Cancer immunotherapy

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Cancer immunotherapy is the name for different methods of immunotherapy for the treatment of cancers .

The classic treatment methods for cancer are surgical tumor removal ( resection ), chemotherapy and radiation therapy . Often two or even all three forms of therapy are used simultaneously on one patient. The latter two methods have significant cytotoxic side effects . The therapeutic index is very low during chemotherapy, so that a high dosage - which would be conducive to enhancing the effect - is usually excluded. If, however, not all cells of the tumor and its metastases are destroyed ( eradicated ) during therapy , further treatment is made significantly more difficult by the development of resistance . For years, research has therefore been carried out on new therapeutic methods that have the highest possible selective effect against cancer cells. The various approaches of cancer immunotherapy have a very promising potential here, which - for example in antibody therapy - has also found its way into clinical practice.

In oncology, a distinction is made between active and passive vaccination for the different therapeutic approaches . In the active immunization of the patient gets cancer vaccines administered , which in his immune system an immune response should trigger. The immune response should ideally lead to the death of the tumor cells or at least to delayed tumor growth. In contrast, with passive immunization, the patient receives antibodies or antibody fragments . These are supposed to bind selectively to tumor cells and thus lead to their demise. In adoptive immunotherapy, leukocytes are taken from the patient , cultivated ex vivo and then re- injected into the patient .

In the area of ​​passive immunization, several approved antibodies against cancer are already in clinical use. A number of drugs for specific active immunization ( tumor vaccination or cancer vaccination ) in the area of ​​cancer indications are still in clinical development .

The HPV vaccines approved in the European Union since September 2006 are not actually cancer immunotherapy. These vaccines are used preventively to immunize against human papillomavirus (HPV), which can cause certain types of cancer, especially cervical cancer .

Cancer immunotherapy
passive immunization active immunization
unspecific specific unspecific specific
Cytokines Antibodies (with and without conjugate) Slotted snail hemocyanin Vaccine from killed tumor cells
Lymphokine-activated killer cells
or cytokine-induced killer cells 		adoptive transfer of T lymphocytes Freund's adjuvant Cell extract vaccines
Peginterferon α   Bacillus Calmette-Guérin Vaccines based on antigens

Classification of cancer immunotherapy with examples.

Cancer and the immune system

Immune surveillance

The theory of immune surveillance ( immunosurveillance ) assumes that the immune system is not only active against foreign pathogens, but also against the body's own degenerate cells. An intact immune system - so the conclusion - is therefore an important element in an organism in order to avoid cancer.

The two examples below make clear what effects a permanently weakened immune system can have in humans.

HI viruses (colored green) that are released by a lymphocyte. ( Scanning electron micrograph)

The human immunodeficiency virus (HIV) destroys CD4 + - T-lymphocytes . These cells , which are part of the white blood cells ( leukocytes ) , play an important role in the immune response . AIDS patients (AIDS = acquired immunodeficiency syndrome = "acquired immunodeficiency syndrome") therefore have a weakened immune system. As a result of this weakened immune system, various cancers, such as lymphoma , Kaposi's sarcoma and cervical carcinoma , are common complications in AIDS patients.

Graph of the increase in certain cancers in patients after solid organ transplantation as a result of ingestion with immunosuppressive drugs

Patients who have received a solid donor organ (such as a kidney or liver ) are given immunosuppressants to prevent the foreign organ from being rejected . These are drugs that reduce the functions of the immune system. Statistically speaking, these patients are three times more likely to develop cancer than comparison groups of the same sex and age group. After ten years of immunosuppression, the chance of developing cancer is 20%. This is especially true for cancers that are of viral origin, such as Kaposi's sarcoma (trigger: human herpes virus 8 ), Hodgkin's disease and non-Hodgkin's lymphoma ( Epstein-Barr virus ), liver cancer ( hepatitis C and hepatitis -B virus ), as well as cervical cancer , vulvar cancer , vaginal cancer , penile cancer and other cancers caused by human papillomavirus . But cancers such as colorectal cancer , kidney cancer , bladder cancer , thyroid cancer , multiple myeloma , leukemia and malignant melanoma - which according to the current state of knowledge are not triggered by viruses - are also increasing significantly. In some cases, regression of the malignancies, for example malignant lymphomas , was observed after the immunosuppression was discontinued .

