Cancer immunotherapy

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cancer_immunotherapy

 

Cancer immunotherapy
Peptide epitope of CD20 bound to rituximab's FAB

Cancer immunotherapy (sometimes called immuno-oncology) is the artificial stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspeciality of oncology. It exploits the fact that cancer cells often have tumor antigens, molecules on their surface that can be detected by the antibody proteins of the immune system, binding to them. The tumor antigens are often proteins or other macromolecules (e.g. carbohydrates). 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. In 2018, James P. Allison and Tasuku Honjo received the Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation.

Categories

Immunotherapies can be categorized as active, passive or hybrid (active and passive). Active immunotherapy directs the immune system to attack tumor cells by targeting tumor antigens. Passive immunotherapies enhance existing anti-tumor responses and include the use of monoclonal antibodies, lymphocytes and cytokines.

A wide range of cancers can be treated by various immunotherapy medicines that have been approved in many jurisdictions around the world.

Passive antibody therapies commonly involve the targeting of Cell surface receptors and include CD20, CD274 and CD279 antibodies. Once bound to a cancer antigen, the modified antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, or prevent a receptor from interacting with its ligand, all of which can lead to cell death. Apart from classical immunomodulatory receptors, cell surface proteoglycans are an emerging class of targets for cancer immunotherapy. 

Approved immunotherapy antibodies include alemtuzumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab and rituximab.

Active cellular therapies usually involve the removal of immune cells from the blood or from a tumor. Those specific for the tumor are grown in culture and returned to the patient where they attack the tumor; alternatively, immune cells can be genetically engineered to express a tumor-specific receptor, cultured and returned to the patient. Cell types that can be used in this way are natural killer (NK) cells, lymphokine-activated killer cells, cytotoxic T cells and dendritic cells. 

Cellular immunotherapy

Dendritic cell therapy

Blood cells are removed from the body, incubated with tumour antigen(s) and activated. Mature dendritic cells are then returned to the original cancer-bearing donor to induce an immune response.

 

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 (APCs) 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 (small parts of protein that correspond to the protein antigens on cancer cells). These peptides are often given in combination with adjuvants (highly immunogenic substances) 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 (GM-CSF). The most common source of antigens used for dendritic cell vaccine in Glioblastoma (GBM) 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 (a solution of broken down tumor cells). These cells (with optional adjuvants) 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.

Approved drugs

Sipuleucel-T (Provenge) 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 (PAP) and reinfused. This process is repeated three times.

CAR-T cell therapy

The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to more effectively target and destroy them. Scientists harvest T cells from people, genetically alter them to add a chimeric antigen receptor (CAR) that specifically recognizes cancer cells, then infuse the resulting CAR-T cells into patients to attack their tumors. 

Approved drugs

Tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR-T) therapy, was approved by FDA in 2017 to treat acute lymphoblastic leukemia (ALL). This treatment removes CD19 positive cells (B-cells) from the body (including the diseased cells, but also normal antibody producing cells). 

Axicabtagene ciloleucel (Yescarta) is another CAR-T therapeutic, approved in 2017 for treatment of diffuse large B-cell lymphoma (DLBCL).

Antibody therapy

Many forms of antibodies can be engineered.

Antibodies are a key component of the adaptive immune response, playing a central role in both recognizing foreign antigens and stimulating an immune response. Antibodies are Y-shaped proteins produced by some B cells and are composed of two regions: an antigen-binding fragment (Fab), which binds to antigens, and a Fragment crystallizable (Fc) region, which interacts with so-called Fc receptors that are expressed on the surface of different immune cell types including macrophages, neutrophils and NK cells. Many immunotherapeutic regimens involve antibodies. Monoclonal antibody technology engineers and generates antibodies against specific antigens, such as those present on tumor surfaces. These antibodies that are specific to the antigens of the tumor, can then be injected into a tumor. 

Antibody types

Conjugation

Two types are used in cancer treatments:

• Naked monoclonal antibodies are antibodies without added elements. Most antibody therapies use this antibody type.
• Conjugated monoclonal antibodies are joined to another molecule, which is either cytotoxic or radioactive. The toxic chemicals are those typically used as chemotherapy drugs, but other toxins can be used. The antibody binds to specific antigens on cancer cell surfaces, directing the therapy to the tumor. Radioactive compound-linked antibodies are referred to as radiolabelled. Chemolabelled or immunotoxins antibodies are tagged with chemotherapeutic molecules or toxins, respectively. Research has also demonstrated conjugation of a TLR agonist to an anti-tumor monoclonal antibody.

