Cancer immunotherapy
Cancer immunotherapy is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.
Cancer immunotherapy exploits the fact that cancer cells often have tumor antigens, molecules on their surface that can bind to antibody proteins or T-cell receptors, triggering an immune system response. The tumor antigens are often proteins or other macromolecules. Normal antibodies bind to external pathogens, but the modified immunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill. The clinical success of cancer immunotherapy is highly variable between different forms of cancer; for instance, certain subtypes of gastric cancer react well to the approach whereas immunotherapy is not effective for other subtypes.
Major types of cancer immunotherapy include immune checkpoint inhibitors, which block inhibitory pathways such as PD-1/PD-L1 and CTLA-4 to enhance T cell activity against tumors. These therapies have shown effectiveness in treating cancers such as melanoma and lung cancer.
Adoptive cell therapies, including chimeric antigen receptor T cell therapy, involve modifying a patient's immune cells to recognize cancer-specific antigens. These therapies have been particularly effective in certain blood cancers. Natural killer cell therapies and CAR-NK cell approaches are also being explored, leveraging NK cells' innate ability to target tumor cells. Other strategies include cancer vaccines, which aim to provoke an immune response against tumor-associated antigens, and may be either preventive or therapeutic. Immunomodulatory agents such as cytokines and Bacillus Calmette-Guerin are used to enhance immune activity or alter the tumor microenvironment. Oncolytic virus therapies, which employ engineered viruses to selectively kill cancer cells while promoting systemic immunity, are also under investigation.
In 2018, American immunologist James P. Allison and Japanese immunologist Tasuku Honjo received the Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation.
History
"During the 17th and 18th centuries, various forms of immunotherapy in cancer became widespread... In the 18th and 19th centuries, septic dressings enclosing ulcerative tumours were used for the treatment of cancer. Surgical wounds were left open to facilitate the development of infection, and purulent sores were created deliberately... One of the most well-known effects of microorganisms on... cancer was reported in 1891, when an American surgeon, William Coley, inoculated patients having inoperable tumours with ." "Coley thoroughly reviewed the literature available at that time and found 38 reports of cancer patients with accidental or iatrogenic feverish erysipelas. In 12 patients, the sarcoma or carcinoma had completely disappeared; the others had substantially improved. Coley decided to attempt the therapeutic use of iatrogenic erysipelas..." "Coley developed a toxin that contained heat-killed bacteria . Until 1963, this treatment was used for the treatment of sarcoma." "Coley injected more than 1000 cancer patients with bacteria or bacterial products." 51.9% of patients with inoperable soft-tissue sarcomas showed complete tumour regression and survived for more than 5 years, and 21.2% of the patients had no clinical evidence of tumour at least 20 years after this treatment..." Research continued in the 20th century under Maria O'Connor Hornung at Tulane Medical School.In the 1980's, researchers at the National Cancer Institute's Center for Cancer Research began exploring the then-heretical idea that a patient's immune system could be harnessed to fight cancer. These researchers included Michael Potter, Ira Pastan, and Steven Rosenberg who developed approaches including monoclonal antibody-based immunotoxins, checkpoint blockade drugs, cytokine-based therapies, and adoptive cell therapy studies.
Types and categories
There are several types of immunotherapy used to treat cancer:- Immune checkpoint inhibitors: drugs that block immune system checkpoints to allow immune cells to respond more strongly to the cancer.
- T-cell transfer therapy: a treatment that takes T-cells from the tumor and selects or changes them in the lab to better attack cancer cells, then reintroduces them into the patient.
- Monoclonal antibodies: designed to bind to specific targets on cancer cells, marking cancer cells so that they will be better seen and destroyed by the immune system.
- Treatment vaccines: also known as therapeutic cancer vaccines, help the immune system learn to recognize and react to mutant proteins specific to the tumor and destroy cancer cells containing them.
- Immune system modulators: agents that enhance the body's immune response against cancer.
