγRI (CD64), FcγRIIA (CD32A), FcγRIIIA (CD16A), and inhibitory FcγRIIB (CD32B) receptors. When an activating FcγR on an effector cell binds the Fc region of an antibody receptor crosslinking and downstream signal propagation occurs. NK cells are the main effector type that mediate ADCC; however other myeloid types such as monocytes, macrophages, neutrophils, eosinophils, and dendritic cells are also capable. Effector cells induce target cell death via cytotoxic granule release, Fas signaling, and initiation of reactive oxygen species. While several myeloid cell types have been demonstrated
Page 26 of 49 to mediate ADCC during immunotherapy, the clinical efficacy of most targeted mAbs is mainly NK cell dependent (Zahavi and Weiner, 2020). Fig (9): 1. Antibody effector mechanisms. ADCC: antibody-dependent cellular cytotoxicity; CDC: complement-dependent cytotoxicity; ADCP: antibody-dependent cellular phagocytosis While many mAbs facilitate several of the above mechanisms there has been debate about which mechanisms are important in vivo. Many of the first mAb therapies were known to mediate ADCC of tumor cells in vitro, but whether ADCC was significant to their therapeutic efficacy was originally poorly understood. Using
Page 27 of 49 mouse models. were the first to demonstrate that ADCC was an essential contributor to the in vivo activity of Trastuzumab and rituximab. Additional mechanistic studies utilizing similar mouse models confirmed that FcγR expression by immune effector cells is required for tumors to respond to mAb therapy. Furthermore, in a novel mouse model whose immune cells had mutant FcγR incapable of ADCC, mAb therapy failed to clear tumors. In most of these studies the mAbs used could also act through additional mechanisms of action such as signaling perturbation. Therefore, while these results indicated ADCC was required for successful mAb therapy they did not prove whether ADCC alone was sufficient. More recent work involving mAbs that rely exclusively on ADCC have verified that ADCC alone can mediate therapeutic benefit. In humans, clinical trials have demonstrated that many mAbs eliminate tumor cells, in part, by causing ADCC. Because functioning FcγRs were critical for mAb efficacy in mouse models, clinical trial data was used to examine whether FcγR polymorphisms would correlate with clinical outcomes. In humans, both FcγRIIA and FcγRIIIA are polymorphic, with certain genotypes coding for FcγRs with higher affinity for IgG1 and therefore stronger ADCC activity. Lymphoma patients who had the polymorphism associated with augmented ADCC were demonstrated to have better clinical responses to rituximab in several studies. Furthermore, both genotypes of FcγRIIA and FcγRIIIA associated with higher affinity for Fc were robust predictors for better survival in colorectal cancer patients treated with Cetuximab and metastatic breast cancer patients treated with Trastuzumab respectively. In recent studies, FcγR polymorphisms in breast cancer patients treated with trastuzumab or neuroblastoma patients treated with anti-GD2 mAbs were directly linked to ADCC amplitude by in vitro studies using patient derived immune cells. These multiple analyses confirm that patients with high
Page 28 of 49 affinity FcγR that mediate stronger ADCC have better clinical outcomes when administered mAb therapy, irrespective of cancer type or target antigen. In addition to examining FcγR polymorphisms, studies have used patient samples from clinical trials to investigate the relative importance of ADCC to therapeutic success. In one study, patients with HER2-positive breast cancer that were treated with trastuzumab had IHC staining for granzyme B performed on their tumor samples as a surrogate marker of ADCC activity. Patients who received trastuzumab were found to have better overall survival and higher levels of ADCC compared to the other cohorts. Furthermore, patient-derived in vitro models demonstrated ADCC as a major therapeutic mechanism of rituximab in non-Hodgkin lymphoma and anti-CD38 antibodies in multiple myeloma. Taken together, there is strong evidence that ADCC plays a critical role in facilitating mAb-based anti-tumor therapeutic responses in patients. In fact, additional variables that would affect ADCC activity such as target antigen expression level and density, mAb isotype, and mAb dose all correlate with clinical response. The ability of mAbs to mediate ADCC is recognized as a major determining factor for mAb therapy success, and research and development of novel mAbs has shifted towards designing mAbs with improved capacity to mediate ADCC. ADCC functionality of antibodies can be enhanced by altering the Fc portion of the mAb to increase their binding affinity to the activating FcγRIIIA via site-directed mutagenesis, changing Fc domain glycosylation, and/or removing Fc domain fucosylation. Next generation mAbs that are afucosylated have shown promise in clinical trials (Zahavi and Weiner, 2020).