In both groups - AIDS patients and patients on immunosuppressants after transplants - high similarities were found in terms of cancer risk, with the cause of the increased cancer rate being essentially the weakened immune system.

The exact mechanisms are not yet fully understood, but immune surveillance plays a crucial role in this.

The thesis of immune monitoring, i.e. the direct and constant fight against spontaneously occurring tumors by the immune system and tumor development as a result of weaknesses or disorders of the immune system, is still controversially discussed to this day. On the other hand, it is generally recognized that the immune system is in principle able to recognize degenerate cells and to fight them successfully. As will be shown later, the immune system does not offer complete, but rather inadequate protection against tumor diseases, which is demonstrated by the fact that people with a completely intact immune system can also develop cancer. The use of the existing mechanisms of the immune system are the starting point for a number of strategies for the immunological therapy of cancer diseases.

Immune Escape

Schematic representation of the MHC class I protein complex. The cell membrane in gray.
Schematic representation of the MHC class II protein complex

It is actually not surprising that the immune system can “fail” in its defense against cancer cells in completely healthy, immune-competent people. After all, tumors form from the body's own cells in a wide variety of tissues that are “out of control”. Accordingly, tumor cells carry the self-antigen on their cell surface , which they identify as “belonging to the body”. This is a completely different situation than with alien "intruders" ( pathogens ), who are relatively easy to recognize by the immune system due to their strangeness. Oncologists therefore do not speak of a “failure of the immune system” when it comes to cancer. On the other hand, an overly sharp immune system that would respond to minimal cellular changes would result in a number of autoimmune diseases .

Many tumor cells do not express mutated peptides ( tumor-specific antigens ) on their surface. This would be an essential prerequisite for the immune system to recognize the degenerated cells as such and destroy them. But even with tumor cells that present antigens on their cell membrane , there is in many cases no adequate immune response. The reason here is that the tumor cells can evade the immune system in various ways. One speaks therefore of the so-called immune escape (" immune escape "). For example, the peptides presented on the MHC-I complex can be changed by mutation. The reduction in the expression of the main histocompatibility complex (MHC) is also, for example, a reaction of the cancer cells. They can also protect themselves by secreting certain immunosuppressive cytokines . The antigen shedding , the dropping of antigens from the outer membrane is to escape, a measure of the cancer cells to the immune system. Some cancer cells are able to express Fas ligands (FasL = Fas ligand; CD95) on their cell surface. If FasL binds to the Fas receptor (FasR), the cancer cells can trigger programmed cell death ( apoptosis ) in the FasR-bearing lymphocytes . This process is called a tumor counterattack (German: "tumor counterattack").

Immunoediting

There is no special strategy or even an independent “intelligence” behind the adaptation of the cancer cells. They are a result of mutation (by the cancer cells themselves) and selection (by the immune system). The best adapted cells survive and continue to multiply ( Survival of the Fittest ). The comparatively high rate of proliferation and mutation of the degenerate cells is advantageous for their evolution. The defense mechanisms used by cancer cells are also present in healthy cells, for example to prevent autoimmunity . The immune system thus does two things in cancer cells: on the one hand, the organism is protected by destroying the degenerate cells and, on the other hand, the tumor is “formed” through the selection process. Since the term immune surveillance, which only looked at the protective function of the immune system, no longer adequately does justice to this expanded thesis, one speaks of immunoediting since the beginning of the 21st century . Tests with transplanted tumors in mice provide evidence for the thesis of immunoediting , i.e. the selection process of non-immunogenic tumor cells . Tumors that were generated in immunocompetent mice with 3-methylcholanthrene (MCA) and that could thus be “shaped” by the mouse's immune system through the selection process, were rejected significantly less often during transplantation into other mice than tumors from immunodeficient mice. Due to the restricted immune system, the tumors from the immunodeficient mice were less influenced by selection processes and thus more immunogenic . The immunoediting is divided into three phases: elimination, balance ( equilibrium ) and escape ( Escape ). The elimination phase corresponds to the original concept of immune surveillance, in which cancer cells are destroyed by the immune system. In the equilibrium phase, after almost complete destruction of the cancer cells, an immune-mediated latency sets in. In the last phase, the escape , the tumor escapes the immune surveillance and only becomes clinically visible in this phase.