Active cellular therapies aim to destroy cancer cells by recognition of distinct markers known as antigens. In cancer vaccines, the goal is to generate an immune response to these antigens through a vaccine. Currently, only one vaccine has been approved. In cell-mediated therapies like CAR-T cell therapy, immune cells are extracted from the patient, genetically engineered to recognize tumor-specific antigens, and returned to the patient. Cell types that can be used in this way are natural killer cells, lymphokine-activated killer cells, cytotoxic T cells, and dendritic cells. Finally, specific antibodies can be developed that recognize cancer cells and target them for destruction by the immune system. Examples of such antibodies include rituximab, trastuzumab, and cetuximab.
Passive antibody therapies aim to increase the activity of the immune system without specifically targeting cancer cells. For example, cytokines directly stimulate the immune system and increase immune activity. Checkpoint inhibitors target proteins that normally dampen the immune response. This enhances the ability of the immune system to attack cancer cells. Current research is identifying new potential targets to enhance immune function. Approved checkpoint inhibitors include antibodies such as ipilimumab, nivolumab, and pembrolizumab.
Cellular immunotherapy
Dendritic cell therapy
Dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. Dendritic cells are antigen-presenting cells in the mammalian immune system. In cancer treatment, they aid cancer antigen targeting. The only approved cellular cancer therapy based on dendritic cells is sipuleucel-T.One method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates or short peptides. These peptides are often given in combination with adjuvants to increase the immune and anti-tumor responses. Other adjuvants include proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte-macrophage colony-stimulating factor. The most common sources of antigens used for dendritic cell vaccine in glioblastoma as an aggressive brain tumor were whole tumor lysate, CMV antigen RNA and tumor-associated peptides like EGFRvIII.
Dendritic cells can also be activated in vivo by making tumor cells express GM-CSF. This can be achieved by either genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF.
Another strategy is to remove dendritic cells from the blood of a patient and activate them outside the body. The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumor cell lysate. These cells are infused and provoke an immune response.
Dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such as TLR3, TLR7, TLR8 or CD40 have been used as antibody targets. Dendritic cell-NK cell interface also has an important role in immunotherapy. The design of new dendritic cell-based vaccination strategies should also encompass NK cell-stimulating potency. It is critical to systematically incorporate NK cells monitoring as an outcome in antitumor DC-based clinical trials.
Drugs
Sipuleucel-T was approved for treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer in 2010. The treatment consists of removal of antigen-presenting cells from blood by leukapheresis and growing them with the fusion protein PA2024 made from GM-CSF and prostate-specific prostatic acid phosphatase and reinfused. This process is repeated three times.Adoptive T-cell therapy
Adoptive T cell therapy is a form of passive immunization by the transfusion of T-cells. They are found in blood and tissue and typically activate when they find foreign pathogens. Activation occurs when the T-cell's surface receptors encounter cells that display parts of foreign proteins. These can be either infected cells or other antigen-presenting cells. The latter are found in normal tissue and in tumor tissue, where they are known as tumor-infiltrating lymphocytes. They are activated by the presence of APCs such as dendritic cells that present tumor antigens. Although these cells can attack tumors, the tumor microenvironment is highly immunosuppressive, interfering with immune-mediated tumour death.Multiple ways of producing tumour-destroying T-cells have been developed. Most commonly, T-cells specific to a tumor antigen can be removed from a tumor sample or filtered from blood. The T-cells can optionally be modified in various ways, cultured and infused into patients. T cells can be modified via genetic engineering, producing CAR-T cell or TCR T cells or by exposing the T cells to tumor antigens in a non-immunosuppressive environment, that they recognize as foreign and learn to attack.
Another approach is transfer of haploidentical γδ T cells or natural killer cells from a healthy donor. The major advantage of this approach is that these cells do not cause graft-versus-host disease. The disadvantage is that transferred cells frequently have impaired function.