Page 29 of 49 Fig (10): The mechanisms by which mAb-based drugs can induce their therapeutic effects. Unconjugated antibodies can induce their therapeutic effect by (A) blocking the binding of growth factors to growth factor receptor and subsequent cell signaling pathways essential for cell proliferation such as anti-EGFR mAb Cetuximab, (B)
Page 30 of 49 blocking and trapping an angiogenic factor such as anti-VEGF mAb Avastin, (C) preventing growth factor receptor– receptor dimerization and subsequent signal transduction pathways such as anti-HER mAb pertuzumab, (D) by blocking a key negative regulator of immune activity on T cells such as anti-CTLA-4 mAb ipilimumab, (E) binding to Fc receptors on effector cells (e.g. NK cells, macrophages, dendritic cells) and inducing ADCC such as anti-CD20 rituximab, (F) activating the complement system and inducing complement-mediated cytotoxicity CDC, (G) inducing apoptosis via upregulation of pro-apoptotic factors and downregulation of anti-apoptotic factors. (H) Blocking a key suppressor of the immune system expressed on tumor cells such as anti-programmed cell death 1 ligand 1 (PD-L1) antibody. In addition, mAbs can be conjugated to a therapeutic radio-isotope, drug or toxin for delivering a lethal dose of such agents to cancer cells (I). Mechanisms of Resistance Although mAb therapy has proven successful in the treatment of cancer, clinical resistance to these agents continues to be a major issue. Only a minority of patients will respond, with the vast majority developing refractory disease within one year. Therapeutic resistance can be considered either innate (primary) or acquired (secondary) with differing mechanisms in each scenario. Innate resistance is mainly due to mutations already present in the tumor cells prior to therapy whereas acquired resistance is the result of immune selection pressure and immunoediting of the tumor during therapy. Preclinical models and clinical trials of mAb therapy have unraveled a myriad of mechanisms of resistance; and they include: Mutations of the antibody target, induction of alternative growth signaling pathways, epithelial to
Page 31 of 49 mesenchymal transition (EMT), and impaired effector cell responses. A limitation of mAb therapy is that efficacy is dependent on tumor cell expression of the target molecules that are able to be bound by the antibodies. While CD20 gene mutations can confer irreversible resistance to rituximab in lymphoma patients, such mutations were rarely detected at both the initiation of treatment and in cases who relapsed following therapy. A S492R mutation in the EGFR ectodomain imparts resistance to Cetuximab but not panitumumab due to their recognition of distinct epitopes. Interestingly, cancer cells expressing EGFR variant III are less sensitive to Cetuximab even though the Cetuximab binding epitope remains intact. Cell lines chronically exposed to rituximab acquire resistance that is associated with the downregulation of CD20 at both the transcriptional and protein level. Likewise, multiple myeloma patients who received the anti-CD38 monoclonal antibody daratumumab lost CD38 expression in their tumors which correlated with impaired response. Cetuximab-mediated ADCC highly correlates with EGFR surface expression in cell lines but clinical response in patients appear to be independent of tumor EGFR expression level. Instead, it has been suggested that mutations and polymorphisms of EGFR are responsible for Cetuximab refractory disease. In HNSCC patients that expressed the EGFR-K521 variant (~40% of cases) there was reduced affinity of Cetuximab to EGFR and efficacy could only be restored with optimization of ADCC. Similarly, KRAS mutation status may affect susceptibility of EGFR overexpressing cancers to ADCC. Cell lines with mutant KRAS had impaired Fas–Fas ligand interactions that are necessary for induction of target cell apoptosis during ADCC. Downregulation of HER2 expression has been proposed as a mechanism of resistance to trastuzumab-mediated ADCC but it remains a controversial issue. Despite conflicting results from in vitro studies there was no