The goals of cancer immunotherapy

Progression-free survival in ovarian cancer, with and without infiltration of the tumor with T cells
Overall survival for ovarian cancer, with and without infiltration of the tumor with T cells

As was shown at the beginning, the immune system plays an important role in the development or prevention of cancer. But even afterwards, when cancer actually breaks out through an immune escape , the immune system has a major influence on the course of the disease. This is shown, among other things, by the fact that the activity of the immune system against cancer cells is an important factor for the prognosis in cancer patients. For example, it has been shown that cell-mediated immunogenicity to tumor-associated antigens (TAA) is a better indicator of survival than staging , grading and status of the lymph nodes . In patients with breast cancer at an early stage, the survival rate is significantly higher if they show a natural humoral immune response against epithelial mucin-1 of the tumor cells. In 2003 over 100 ovarian carcinomas were examined immunohistologically in a study . A significant correlation between progression-free survival or overall survival and the infiltration of the tumor tissue with T cells (TIL = tumor infiltrating lymphocytes ) could be established. The five-year survival rate for patients with T-cell infiltrated tumors was 38%, while it was only 4.5% for patients without T-cells in the tumor. Similar correlations have been found, for example, for malignant melanoma , bladder cancer , colorectal cancer , prostate , rectal cancer , and neuroblastoma .

The inadequacies and weaknesses of the immune system against cancer cells described in the previous paragraph are the starting point of cancer immunotherapy. Several strategies, some of them very different, were developed to fight cancer cells directly or indirectly via the immune system. The common goal of all these approaches is to use the immune system to destroy cancer cells. This can happen , for example, through unspecific stimulation of the immune system, which results in an increase in the most important cytotoxic cells . The "marking" of tumor cells with monoclonal antibodies to trigger an immune reaction is a cancer immunotherapy procedure, even if the treatment with antibodies is incorrectly referred to as "chemotherapy", and not just colloquially.

Unfortunately, the currently established treatment regimens - with all the indisputable therapeutic successes - have the opposite effect on the immune system: Both chemotherapeutic and radiotherapeutic measures weaken the immune system. The proliferation and the function of lymphocytes is clearly restricted after chemotherapy. For example, there are significantly fewer T cells in the bone marrow of patients after adjuvant (supportive) systemic chemotherapy for breast cancer, and the number of activated NK cells is also reduced over a longer period of time.

Tumor antigens

→ see main article tumor antigen

Tumor antigens are fragments of proteins produced in tumors. These fragments are located on the outer cell membrane of the tumor cells, in the cell plasma and in the cell nucleus. The tumor antigens arise as a result of the genome changed in cancer cells or as a result of a change in gene expression ("switching on and off" genes ). These changes can result in new gene products that are foreign to the body or proteins that are normally only present in the embryonic development phase , for example . Often certain proteins - also present in healthy cells of the body at the time of the illness - are produced ( overexpressed ) in large quantities .

Almost all previously known tumor antigens are presented on the cell membrane via the MHC-I complex ( antigen presentation ). The protein fragments presented there consist of about nine to ten amino acids. The differences in the structure of the antigen or in the frequency of its expression - compared to a normal cell - make them potential target structures ( targets ) for effector cells of the immune system and antibodies. Cytotoxic T cells can recognize the tumor antigens presented via the MHC-I complex via their T cell receptor with the aid of the CD8 receptor and, if necessary, destroy the target cell with the tumor antigen.

As a target structure, the tumor antigens are the basis for most concepts in cancer immunotherapy. Over 2000 tumor antigens are known to date. The ideal tumor antigen - which does not exist in this form - would have the following properties:

  • It will only be expressed on the cell membrane by cancer cells. In contrast, it is not present in healthy cells. In such cases one speaks of a tumor-specific antigen (TSA).
  • It consists of peptide fragments that are presented on the cell membrane via the MHC-I complex and are recognized by T cells in the MHC-restricted mode.
  • Expression on the cell surface should be guaranteed over the entire cell cycle and at the highest possible density and should not be downregulated .
  • The tumor antigen is expressed by all cancer cells in all cancer diseases.