Fc regions

Fc's ability to bind Fc receptors is important because it allows antibodies to activate the immune system. Fc regions are varied: they exist in numerous subtypes and can be further modified, for example with the addition of sugars in a process called glycosylation. Changes in the Fc region can alter an antibody's ability to engage Fc receptors and, by extension, will determine the type of immune response that the antibody triggers. Many cancer immunotherapy drugs, including PD-1 and PD-L1 inhibitors, are antibodies. For example, immune checkpoint blockers targeting PD-1 are antibodies designed to bind PD-1 expressed by T cells and reactivate these cells to eliminate tumors. Anti-PD-1 drugs contain not only an Fab region that binds PD-1 but also an Fc region. Experimental work indicates that the Fc portion of cancer immunotherapy drugs can affect the outcome of treatment. For example, anti-PD-1 drugs with Fc regions that bind inhibitory Fc receptors can have decreased therapeutic efficacy. Imaging studies have further shown that the Fc region of anti-PD-1 drugs can bind Fc receptors expressed by tumor-associated macrophages. This process removes the drugs from their intended targets (i.e. PD-1 molecules expressed on the surface of T cells) and limits therapeutic efficacy. Furthermore, antibodies targeting the co-stimulatory protein CD40 require engagement with selective Fc receptors for optimal therapeutic efficacy. Together, these studies underscore the importance of Fc status in antibody-based immune checkpoint targeting strategies.

Human/non-human balance

Antibodies may also referred to as murine, chimeric, humanized or human. Murine antibodies are from mice and carry a risk of immune reaction. Chimeric antibodies attempt to reduce murine antibodies' immunogenicity by replacing part of the antibody with the corresponding human counterpart, known as the constant region. Humanized antibodies are almost completely human; only the complementarity determining regions of the variable regions are derived from murine sources. Human antibodies have been produced using unmodified human DNA.

Antibody-dependent cell-mediated cytotoxicity. When the Fc receptors on natural killer (NK) cells interact with Fc regions of antibodies bound to cancer cells, the NK cell releases perforin and granzyme, leading to cancer cell apoptosis.

 

Cell death mechanisms

Antibody-dependent cell-mediated cytotoxicity (ADCC)

Antibody-dependent cell-mediated cytotoxicity (ADCC) requires antibodies to bind to target cell surfaces. Antibodies are formed of a binding region (Fab) and the Fc region that can be detected by immune system cells via their Fc surface receptors. Fc receptors are found on many immune system cells, including NK cells. When NK cells encounter antibody-coated cells, the latter's Fc regions interact with their Fc receptors, releasing perforin and granzyme B to kill the tumor cell. Examples include Rituximab, Ofatumumab, Elotuzumab, and Alemtuzumab. Antibodies under development have altered Fc regions that have higher affinity for a specific type of Fc receptor, FcγRIIIA, which can dramatically increase effectiveness.

Complement

The complement system includes blood proteins that can cause cell death after an antibody binds to the cell surface (the classical complement pathway, among the ways of complement activation). Generally the system deals with foreign pathogens, but can be activated with therapeutic antibodies in cancer. The system can be triggered if the antibody is chimeric, humanized or human; as long as it contains the IgG1 Fc region. Complement can lead to cell death by activation of the membrane attack complex, known as complement-dependent cytotoxicity; enhancement of antibody-dependent cell-mediated cytotoxicity; and CR3-dependent cellular cytotoxicity. Complement-dependent cytotoxicity occurs when antibodies bind to the cancer cell surface, the C1 complex binds to these antibodies and subsequently protein pores are formed in the cancer cell membrane.

