Achievements of antitumor immunotherapy
Using the patient's own immune cells to fight cancer
In a colored photograph obtained using a scanning electron microscope,
the T-lymphocytes (green), bound to antigens on the surface of a cancer cell, are depicted.
More than a hundred years ago, an American oncologist surgeon William Coley encountered the case of Fred Stein, who fell ill with erysipelas, an infection caused by purulent streptococcus pyogenes, which entered the body during partial surgical removal of a large tumor on the neck. 7 years after that, Koli found Stein, who was alive, and the undeleted part of the tumor had completely disappeared. Surprised by this fact, Kohli suggested that the immune response to bacterial infection played a key role in the fight against the tumor and conducted a study in which he infected 10 patients with purulent streptococcus with inoperable tumors. As a result, a decrease in the size of the tumor was registered in several of the infected and one of the deceased patients.
Subsequently, Kohli analyzed the effects of introducing dead bacteria into tumors in the hope of stimulating an immune response without the risk of developing a fatal infection. As a result, a complete regression of neoplasms occurred in several patients with sarcoma – a malignant tumor affecting bones, muscles and adipose tissue. Unfortunately, against the background of the growing use of radiotherapy and the invention of systemic chemotherapy, by the time of Kohli's death in 1936, most of his research had been forgotten.
However, at present, the approach of modulating the immune system to fight cancer has finally attracted due attention. Unlike chemo- and radiotherapy that directly affect malignant cells, immunotherapeutic agents stimulate the body's own immune mechanisms, enhancing its ability to fight tumors. This strategy involves the introduction of agents that directly stimulate the activity of immune cells, or synthetic proteins that are analogs of components of the normal immune response, to enhance the immune response. Last year, the journal Science called cancer immunotherapy the "breakthrough of the year", which equated it in importance to the appearance of the first cloned mammal and the complete sequencing of the human genome. Several immunotherapeutic approaches that are already available to clinicians, and several dozen more that demonstrate success at different stages of clinical development, indicate the inevitability of a revolution in clinical oncology.
The strength of the immune responseThe body's immune system regulates processes that ensure continuous monitoring of the body's condition and its protection from infection.
The well–coordinated joint work of the two main components of the immune system – innate and acquired immunity - ensures the fight against infections and the preservation of information about pathogens that the body has already encountered. Alerted by danger signals in the form of microbial peptides, surface molecules or DNA sequences, cells belonging to an innate component of the immune system, such as macrophages and neutrophils, trigger many mechanisms aimed at quickly getting rid of infectious agents. At the same time, B-lymphocytes, which are components of the acquired immunity system, develop a highly specific immune response consisting in the synthesis of antibodies that recognize and destroy certain pathogens. Antigen-specific T-lymphocytes activated by cells of the innate immune system that absorb and digest infectious agents further stimulate the body's response. These specific B and T cells have a long memory, which allows the immune system to quickly develop a strong immune response during subsequent encounters with the pathogen.
In 1960-70 . Lloyd Old from Memorial Sloan-Kettering Cancer Center contributed to the return of interest in cancer immunotherapy with his observation that the antigens expressed on the surface of malignant cells differ from the surface antigens of healthy cells. These so-called tumor-associated antigens are used in the development of antitumor vaccines designed to stimulate a tumor-specific immune response. In the 1980s, Old's observations were supplemented by data obtained by Steven Rosenberg from the US National Institutes of Health, who was studying the possibilities of using cytokines in oncology - compounds used by the body to stimulate the immune system.
Some time later, the method of "checkpoint blockade" - blockade of immune control points, developed by James Allison, who at that time worked at Memorial Sloan–Kettering Cancer Center, added immunotherapy to the arsenal of oncologists-clinicians. In order to avoid hyperactivation of the immune system and damage to healthy tissues, regulatory T lymphocytes (Treg) and myeloid suppressor cells secrete anti-inflammatory factors or directly inhibit pro-inflammatory immune cells. In addition, immune "control proteins" expressed on the surface of activated immune cells perform the function of suppressing the immune response. Tumors can use these anti-inflammatory mechanisms to avoid recognition by the immune system. Ellison proposed an approach that blocks the control proteins and opens the immune system access to the tumor.
These new treatments can prolong the life of patients with tumors that were previously considered high-mortality, including kidney cancer and melanomas.
Vaccination as cancer therapyThe use of most of the antitumor vaccines being developed consists in the introduction of a drug containing a component of a tumor-specific antigen.
This is done in order to stimulate the tumor-specific activity of the immune system.
Vaccines of another type involve the isolation of antigen-presenting cells (APC) of the patient and their cultivation in an environment containing the antigen of his tumor and immunostimulating factors, which gives APC the ability to activate T-lymphocytes.