In reality it looks different. Most tumor antigens are not tumor-specific (TSA), but tumor-associated (TAA). This means that they are also expressed by healthy cells. However, the tumor antigens are overexpressed in many tumors. Structural changes in the protein sequence can also occur through mutations in the genome. Many tumor antigens only occur in certain types of tumor and there often only in certain cases. For example, HER2 / neu is only overexpressed in 20 to 25% of all breast cancer tumors, which is why therapy with the HER2 / neu-specific antibody trastuzumab only makes sense in these cases . In addition, tumor cells can shut down antigen presentation via the MHC-I complex , for example as a result of the immune escape .

The identification of tumor antigens with high immunogenicity , which come as close as possible to the ideal picture shown above, is one of the greatest challenges for tumor immunology and the key to successful specific immunizations. A rationale in identifying tumor antigens is that their perception by the immune system is an indicator of their relevance in an anti-tumor response. In the past, tumor antigens were essentially identified by analyzing the anti-tumor response in patients. For this purpose, either the peripheral or tumor-infiltrating lymphocytes (TIL) were examined or the humoral immune response was analyzed.Through the knowledge gained in the context of the human genome project and with the help of improved analytical methods, reverse immunology has been established as a powerful high-throughput method for the identification of tumor antigens for several years .

Passive cancer immunotherapy

Monoclonal antibodies

Schematic representation of various antibodies and antibody fragments
→ see main article Antibodies and Monoclonal Antibodies

Antibodies are protein structures that, with the help of the lock and key principle, are able to recognize antigens and adhere to them. This also applies to tumor antigens as target structures. In the human body, antibodies are produced by differentiated B lymphocytes , i.e. plasmablasts and plasma cells . Each B-lymphocyte produces a different antibody. However, they only differ in the variable part that matches the antigen epitope - the so-called paratope - at the upper end of the Y structure. If antibodies bind to an antigen epitope of a cell via their paratope, macrophages , for example, recognize this immune complex and subsequently try to destroy the cell marked in this way.

The body's own polyclonal antibodies only play a very minor role in the fight against cancer cells. Most cancer cells do not present antigens that are sufficiently modified for the body's own antibodies to bind to them in sufficient numbers. If the polyclonal antibodies were more sensitive, they would also increasingly bind to healthy cells and trigger autoimmune reactions there. Monoclonal antibodies, on the other hand, are completely identical in their structure and only target one epitope of an antigen.

Antibodies play an important role in cancer diagnosis in particular. For example, in immunoscintigraphy, monoclonal antibodies are marked with radionuclides that can be tracked in a patient's body using SPECT ( radiotracer ). If the monoclonal antibodies marked in this way accumulate in certain organ tissues, this can be an indication of metastasis.

After rituximab was approved by the FDA in the United States in 1997, the first therapeutic monoclonal antibody (against B-cell non-Hodgkin lymphoma) was launched. A year later, trastuzumab was approved for use in metastatic breast cancer. Since then, other monoclonal antibodies against other forms of cancer have been developed and approved for their treatment.

The effect of monoclonal antibodies is based on the binding to target structures that are located on the surface of the target cell. You can work either directly or indirectly. With direct action, the antibodies can trigger an intracellular signal cascade in the cancer cell by cross-linking the tumor antigen. This can result in an anti-proliferative effect or an immediate apoptosis of the cell. Rituximab, for example, can trigger apoptosis by cross-linking the tumor antigen CD20 . The cross-linking of tumor antigens such as CD22, CD33 or HLA II with antibodies, however, has an anti-proliferative effect in the target cells. Monoclonal antibodies can also act on cancer cells by blocking certain ligands. Trastuzumab blocks the Her2 / neu receptor, which disrupts the signal chain to the epidermal growth factor and inhibits proliferation. As a result, tumor growth slows down.

