The finest hour of cancer immunotherapy
Nonspecific cancer immunotherapy and adjuvants
Anna Petrenko
MedNovosti completes a series of publications on immunotherapy in oncology. The fourth part is devoted to nonspecific immunotherapy of cancer.
Previous articles of the cycle:
- Immunity against cancerCancer immunotherapy: monoclonal antibodies
- Cancer vaccines: prevent, overcome, reassure
Nonspecific immunotherapy is aimed not at the tumor, but at the entire immune system. But this action also leads to the death of cancer cells. Such therapy can be used independently or as an adjuvant – an addition to the main treatment that stimulates immune cells.
Strengthening the immune systemSome substances strengthen the immune system, but they are not produced naturally in the human body.
Such immunomodulatory drugs include thalidomide (Thalomid), lenalidomide (Revlimid) and pomalidomide (Pomalyst), which are used to treat multiple myeloma and other cancers.
In addition, the Calmette-Guerin bacillus belongs to this group. Scientists have been trying to arm themselves with BCG in the fight against cancer for a long time, but success did not always await them. It is now approved by the FDA for the treatment of early-stage bladder cancer and certain types of melanoma. In the first case, the vaccine is injected into the bladder through a catheter, in the second – injected directly into the tumor. The immune system reacts to BCG and activates it, and that in turn is already fighting cancer.
CytokinesThe second extensive group is cytokines.
These are molecules that secrete the cells of the immune system themselves to control the growth and activity of other immune cells and blood cells. Cytokines are similar to the previous group of drugs, only they are released in the human body and naturally.
One of the most well–known groups of cytokines is interleukins, signaling molecules of white blood cells. Interleukin-2 (IL-2) stimulates the growth and division of cells of the immune system. Created in the laboratory, IL-2 is approved for the treatment of advanced kidney cancer and metastatic melanoma. It can be used alone or together with chemotherapy or other cytokines, for example, interferon alpha. It is believed that such a joint use increases the effectiveness of treatment, although, unfortunately, the side effects are also summed up.
In 2014, scientists from the Laboratory of Cell Oncology of the Research Department for Cell Differentiation and Oncology of the Faculty of Higher Studies from the National Autonomous University of Mexico in Zaragoza (Laboratory of Cellular Oncology, Research Unit in Cell Differentiation and Cancer, of the Faculty of Higher Studies (FES) Zaragoza UNAM (National Autonomous University of Mexico) announced about the development of therapy against cervical cancer. The drug was tested on an animal model. It consists of nanoparticles with IL-2 included, which, as the developers explain, create a "bridge" of antitumor activation between T-lymphocytes and cancer cells. In addition, the drug allows the accumulation of cytokines in tumor growth zones, which reduces the side effects of conventional IL-2 injected into the general bloodstream.
This year, researchers modified IL-2 so that it was possible to strengthen or stop immune reactions depending on the goal at the request of doctors. The development has already been tested in the laboratory on cell culture and on a mouse model. It has been shown that a new form of cytokine in vitro blocks the growth of T-cells of a patient with chronic/smoldering forms of T-cell leukemia and increases the survival of animals in a graft-versus-host situation.
Other interleukins are also used as independent treatment and adjuvants, for example, IL-7, IL-12 and IL-21.
Interferon alpha (IFN-alpha) is another cytokine blend approved for the treatment of cancer. They belong to interferons, whose main task is to fight viruses. IFN-alpha directly slows down the growth of the neoplasm and the blood vessels that feed it. In addition, it involves immune cells in the fight against malignized. The FDA has approved IFN-alpha for the treatment of hairy cell leukemia, chronic myeloid leukemia, follicular non-Hodgkin lymphoma, cutaneous T-cell lymphoma, kidney cancer, melanoma and Kaposi's sarcoma.
Another cytokine with a very long name used for the treatment of tumors is granulocyte-macrophage colony stimulating factor (GM-CSF/GM-CSF). Normally, it plays a role in the formation of certain types of immune and blood cells from bone marrow stem cells. The human–synthesized form, sargramostim (Leukine), is used to increase the number of white blood cells after chemotherapy. In addition, they are now studying how GM-CSF can be used as a non-specific immunotherapy and as an adjuvant for different types of cancer.