Page 32 of 49 reduction found in HER2 expression in breast cancer patients who received trastuzumab. However, it is known that interferon gamma (IFNγ) exposure can lead to HER2 downregulation through STAT1 mediated pathways. Furthermore, trastuzumab-mediated ADCC induces IFNγ release from NK cells which leads to a STAT1 dependent downregulation of HER2 expression and concomitant resistance to trastuzumab. It is also known that IFNγ-induced activation of STAT1 signaling leads to PD-L1 upregulation on the tumor cell surface that confers resistance to NK cell-mediated ADCC. Mutations of the antibody target and associated downstream signaling molecules can lead to acquired resistance to mAb therapy by activating alternative growth or survival signaling pathways. In colorectal cancers, the most frequent mechanism of cetuximab resistance has been reported as genomic alterations in downstream effectors of EGFR such as KRAS, NRAS, BRAF, and PIK3CA. Alterations in these pathways bypass EGFR signaling inhibition by cetuximab. For example, KRAS point mutations are causally linked with acquired resistance to cetuximab treatment in colorectal cancer. In metastatic colorectal cancer patients, activating mutations of the oncogenes RAS, BRAF, and/or PIK3CA were identified as significant predictors of primary resistance to cetuximab. The resulting enhanced signaling through the downstream MAPK and PI3K/AKT pathways and increased expression of anti-apoptotic BCL-2 proteins is a main mechanism of resistance to mAb induced apoptosis. Furthermore, NRAS mutations that maintain MAPK signaling prevent cetuximab efficacy by preserving the dysregulated ligand less signaling of the pro-tumorigenic EphA2 receptor. Activation of alternative proliferative and survival pathways such as MAPK and eIF5A2 has also been discovered in HNSCC and hepatocellular carcinoma respectively in response to cetuximab. HER2 mutations in
Page 33 of 49 breast cancer can confer resistance to trastuzumab; however, trastuzumab is still able to bind the mutant HER2. Mutant HER2 leads to dysregulation of the PI3K-AKT signaling pathway and enables trastuzumab resistance through similar anti-apoptotic effector molecules. Furthermore, activating mutations of the PI3K/AKT/mTOR pathway also contribute to trastuzumab resistance in breast cancer. Several studies have reported overexpression of compensatory growth factors such as insulin-like growth Factor-I receptor or EGFR as additional potential mechanisms of resistance to trastuzumab. Other signaling pathways implicated in trastuzumab resistance include aberrant activation of the tyrosine kinase SRC, cyclin E/cyclin-dependent kinase (CDK) 2, and cyclin D1/CDK4/6. In one study of esophageal squamous cell carcinoma, trastuzumab resistant tumor clones had a reduced susceptibility to the perforin-granzyme system. Similarly, X-linked inhibitor of apoptosis protein, which is overexpressed in breast cancer, drove resistance to ADCC mediated by both cetuximab and trastuzumab. In an in vitro study of rituximab-resistant lymphoma clones, major survival pathways such as NF-κB and ERK1/2 became constitutively hyper-activated after treatment, which led to overexpression of factors such as Bcl-2, Bcl-xL, and Mcl-1 that prevented the induction of apoptosis by rituximab. Epithelial to mesenchymal transition (EMT) is a process in which cancer cells lose their epithelial phenotype characterized by cell-to-cell adhesion and instead gain the invasive properties of mesenchymal cells. In preclinical models, EMT was uncovered as a possible mechanism of cetuximab resistance. The induction of EMT was later confirmed to occur early on in head and neck cancer patients receiving cetuximab. Multiple subsequent studies have revealed EMT mediates acquired resistance to cetuximab via a myriad of mechanisms which include loss of EGFR expression. Moreover, activation of the EMT pathway is a key predictor of
Page 34 of 49 cetuximab resistance in colorectal cancer. In breast cancer, molecular features associated with EMT are linked to primary resistance to trastuzumab. Additionally, sustained treatment of HER2 positive/PTEN negative breast cancers with trastuzumab induced EMT in a subset of patients which conferred acquired resistance. ADCC is considered a main therapeutic mechanism of mAb therapy, and clinical resistance often involves impaired cytotoxic immune effector cell responses. Capuano et al. described a novel mechanism of immune exhaustion, whereby NK cells chronically exposed to rituximab lost their cytotoxic functions due to CD16 ligation. NK cell checkpoints can also regulate ADCC. Poliovirus receptor-like receptors such as TIGIT are known to be involved in trastuzumab-mediated ADCC of cancer cells by NK cells, and blockade of those receptors was able to enhance trastuzumab based responses in breast cancer patients. Finally, NK cell-mediated ADCC is also dependent on the expression of several proteins that are important members of the immune synapse. ADCC is partly dependent on recognition through ICAM-1 and CD18, though this appears to be less important for trastuzumab-mediated ADCC. Cancer cell loss of ligands for the activating NKG2D receptor on NK cells such as MICA and dysregulation of the NKG2A-HLA-E axis can also prevent NK cell initiation of ADCC. A recently reported novel mechanism of resistance to ADCC involves the downregulation of multiple cell surface proteins associated with the immune synapse in response to cetuximab and trastuzumab (Zahavi and Weiner, 2020).