Schematic representation of the complement cascade

The indirect mechanisms of action of the monoclonal antibodies are based on the Fc receptor binding site (Fc = fragment crystallizable ) - the lower part of the Y structure. This activates the effector functions. These include complement-dependent cytolysis ( Complement Dependent Cytolysis , CDC) and antibody-dependent cell-mediated cytotoxicity ( antibody dependent cellular cytotoxicity , ADCC). In CDC, complement fixation (CF) triggers the complement cascade , which leads to lysis of the target cell. However, it is still unclear what significance, or what part, the CDC has for therapeutic success. In ADCC, antibodies direct cytotoxic effector cells, such as NK cells, which themselves do not have any antigen specificity, to the cancer cell via the Fc part. The g chain of the Fc part causes the signal transduction to the cytoplasm of the effector cell. The effector cells release lytic granules , consisting of perforin and granzyme , on the cancer cells , which lead to apoptosis of the cancer cells. For many therapeutic antibodies, such as rituximab, alemtuzumab , trastuzumab or cetuximab , the ADCC is the most important mechanism of action. Phagocytic cells such as macrophages can also be activated via the Fc part of an antibody and phagocytize the cell marked with the antibody. In general, the indirect mechanisms of action are more important in tumor therapy than the direct ones.

The therapeutic limits of monoclonal antibodies

A general problem for the therapeutic effectiveness of the monoclonal antibodies is the ability of the antibodies to bind to the cancer cells. Even with cancer cells that present sufficient tumor antigens, the binding rate is often not sufficiently high. Direct cell damage by associated monoclonal antibodies is the rare exception. The normal case is the triggering of an immune reaction by the resulting immune complex, which - as in the case of the body's own polyclonal antibodies - activates NK cells , macrophages, lymphocytes and granulocytes to destroy the cells marked in this way. For the treatment of larger solid tumors, monoclonal antibodies are largely unsuitable. In these cases there is a problem with distribution and reach. The ratio of tumor cells with corresponding tumor antigens to monoclonal antibodies is too unfavorable here to mark sufficient tumor cells and to kill them by immune defense cells, which are also insufficient in number. With a molecular mass of around 150  kDa , antibodies are generally restricted in their tissue penetration and can only inadequately penetrate deeper layers in solid tumors. Antibody fragments such as Fab , F (ab) 2 or scFv have considerable advantages here because of their significantly smaller size. However, they are also eliminated from the body much faster. The patient's immune system can produce anti-antibodies against murine and chimeric antibodies . If a therapy cycle is repeated, the effectiveness may therefore be reduced. This is true even for humanized and human antibodies. The immune escape described above also means that not enough antibodies reach the tumor. For example, as a result of the antigen shedding , the tumor cells release tumor antigens and release them into the bloodstream. There they bind to the antibodies and make them ineffective. For some forms of cancer, such as leukemia or non-Hodgkin lymphoma , which do not form tumors, so that the concentration and distribution problem for the monoclonal antibodies does not exist, the best therapeutic results are achieved with monoclonal antibodies. In the case of solid tumors, therapy with the corresponding monoclonal antibodies is usually carried out after surgical removal of the tumor, chemotherapy or radiation in order to destroy individual free tumor cells in the body and thereby prevent the formation of metastases.

Bispecific antibodies

→ see main article on bispecific antibodies

Antibody conjugates

→ see main article immunoconjugate
Schematic representation of the different concepts of the use of antibodies in cancer therapy
Schematic representation of the endocytosis of an immunotoxin in a cancer cell

In order to increase the relatively weak effect of the monoclonal antibodies in cancer diseases, various drug targeting strategies have been developed in order to use the antibodies as carriers for more potent drugs. In this case, the antibody serves as a “transport vehicle” in order to deliver the active substance as specifically as possible only to tumor cells and to kill them in a targeted manner. The healthy tissue should be spared as much as possible, whereby the side effects can be reduced. Radionuclides , toxins (for example diphtheria toxin ), cytostatics or even cytokines (such as interleukin-2 ) are bound (conjugated) to the corresponding antibody as active ingredients . One speaks in these cases of "armed antibodies" (English. Armed antibodies ). In the case of cytokines, one speaks of immune cytokines .