In 1990, the method of localized administration of BCG anti-tuberculosis vaccine (Calmette–Guerin bacillus), made from a weakened causative agent of bovine tuberculosis - Mycobacterium bovis, received official approval for the treatment of bladder cancer. This approach was the first method of antitumor immunotherapy approved by the U.S. Food and Drug Administration (FDA). The idea that infection with mycobacteria can help in the treatment of cancer was first proposed in 1929 by a biogerontologist from Johns Hopkins University, Raymond Pearl, who noticed that at the time of the autopsy, malignant tumors were less common in patients with active tuberculosis than in the general population. In the late 1950s, Lloyd Auld demonstrated in animal models that BCG injections inhibit tumor growth. Subsequent clinical studies conducted in 1970-80 showed that, against the background of slowing the growth of bladder tumors and improving survival, regular intra-tumor BCG injections in some cases led to tumor regression, and also reduced the risk of relapses by 12%. 20 years after its introduction into clinical practice, BCG remains the most effective noninvasive treatment of bladder cancer available, providing a cure for 70% of patients who do not have contraindications for this therapy.
Weakened bacteria inhibit tumor growth by attaching to the tumor and surrounding cells, which attracts immune cells to the tumor area, actively releasing pro-inflammatory cytokines. The result of this is phagocytosis of cancer cells by activated neutrophils and macrophages. Such an inflammatory reaction ensures the destruction of the tumor, but it can cause damage to healthy tissues, causing side effects manifested by symptoms of inflammation of the genitourinary tract: a moderate increase in body temperature and soreness during urination. The researchers hope that these adverse events will be avoided with the help of new vaccines that trigger a systemic antitumor immune response due to selective interaction with tumor proteins.
Unfortunately, tumor-specific vaccines have so far rarely demonstrated significant antitumor activity and improved patient survival. To date, there is only one vaccine of this type on the market – Sipuleucel-T (Provenge), developed by the Seattle company Dendreon. In 2010, the FDA approved the use of this vaccine as a last-resort therapy in the treatment of metastatic prostate cancer. In this case, the production of the vaccine consists in the isolation of the patient's own antigen–presenting cells (APC) - a subtype of leukocytes that performs the function of activating T cells – and their incubation in the presence of immunostimulating factors and prostatic acid phosphatase – an antigen expressed on the surface of 95% of prostate cancer cells. After several days of incubation, the cells are injected back into the patient's bloodstream, where they trigger an immune response against the tumor. The results of controlled randomized clinical trials have shown that such therapy increases the life expectancy of patients with no contraindications to its implementation by an average of 4 months.
There is evidence that systemic administration of prostatic acid phosphatase or similar antigens specific to other types of tumors causes an immune response against the corresponding tumors. However, the effectiveness of this approach in improving patient survival has not been proven. Hundreds of antitumor vaccines are currently at different stages of clinical trials. Several vaccines for the treatment of breast, lung, kidney and melanoma cancers have already reached phase 3, the purpose of which is to assess their ability to actually ensure the development of a tumor-specific immune response and help patients.
Blocking immune inhibitionThe immune checkpoint blockade method ("checkpoint blockade") works by preventing the suppression of the immune response.
This therapeutic approach makes it possible to maintain immune activity by blocking immune control points with the help of molecules binding to surface T-lymphocyte receptors, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed cell death receptor-1 (PD-1) expressed on the surface of activated T cells and usually reducing the activity of the immune response.
Another promising and rapidly developing area of immunotherapy is the method of blockade of immune control points ("checkpoint blockade"). Immune checkpoints are inhibitory mechanisms that prevent excessive stimulation of the immune system. Proteins expressed on the surface of activated immune cells suppress the activity of these cells when their mission can be considered fulfilled. Cytotoxic T-lymphocytic antigen-4 (CTLA-4), for example, is usually localized inside the cell, and when moved to the cell surface, it acts as a "brake", suppressing the activity of the immune response.
In the mid-1990s, Ellison suggested that temporarily suppressing the inhibitory effect of CTLA-4 could help the immune system fight tumors. In experiments on preclinical models, he demonstrated that therapy with antibodies against CTLA-4 cures mice from tumors formed as a result of subcutaneous injection of mouse rectal cancer cells. Early clinical studies involving patients with melanoma demonstrated the safety of this approach and gave hope for its effectiveness. A large phase 3 clinical trial conducted in 2010 showed that blocking CTLA-4 using humanized monoclonal antibodies, which are the active ingredient of the drug ipilimumab (Yervoy is a trademark of Bristol–Myers Squibb), improved the survival of patients with advanced stages of melanoma.
Despite the low responsiveness (only 10% of patients had tumor reduction and 18% had stabilization of disease progression), ipilimumab became the first drug to improve the survival of patients who, when using traditional chemotherapeutic protocols, usually die within 6-9 months after diagnosis. Moreover, the majority of patients who responded to ipilimumab had an improvement in their condition for more than 2 years. In 2011, the FDA approved this drug for the treatment of late-stage melanoma, and subsequent monitoring of the condition of participants in early studies showed that some of them were alive 10 years after the therapy. Currently, ipilimumab is in phases 2 and 3 of many clinical trials, which are exploring the possibility of its use for the treatment of many types of cancer, including non-small cell lung cancer, prostate cancer, kidney cancer and ovarian cancer.