Page 35 of 49 Immune Checkpoint Inhibitors Programmed death protein 1 (PD1) is a common immunosuppressive member on the surface of T cells and plays an imperative part in downregulating the immune system and advancing self-tolerance. Its ligand programmed cell death ligand 1 (PDL1) is overexpressed on the surface of malignant tumor cells, where it binds to PD1, inhibits the proliferation of PD1-positive cells, and participates in the immune evasion of tumors leading to treatment failure. The PD1/PDL1-based pathway is of great value in immunotherapy of cancer and has become an important immune checkpoint in recent years, so understanding the mechanism of PD1/PDL1 action is of great significance for combined immunotherapy and patient prognosis. The inhibitors of PD1/PDL1 have shown clinical efficacy in many tumors, for example, blockade of PD1 or PDL1 with specific antibodies enhances T cell responses and mediates antitumor activity. However, some patients are prone to develop drug resistance, resulting in poor treatment outcomes, which is rooted in the insensitivity of patients to targeted inhibitors. Through the process of tumor immune editing, tumor cells acquire multiple methods of evading host immunity in the tumor microenvironment (TME). Studies on tumor immune escape have shown that PD1/PDL1-mediated immune checkpoint in TME is an important component of the tumor immune escape mechanism. Early preclinical evidence suggests that activation of PD1/PDL1 signaling pathway may be the mechanism by which tumors escape the antigen-specific T cell immune response. PD1 on immune cells interacts with PDL1 on tumor cells can protect tumor cells from killing by immune cells. PD1 was first described in the early 1990s as it is expressed in the course of inducing apoptosis in T cell hybridoma. As research
Page 36 of 49 progressed, PD1 was found to be taken part in the negative regulation of apoptotic T cell-mediated immunological reaction through binding to PD-L1. Studies have shown that immunotherapy is effective in treating melanoma and renal cell carcinoma, etc. Recent years, checkpoint inhibitors targeting the PD1/PDL1 or Cytotoxic T lymphocyte associated protein 4 (CTLA-4) pathways have shown great success, and driven the development of immunotherapy. The anti-CTLA-4 antibody ipilimumab has shown durable anti-tumor activity and prolonged survival in patients with advanced melanoma, but is prone to immune-related adverse events (IAEs). PD1/PDL1 inhibitors are promising immunotherapeutic agents that can achieve satisfactory efficacy for different tumor types, different treatment routes, different drug combinations and different treatment regimens. The incidence of PD1/PDL1 inhibitor-mediated IAEs was significantly lower compared to CTLA-4 blockade. Study shows that PD-1 pathway blockade is more efficient than CTLA-4 blockade in advanced melanoma (Liu et al,2021). Biological Function of PD1/PDL1 in Tumor Immunity PD1 is a checkpoint protein and a composition of the CD28 family. It pertains to a group of suppressor T-cell receptors that was not expressed by T cells alone, but was upregulated by antigen stimulation and cytokines caused by T cell excitation. PD1 is also expressed by B cells, monocytes, and dendritic cells (DCs), and regulates various aspects of its immune function. PDL1 is a type 1 transmembrane glycoprotein of the B7 ligand family. Which is not only expressed on activated T cells and B cells but also on some non-hematopoietic cells. It is in a favorable position to regulate T cell function in DCs and other antigen-presenting cells (APCs). T cells recognize tumor cells in the human body and kill them, but when
Page 37 of 49 tumor cells recognize PD1 protein on T cells, the tumor cells will upregulate the PDL1 protein and PD1 binds to PDL1 leading to apoptosis of the T cells. PDL1 on the surface of tumor cells can be upregulated by interferon gamma (IFN-γ) produced by activated T cells. PD1/PDL1 signal transduction pathway is a vital component of tumor immunosuppression, which can inhibit the excitation of T lymphocytes and strengthen the tumor cellular immune tolerance, so as to achieve tumor immune escape. In summary, PD1 binds to PDL1 can diminish T cell-mediated immune surveillance, resulting in an absence of immunoreaction and even to apoptosis of T cells. It also inhibits tumor-infiltrating CD4+/CD8+ T cells (CD4+/CD8+ TILs) and leads to a decrease in cytokines including tumor necrosis factor (TNF), IFN-γ and Interleucina-2 (IL-2), so as to provide a way for cancer cells to escape the immunoreaction. PD1/PDL1 inhibiters unblock the immune suppression of anti-tumor T cells, which results in T cell multiplication and permeation into the TME and inducing an anti-tumor response. Existing anti-PD1/PDL1 therapy interdicts the combination between PD1 and PDL1, and effectively activates depleted immune cells and triggers an anti-tumor immune response (Liu et al,2021).