In principle, it is possible to bind highly potent active ingredients to antibodies which, if freely administered systemically, would lead to unacceptable side effects due to their high toxicity. The conjugate of antibodies or antibody fragments with the active ingredient can be viewed as a prodrug which, when administered systemically, has the lowest possible toxicity and only unfolds its full effect at the site of action, the tumor or an individual cancer cell.

The antibody conjugates consist of three components:

  • the antibody or antibody fragment,
  • the active ingredient and
  • the connecting piece ( linker ) between antibody and active ingredient.
→ For detailed information reference is made to the respective main article Chemoimmunkonjugat , immunotoxin and radioimmunotherapy directed

Active cancer immunotherapy

Cancer therapy by blocking inhibiting immune regulators (CTLA4 and PD1)

Active immunotherapy is usually divided into specific and non-specific cancer immunotherapy. In unspecific immunotherapy, the immune system is stimulated in its entirety by the administration of a drug. With specific immunotherapy, only certain target cells of the immune system are stimulated. An example of a promising active immunotherapy is the administration of so-called immune checkpoint inhibitors , such as CTLA-4 blocking antibodies or PD-1 / PD-L1 specific antibodies in melanoma. Both checkpoint inhibitors lead to a targeted activation of the immune system and have achieved promising results in recently published clinical studies.

Slotted snail hemocyanin

→ see main article slotted snail hemocyanin

Keyhole limpet hemocyanin (KLH) is the oxygen transport protein of the large California keyhole limpet ( Megathura crenulata ). The protein of this water snail from the family of keyhole limbs (Fissurellidae), which lives at adepth of 40 m,is based on the copper complex hemocyanin , whichtriggers a strong immune responsein mammals - whose oxygen transport protein hemoglobin is based on an iron complex . It is approved under the international non-proprietary name Immunocyanin (brand name Immucothel ) in the Netherlands , Austria and South Korea , but not in Germany, for redicative prophylaxis in bladder cancer after transurethral resection .

The immune-stimulating effect of hemocyanin in mammals was first established in the mid-1960s. From 1967 onwards, KLH was used in humans for diagnostic purposes in immunocompetence tests. The US urologist Carl A. Olsson also used KLH for immunodiagnostic purposes in patients with superficial bladder cancer. As a result, he noted that the patients who were tested developed significantly fewer relapses than the untested patients.

The immune-stimulating effect of KLH can be explained by the secondary structure of hemocyanin, which is partly similar to that of antibodies, histocompatibility molecules or Bence Jones proteins . There are also epitope-like sequences on the surface of the protein.

KLH is also used as a carrier for haptens . In this case, non-immunogenic epitopes are linked with the immunogenic KLH to form an immunoconjugate in order to achieve an immunogenic effect on the epitope. The molecules of many antigen epitopes are too small to be recognized by the immune system. This method can also be used to present antigens to the immune system as "hostile" that the body would otherwise tolerate. In the case of large carrier molecules such as KLH, several different antigens can also be bound to the surface of the carrier.

Bacillus Calmette-Guérin

Micrograph of the Bacillus Calmette-Guérin (with Ziehl-Neelsen staining )
→ see main article Bacillus Calmette-Guérin

Bacillus Calmette-Guérin (BCG) was obtained from bovine tubercle bacilli at the beginning of the 20th century and used as a live vaccine against tuberculosis . In 1959, mice with transplanted tumors were found for the first time to have a positive effect on tumor regression when infected with BCG. The infection increased the activity of the reticulohistiocytic system and the number of antibodies in the test animals.

With direct injection into tumors, regression of the tumor could be observed in many cases. The treatment attempts for metastatic melanoma were promising , where the systemic administration of BCG also led to a regression of the metastases and the survival rate of the patients treated in this way was significantly increased. However , the positive results could not be confirmed in randomized, controlled studies .

In 1976, positive results in the treatment of superficial bladder cancer with BCG were published for the first time . BCG was injected directly into the urinary bladder (intravesically). The therapeutic efficacy in the treatment of superficial bladder cancer - the tumor is limited to the inner lining of the urinary bladder - has been proven in a large number of clinical studies . BCG therapy is the gold standard for this disease . According to several authors, this is the most successful cancer immunotherapy to date. BCG is clearly superior to any chemotherapeutic agent. The likelihood of tumor recurrence is only half as high compared to intravesical chemotherapy. In over 80% of cases, eradication , i.e. complete elimination of the tumor, is achieved.