The most common side effects of ipilimumab therapy were of an immune nature and were due to the stimulating effect of the drug on the immune system. These included colitis, dermatitis and hepatitis caused by excessive inflammatory reactions. Given the low level of responsiveness to the drug, further studies are necessary to increase the effectiveness of therapy.
One of the solutions to the problem may be blocking other immune control points, such as the mechanism of interaction between the programmed cell death receptor-1 (PD-1) on T-lymphocytes and its ligand (PD-L1) on antigen-presenting cells. As well as CTLA-4, PD-L1 is expressed on activated T-lymphocytes and on "depleted" T-lymphocytes that are inactive despite the presence of the pathogen. The interaction between PD-1 and PD-L1 weakens the immune response. An interesting fact is that PD-L1 is expressed by tumor cells, which, apparently, helps them avoid collisions with the immune system. The results of early clinical studies of the nivolumab drug developed by Bristol-Myers Squibb, the active ingredient of which is anti-PD-1 antibodies, have shown promising results when used for the treatment of non-small cell lung cancer and kidney cancer. Phase 3 clinical trials are currently underway to investigate its potential ability to improve patient survival. Similar studies are being conducted for PD-L1 inhibitors.
The results of early studies on the effectiveness of a combination of anti-CTLA-4 and anti-PD-1 agents also indicate the advantages of simultaneously blocking two immune control points. During the study, the results of which were published in July 2013 in the New England Journal of Medicine, more than half of the patients with metastatic melanoma who received the maximum combined dose of nivolumab and ipilimumab, the tumor mass decreased by more than 80%. At the same time, more than 80% of these patients were alive a year after the therapy.
T-cells rush to the rescue During adaptive transfer of T-lymphocytes, cells isolated from the patient's blood or tumor are trasfected using a viral vector.
As a result, they begin to express tumor-specific chimeric antigenic receptors that set up cells to destroy the tumor when they are re-administered to the patient.
The third way to stimulate the immune response directed against the tumor is to isolate the patient's T-lymphocytes, multiply them in the laboratory and re-inject the patient as specially trained tumor fighters.
Known as adaptive T-lymphocyte transfer, this procedure was previously performed by isolating tumor–infiltrating lymphocytes - a subpopulation of T–lymphocytes leaving the bloodstream and migrating into solid tumors - that can be isolated from surgically removed tumor tissue. Unfortunately, in some patients, the disease progresses too quickly, which leaves no time for manipulations carried out outside the body, sometimes lasting for a month. However, it brings some relief to some patients. According to the results of a phase 2 clinical trial published in 2010, half of the 20 participants with stage IV melanoma showed significant improvement after such therapy, two of them even went into complete remission.
The possibilities of this strategy are limited by the fact that in some patients there are no tumor foci that could be surgically removed, or the removed tumor does not contain infiltrating lymphocytes capable of proliferating or exhibiting antitumor activity in the laboratory. In order to overcome these difficulties, researchers have developed a method of genetic modification of T-lymphocytes circulating in the blood, giving them the ability to attack tumor cells with the help of so-called chimeric antigenic receptors. These receptors contain an antigen-recognizing domain or a modified antibody segment capable of recognizing a specific protein on the surface of tumor cells, and an intracellular domain that activates T cells and stimulates their proliferation in the body.
Researchers have developed chimeric antigen receptors for the treatment of a wide range of oncological diseases, including chronic lymphocytic leukemia. In one case, they isolated T-lymphocytes from the blood of a patient with this disease and modified them so that chimeric antigenic receptors for CD19, a protein expressed on the surface of normal and malignant B–lymphocytes, appeared on their surface. The cells multiplied in the laboratory were injected back into the patient who did not respond to any of the traditional treatment protocols. As a result, this patient, as well as many subsequent ones, had a complete cure.
To date, the FDA has not yet approved therapies involving such manipulations with T-lymphocytes. However, many phase 1 and phase 2 clinical trials are already being conducted, the purpose of which is to study the safety of these methods and their impact on the survival of patients with various types of cancer, including leukemia, lymphoma, melanoma, pancreatic, breast and prostate cancer.
The future of immunotherapyImmunotherapy is rapidly becoming a powerful weapon against cancer, and researchers continue to improve its effectiveness and expand the population of patients who will benefit from this approach.
Many scientists are currently studying the feasibility of using combinations of several immunotherapeutic approaches, such as blockade of immune checkpoints and adaptive transfer of T-lymphocytes or parallel administration of antitumor vaccine and cytokines. In the coming years, it will be possible to observe with excitement what a profound impact immunotherapeutic drugs will have on the survival of cancer patients, as hundreds of ongoing clinical studies bring this approach closer to clinical practice.
For references to the 11 literary sources used by the authors, see the original article.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of The Scientist:
Jamie Green and Charlotte Ariyan, Deploying the Body's Army.
09.04.2014