Page 38 of 49 PD1/PDL1 inhibitors in TME Mechanism of Action and Treatment of PD1/PDL1 Inhibitors Peptides/Polysaccharides and Small Molecules Target Treatment Recently, a great number of research has been devoted to the exploitation of peptide-based inhibitors and nonpeptidic small-molecules targeting. Furthermore, through structural modification of peptidomimetic inhibitors, small molecules can be developed. Compared to monoclonal antibodies, small-molecule drugs offer significant advantages (Liu et al,2021).
Page 39 of 49 Peptide-Based PD1/PDL1 Inhibitors The first inhibitor AUNP-12, which was reportedly patented in, is a 29-amino acid branching peptide. In an animal study, tumor cell growth and metastasis were effectively inhibited by AUNP-12 with few adverse reactions. In addition to AUNP-12, other peptide-based PD1/PDL1 inhibitors also have been developed. For example, a small peptide mimicking a peptide containing 7–8 amino acids, showed the best bioactivity in mice infected with melanoma B16F10 cancer cells, reducing lung metastases by 64 percent. Another compound is a cyclopeptide derivative of 7–9 amino acids, characterized by the formation of a circular structure by an amide bond between the N and C ends of the amino acid residues. In Crystal Field Stabilization Energies (CFSE) detection. found that a cyclic peptide derivative can induce the proliferation of spleen cells in mice with high expression of PDL1 in human breast MDA-MB-231 cancer cells and reduce the lung metastasis of mice with melanoma B16F10 cancer cells by 54% (Liu et al,2021). Aptamer Therapy Aptamer-Drug Conjugates (APDCs) are a very promising platform. Studies have shown that APDC can deliver immunomodulators, restrict immunomodulatory co-stimulation to tumor regions, induce neoantigens in tumors, block depletion-induced immune checkpoints, activate functional immune cells and prolong anti-tumor immunity. designed and synthesized an amphiphilic telomeric dimer, aptamer polyvalent drug conjugate (ApMDC). And described the use of ApMDC nanoparticles to enhance the antitumor reaction of α-PD1 immunotherapy with
Page 40 of 49 targeted chemotherapy to tumors. They established 4t1 (breast cancer cell) and h22 (hepatoma carcinoma cell) tumor-bearing mouse models and draw a conclusion that the increased antitumor immunity accelerated the therapeutic reaction of α-PD1. In one study, researchers developed a DNA inducer for PD1/PDL1 signaling pathway to reverse immune evasion and stimulate antitumor immunity. DNA aptamer blocks the interaction of PD1/PDL1 by specifically binding to the extracellular domain of mouse PD1. MP7 is one of the aptamers, which can inhibit the inhibition of IL-2 secretion by primary T cells mediated by PD-L1. PEGylated MP7 directly blocks PD1 binding to PDL1. The PEGylated form of MP7 is equivalent to the antagonistic PD1 antibody, and can significantly inhibit the growth of PD-L1+ colon cancer cells in vivo for it retains the ability to block the PD1/PDL1 interaction. According to another study, aptPDL1 stop the combination between PD1 and PDL1 in humans. Experiments in mouse models have shown that aptPDL1 promotes lymphocyte proliferation in vitro and inhibits tumor growth in vivo without causing significant hepatorenal toxicity. Further analysis of