The exact mechanism of action of BCG is not yet clear. The bladder is a largely isolated and closed organ in which BCG can reach a very high local concentration and cause a complex, long-lasting local activation of the immune system. As a result of the local activation, various cytokines are released into the urine or to the bladder tissue. At the same time , granulocytes and monocytes infiltrate the bladder wall. Dendritic cells release TNF-α and interleukin-12 (IL-12). The release of these cytokines in turn activates cells of the innate immune system (STIL), which means that IL-12 receptor-expressing NK cells multiply (proliferate).

The most important side effects of therapy with BCG are: cystitis (inflammation of the urinary bladder), pollakiuria (frequent urination), hematuria (blood in the urine) and fever . In studies involving more than 500 patients, no BCG-related death is known.

Adoptive cell transfer

Tumors can also be treated with adoptive cell transfer . For this therapy, for example, autologous T cells (i.e. those derived from the patient himself) are used which have been equipped with a tumor antigen- specific T cell receptor or a chimeric antigen receptor (CAR). This gives the T cells a new specificity directed against the tumor. If the tumor cells present the antigens corresponding to the receptor on their surface, they can be eliminated by the T cells. Therapy with tumor-infiltrating lymphocytes (TILs) or with antigen-laden dendritic cells is also possible. The latter serves to induce an immune response in vivo and activate tumor antigen-specific T cells in the patient's body.

history

A section of the Ebers papyrus (ca.1550 BC)

The idea of ​​influencing the immune system so that it is able to recognize and destroy neoplasms is very old. The first reports of tumor regressions after infectious diseases date back to 1550 BC. In the Ebers papyrus , the recommended treatment for swellings (tumors) was a cataplasm (a kind of pulp containing a mixture of plant powders, seeds and other medicinal substances), followed by an incision in the tumor. Such treatment leads to infection of the tumor.

The first immunological experiments of the modern age were carried out in 1777 by James Nooth , physician to Edward Augustus, Duke of Kent and Strathearn , and member of the Royal Collage of Surgeons . Nooth implanted foreign tumor tissue several times in small incisions in his arm in order to achieve cancer prophylaxis . The implantation only resulted in inflammatory reactions and less pain. A similar result was obtained in 1808 by Jean-Louis Alibert , the personal physician of King Louis XVIII. who had a colleague inject liquid into a breast cancer patient. There was only an inflammatory reaction.

Paul von Bruns (1901)
William Coley with colleagues in 1892

In contrast, the experiments of the American William Coley (1862–1936), who is considered a pioneer of cancer immunotherapy, were much more successful . Coley was a doctor at Memorial Sloan-Kettering Cancer Center in New York City . He had heard of a cancer patient who went into complete remission after a high fever caused by erysipelas ( sore throat , a bacterial infection of the upper layers of the skin and lymphatic system). Coley noted that Robert Koch , Louis Pasteur , Paul von Bruns, and Emil von Behring had also described similar cases after erysipelas. In 1888, for example, Bruns published a summary of his clinical observations on complete sarcoma regressions in spontaneous or artificially induced erysipelas. In 1891 Coley injected a cancer patient - a 40-year-old Italian immigrant who had already had two operations after relapses and only a few weeks to go according to the prognosis - the erysipelas of the species Streptococcus pyogenes directly into the tumor. Coley repeated the injections over several months and the patient's tumor regressed. The patient survived eight years. Coley later used a mixture ( Coley's Toxin ) of killed bacteria of the species Streptococcus pyogenes and Serratia marcescens , together with the still active endotoxins , directly in tumors. With his method, Coley achieved the remarkable cure rate of 10% for soft tissue sarcomas. The response rates varied widely and the side effects were considerable. From 1899 the Parke-Davis Corporation produced Coley’s toxin , which was widely used for the next 30 years. A major reason for its spread was that it was the only systemic cancer therapy until 1934. With the development of radiation therapy and advances in chemotherapy , Coley's toxin was largely forgotten. Parke-Davis ceased production of Coley's toxin in 1952 , and the FDA denied approval as a tested drug in 1962. The exact mechanism of action is still unclear to this day, but is very likely based on the triggering of a cytokine cascade, which results in a specific and unspecific immune response.