Immunocepoint RegulatorsOne of the important tasks of the immune system is not to attack the body's own cells, that is, not to take them for foreign and dangerous.
To do this, "their" healthy cells have special molecules on the surface, the presence of which depends on whether they will fight them or not. Since at this level a decision is made about the future fate of the cell, such molecules are called "checkpoints", test points. If the immune cell does not detect them, it attacks. Some cancer cells have learned to trick the immune system by using just such molecules. But a person has also learned how to use them: immunocepoint regulators show excellent results.
Among such "tags" of internal protection that protect the cells of the body is CTLA–4, a membrane protein of T cells. In some cases, it prevents cancer cells from attacking. Monoclonal antibodies from the drug ipilimumab (Yervoy) block CTLA-4. This enhances the immune response against cancer cells. The drug is used to prolong the life of patients with melanoma and other types of cancer.
Another pathway that scientists use is PD-1 (programmed death protein 1) and PD-L1 (ligand of programmed death protein 1, it is usually used to prevent autoimmune diseases). Doctors immodestly believe that some drugs aimed at them can usher in a new era of fighting cancer, because they deprive cancer cells of "masking" from the immune system. This can make a whole range of tumors vulnerable.
PD-1 is also located on the surface of T cells. Compared to CTLA-4, it is more often found on T-cells of inflamed tissues and tumors. If PD-1 binds to its PD-L1 ligand on another cell, then the immune cell does not touch it. This is what tumors use: some cancer cells expose a large amount of PD-L1 to the surface.
An international team studied a drug that blocks PD-L1. Roche's drug is called MPDL3280A, or anti-PD-L1). The study involved 68 people with bladder cancer. All the patients had already gone through chemotherapy, and, according to doctors, they had six to eight months to live. After using the drug, more than half of the patients showed signs of recovery. Two patients were completely cured – the tumors disappeared after therapy. The drug was called a "therapeutic breakthrough" in the USA. If a larger study confirms the previous results, it is possible that the drug will be available to a wide range of patients in the United States by the end of 2015.
Another study involving 175 patients was led by researchers from Yale University. Melanoma, kidney cancer and other oncological diseases responded to treatment.
So far, the results are confirmed by studies of similar therapy on 411 patients with melanoma. As it was stated at the conference of the American Society of Clinical Oncology (ASCO American Society of Clinical Oncology) held a year ago in Chicago, when using the drug pembrolizumab, 69% of patients lived for at least another year.
Blocking PD-1 and PD-L1 during monotherapy treatment resulted in a response of 20% and 25%, respectively, in non-small cell lung cancer. In addition, it turned out that PD-L1 expression is associated with an EGFR mutation. Scientists suggest that double blockade of these receptors, i.e. inhibition of immunocepoints and EGFR tyrosine kinase, may be very effective for a certain group of patients. Researchers believe that very soon such drugs will enter clinical practice for the treatment of non-small cell lung cancer.
In addition, treatment associated with PD-L1 also helps with triple negative breast cancer. The prognosis for this type of cancer is poor, and it is extremely difficult to treat it due to the lack of HER, progesterone and estrogen receptors. The study was conducted by the Mayo Clinic and Caris Life Science.
Finally, in a newly published paper, researchers from Johns Hopkins University in Baltimore, scientists have shown that even for tumors that, it would seem, no longer takes any treatment, pembrolizumab (pembrolizumab) can work. The study involved patients with advanced colon cancer and other cancers who stopped responding to therapy. If the tumors had mistakenly paired nucleotides in the genome after DNA repair, then they reacted to PD-1 inhibitors.
ConclusionFor cancer immunotherapy, from monoclonal antibodies and vaccines to nonspecific therapy, now is the finest hour.
Many technologies that have been developed in laboratories for a long time are finally moving into clinical practice. As a supplement to the May 27 issue, Nature published a special selection of exciting articles on this topic that can be read in the public domain.
We can only hope that the moment is getting closer when the use of chemotherapy and radiation will become just a point in the historical review of cancer treatment, and there will be no tumor that cannot be cured.
Portal "Eternal youth" http://vechnayamolodost.ru02.06.2015