tumors treated with aptPD-L1 revealed increased levels of invasive CD4+ and CD8+ T cells, IL-2, TNF-α, and IFN-γ(Figure 11). Chemokine receptor 3(CXCR3) expression was higher in CD8+ T cells treated with aptPD-L1 than in tumors treated with random sequence oligonucleotide. Researchers have developed a novel PDL1 aptamer, a short single strand of DNA that is smaller than the PDL1 antibody, which can effectively avoid the effects of glycosylation that block PD-L1 binding. The selected adapter is more possibly to be glycosylated by PDL1 as peptide antigens, which is hopeful to provide a higher effectiveness of recognition while compared with PDL1 antibodies from extracellular cells (Huang et al., 2020). Liu’s team found that in the presence of dual
Page 41 of 49 targets (PDL1 as a natural receptor and azide modified glycoprotein as a chemical receptor), the cyclooctyne-coupled PDL1 (D-APDL1) can be covalently coupled to the surface membrane of cancer cells through APDL1 aptamer recognition and DNA logic calculation reaction of cyclooctyne/azide biological orthogonal reaction. This in turn triggers precise and sustained T cell-mediated anti-tumor immunotherapy (Yang et al., 2021). Besides, they also found that this logical calculation could achieve long-term retention in the tumor by inducing covalent coupling of the PDL1 aptamer on the tumor cell surface, thus providing effective and precise checkpoint-blocking immunotherapy (Liu et al,2021). Fig (11): APTPD-L1 can inhibit the PD1/PDL1 interaction and weaken the inhibition of T cells
Page 42 of 49 Antibody Therapy Antibody-based inhibitors of PD1/PDL1 induce persistent tumor remission in various kinds of advanced cancer patients, making inhibition of the PD1/PDL1 signaling pathway clinically important in the treatment of tumors. So far, Food and Drug Administration (FDA) has approved six monoclonal antibodies targeting PD1 (nivolumab, pembrolizumab, and cemiplimab) or PDL1 (atezolizumab, Durvalumab and avelumab) for the treatment of hematological and solid malignancies. Monoclonal antibodies (mAb), known as checkpoint inhibitors, overcome the shortcomings of traditional anticancer therapies and inhibit the PD1/PDL1 mutual effect. Using in vivo and in vitro studies, have found that T cell function can be enhanced by blocking PD1 with antibodies. Within tolerable limits, monoclonal antibodies can significantly reduce toxicity, reduce solid tumor size, inhibit advanced tumors and metastases, and improve overall survival in patients. Nivolumab and pembrolizumab have been given permission for the therapy of terminal melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) by targeting PD1 and blocking its interaction with PDL1 and PDL2. Phase I clinical trials of pembrolizumab or atezolizumab in patients with mTNBC showed promising results, with objective response rates (ORR) of 18.5 and 33%, respectively. However, due to its long half-life and binding time with the target, it is easy to result in severe immune-related adverse reactions. Besides, mAb drugs are expensive, complex to produce, and difficult to store and transport. Therefore, how to use the PD1/PDL1 signaling pathway to develop simple and efficient non-monoclonal antibody treatment strategy is the focus of our current work (Liu et al,2021).