Paul Ehrlich around 1900 in his office in Frankfurt

In 1909 Paul Ehrlich was the first to formulate the thesis that the immune system can recognize and eliminate tumor cells. In this way, many tumors would be eliminated at a very early stage and the body would be protected from a significantly higher incidence of malignant tumors.

“I am convinced that aberrant germs occur extremely frequently in the colossally complicated course of fetal and post-fetal development, but that fortunately they remain completely latent in the vast majority of people, thanks to the protective devices of the organism. If this did not exist, one could assume that the carcinoma would occur with an almost monstrous frequency "

- Paul Ehrlich, 1908.

The American biostatistician Raymond Pearl published an autopsy study in 1929 in which he found a significantly lower cancer rate in patients with tuberculosis. When the Lübeck vaccination accident with the Bacillus Calmette-Guérin (BCG) - a vaccine against tuberculosis - occurred the following year, this meant the temporary end of appropriate therapeutic approaches in oncology. It was not until the late 1950s that Lloyd J. Old took up the idea again and successfully introduced BCG into cancer immunotherapy. From 1969 BCG was then used in clinical practice.

Frank Macfarlane Burnet in his laboratory in 1945

Lewis Thomas (1913–1993) and the later Nobel Prize winner Frank Macfarlane Burnet took up Ehrlich's thesis independently of one another in the 1950s and 1970s and formulated the hypothesis of “immune surveillance” ( immunosurveillance ) in tumor development. Both Thomas and Burnet hypothesized that T cells play an essential role in immunological surveillance.

A nude mouse has a very limited immune system due to the lack of a thymus.

The immunological surveillance hypothesis was very controversial for a long time and even seemed to have been refuted by experiments with nude mice in the 1970s. Naked mice, also called athymic mice, have a severely restricted immune system due to the lack of a thymus . According to the thesis of immune surveillance, these mice should develop tumors significantly more frequently than mice of the wild type . In comparative experiments with 3-methylcholanthrene - a strong carcinogen that induces sarcomas in mice - no significant difference in the tumor rate between athymic and normal mice was found. A few years later, however, it was found that, contrary to initial assumptions, nude mice are not completely free of T cells and also have a normal number of NK cells. The NK cells in particular can become active against tumor cells on their own.

The definitive evidence of immune surveillance was provided in 2001 by Vijay Shankaran and colleagues. Knockout mice in which the RAG2 and STAT1 genes were switched off had a significantly increased incidence of spontaneous or chemically induced tumor formation. The gene products of RAG2 and STAT1 play an important role in the maturation of T and B cells and in signal transmission after binding to the γ-interferon receptor.

Pierre van der Bruggen and colleagues identified in 1991 at the Ludwig Institute for Cancer Research in Brussels with MAGEA1 ( melanoma antigen family A, 1 ) the first time an epitope malignant origin, which is recognized by T cells. As a result, more than 70 other tumor-associated antigens with immunogenic properties were found , including with cDNA expression cloning .

In March 2015, the two American immunotherapists James P. Allison and Carl H. June were awarded the € 100,000 Paul Ehrlich and Ludwig Darmstaedter Prize for their groundbreaking work on cancer immunotherapy . James Allison pioneered checkpoint inhibition for the treatment of advanced melanoma , while Carl June developed the CART-19 therapy for leukemia .

literature

Individual evidence

  1. ↑ a b S. Lang: Recombinant Parvoviruses in the gene therapy of cancer: vector characterization and analysis of the effectiveness. Dissertation, Ruprecht-Karls-Universität Heidelberg, 2003.
  2. ↑ a b F. O. Losch: Activation of T lymphocytes by melanoma-specific variant antigen receptors. Dissertation, Albert-Ludwigs-Universität Freiburg, 2001
  3. ↑ Tumor Immunology. ( Memento of the original from March 22, 2005 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 1.9 MB) Institute for Immunology at the University of Kiel @1@ 2Template: Webachiv / IABot / www.uni-kiel.de
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