Page 43 of 49 | Mechanism of PD1/PDL1 blockade. The CD8+ T cell activates upon recognizing the tumor antigen presented on MHC class I and releases IFN-γ to bind to IFN-γ receptor, and consequently induces the expression of PDL1 on tumor cells. PDL1 conjugates the elevated PD1 on T cell surface, triggering inhibitory effect of PD1/PDL1 axis. Anti-PD1 or anti-PDL1 antibody blocks the interaction of PD1 and PDL1, and abolishes the inhibition of CD8+ T cell thus enhancing the antitumor activity. Mechanism of Drug Resistance in PD1/PDL1 Inhibitor Therapy Although immune checkpoint blocking therapy has achieved great success in clinic, the response rate of immunotherapy is still low Research has suggested that only 10–
Page 44 of 49 30% of the patients can produce long-term and sustained efficacy after receiving PD1/PDL1 inhibitors. The majority of patients have no obvious response to the treatment or will remain resistant to it. The development of PD1/PDL1 antibody resistance involves many tumor-related processes, including PD-L1 expression, tumor neoantigens expression and delivery, related cellular signaling pathways, tumor microenvironment, and epigenetic modifications. The lack of tumor antigens causes T cells to fail to recognize PD1/PDL1 antibodies, leading to drug resistance. In addition, molecules that process and deliver antigens, such as MHC class I molecules and β2 microglobulin, can also lead to resistance to immune checkpoint inhibitors (ICIs) when their genetic code is altered. Aberrant cell signaling is also a factor contributing to immunotherapy resistance, such as the PI3K/Akt pathway, Wnt/β-linked protein pathway, JAK/STAT/IFN-γ pathway, and mitogen-activated protein kinase (MAPK) pathway (Liu et al,2021). Oncolytic Virus Therapy For more than a century, doctors have been interested in using viruses to treat cancer, and in recent years a small but growing number of patients have begun to benefit from this approach. Some viruses tend to infect and kill tumor cells. Known as oncolytic viruses, this group includes viruses found in nature as well as viruses modified in the laboratory to reproduce efficiently in cancer cells without harming healthy cells. To date, only one oncolytic virus—a genetically modified form of a herpesvirus for treating melanoma—has been approved by the Food and Drug Administration (FDA), though a number of viruses are being evaluated as potential treatments for cancer in clinical trials. Oncolytic viruses have long been viewed as
Page 45 of 49 tools for directly killing cancer cells. But a growing body of research suggests that some oncolytic viruses may work—at least in part—by triggering an immune response in the body against the cancer. When a virus infects a tumor cell, the virus makes copies of itself until the cell bursts. The dying cancer cell releases materials, such as tumor antigens, that allow the cancer to be recognized, or “seen,” by the immune system. “Oncolytic viruses are alerting the immune system that something’s wrong,” said Jason Chesney, M.D., Ph.D., director of the University of Louisville’s James Graham Brown Cancer Center. This can lead to an immune response against nearby tumor cells (a local response) or tumor cells in other parts of the body (a systemic response). For this reason, some researchers consider oncolytic viruses to be a form of immunotherapy—a treatment that harnesses the immune system against cancer. But many in the field would agree that more studies are needed to learn how different oncolytic viruses work against cancer (National Cancer Institute, 2021). Figure 12. There are two distinct ways on how these viruses target a particular cancer cell or tumor. The virus will infect the cancer cell and replicate itself. This results in destruction of the cancer cell (cell lysis) – releasing the tumor antigens and activating antibodies. T-cells will be activated and generates anti-tumor response causing the cancer cell to die.
Page 46 of 49 Conclusion Since 1891 there have been significant discoveries and success in using immunotherapy to prevent and treat cancer. Immunotherapy has become a pillar of cancer therapy, along with chemotherapy, surgery, radiation, and targeted therapies. Studies to prevent and combat immunotherapy resistance, to determine how to make a tumor “immune active” so that there is better response to immunotherapy, and immunotherapy in combination with other immune therapies or other treatment modalities are ongoing. Immunotherapy is not yet a cure-all for cancer because not all tumors respond and not all patients survive, but there is promise for further development and efficacy in the future.
Page 47 of 49 ACKNOWLEDGMENTS After the grace and generosity of Allah, I would to thank Prof. Dr. Mona Hegazi for agreeing to my desire for the subject of the project and not costing me more than my ability, taking into considerations the circumstances of the study. Dr. Heba Taha, lecture assistant in the Department of Botany, who is credited with teaching me the fundamentals of scientific research and the components of the research paper, as well as how to gather information and use trustworthy Certified websites and how to access them if they are paid. my sincere thanks goes to Dr. Fatima Al-Sharkawy, lecture assistant of zoology department for supplying me with morale, activity, love of pursuit, and perseverance, as well as more information on scientific research. Thanks to my colleagues in the department for their support and encouragement particularly Sara Farag. Last but not the least, I would like to thank my family, especially my mother for her love and support.
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Page 49 of 49 Zahavi D., and Weiner L. (2020). Monoclonal Antibodies in Cancer Therapy. Journal of Antibodies 9(3), 34; https://doi.org/10.3390/antib9030034. Available at: Antibodies | Free Full-Text | Monoclonal Antibodies in Cancer Therapy (mdpi.com)

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