FDA-approved antibodies

Cancer immunotherapy:Monoclonal antibodies

Antibody	Brand name	Type	Target	Approval date	Approved treatment(s)
Alemtuzumab	Campath	humanized	CD52	2001	B-cell chronic lymphocytic leukemia (CLL)
Atezolizumab	Tecentriq	humanized	PD-L1	2016	bladder cancer
Avelumab	Bavencio	human	PD-L1	2017	metastatic Merkel cell carcinoma
Ipilimumab	Yervoy	human	CTLA4	2011	metastatic melanoma
Elotuzumab	Empliciti	humanized	SLAMF7	2015	Multiple myeloma
Ofatumumab	Arzerra	human	CD20	2009	refractory CLL
Nivolumab	Opdivo	human	PD-1	2014	unresectable or metastatic melanoma, squamous non-small cell lung cancer, Renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, classical hodgkin lymphoma
Pembrolizumab	Keytruda	humanized	PD-1	2014	unresectable or metastatic melanoma, squamous non-small cell lung cancer (NSCLC) , Hodgkin's lymphoma, Merkel-cell carcinoma (MCC), primary mediastinal B-cell lymphoma (PMBCL), stomach cancer, cervical cancer
Rituximab	Rituxan, Mabthera	chimeric	CD20	1997	non-Hodgkin lymphoma
Durvalumab	Imfinzi	human	PD-L1	2017	bladder cancer non-small cell lung cancer

Alemtuzumab

Alemtuzumab (Campath-1H) is an anti-CD52 humanized IgG1 monoclonal antibody indicated for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, peripheral T-cell lymphoma and T-cell prolymphocytic leukemia. CD52 is found on >95% of peripheral blood lymphocytes (both T-cells and B-cells) and monocytes, but its function in lymphocytes is unknown. It binds to CD52 and initiates its cytotoxic effect by complement fixation and ADCC mechanisms. Due to the antibody target (cells of the immune system) common complications of alemtuzumab therapy are infection, toxicity and myelosuppression.

Durvalumab

Durvalumab (Imfinzi) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules. Durvalumab is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

• have disease progression during or following platinum-containing chemotherapy.
• have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

On 16 February 2018, the Food and Drug Administration approved durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. 

Ipilimumab

Ipilimumab (Yervoy) is a human IgG1 antibody that binds the surface protein CTLA4. In normal physiology T-cells are activated by two signals: the T-cell receptor binding to an antigen-MHC complex and T-cell surface receptor CD28 binding to CD80 or CD86 proteins. CTLA4 binds to CD80 or CD86, preventing the binding of CD28 to these surface proteins and therefore negatively regulates the activation of T-cells.

Active cytotoxic T-cells are required for the immune system to attack melanoma cells. Normally inhibited active melanoma-specific cytotoxic T-cells can produce an effective anti-tumor response. Ipilumumab can cause a shift in the ratio of regulatory T-cells to cytotoxic T-cells to increase the anti-tumor response. Regulatory T-cells inhibit other T-cells, which may benefit the tumor.

Nivolumab

Ofatumumab

Ofatumumab is a second generation human IgG1 antibody that binds to CD20. It is used in the treatment of chronic lymphocytic leukemia (CLL) because the cancerous cells of CLL are usually CD20-expressing B-cells. Unlike rituximab, which binds to a large loop of the CD20 protein, ofatumumab binds to a separate, small loop. This may explain their different characteristics. Compared to rituximab, ofatumumab induces complement-dependent cytotoxicity at a lower dose with less immunogenicity.

Pembrolizumab

As of 2019, pembrolizumab, which blocks PD-1, programmed cell death protein 1, has been used via intravenous infusion to treat inoperable or metastatic melanoma, metastatic non-small cell lung cancer (NSCLC) in certain situations, as a second-line treatment for head and neck squamous cell carcinoma (HNSCC), after platinum-based chemotherapy, and for the treatment of adult and pediatric patients with refractory classic Hodgkin's lymphoma (cHL). It is also indicated for certain patients with urothelial carcinoma, stomach cancer and cervical cancer.

Rituximab

Rituximab is a chimeric monoclonal IgG1 antibody specific for CD20, developed from its parent antibody Ibritumomab. As with ibritumomab, rituximab targets CD20, making it effective in treating certain B-cell malignancies. These include aggressive and indolent lymphomas such as diffuse large B-cell lymphoma and follicular lymphoma and leukemias such as B-cell chronic lymphocytic leukemia. Although the function of CD20 is relatively unknown, CD20 may be a calcium channel involved in B-cell activation. The antibody's mode of action is primarily through the induction of ADCC and complement-mediated cytotoxicity. Other mechanisms include apoptosis and cellular growth arrest. Rituximab also increases the sensitivity of cancerous B-cells to chemotherapy.

Cytokine therapy

Cytokines are proteins produced by many types of cells present within a tumor. They can modulate immune responses. The tumor often employs them to allow it to grow and reduce the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response. Two commonly used cytokines are interferons and interleukins.

Interleukin-2 and interferon-α are cytokines, proteins that regulate and coordinate the behavior of the immune system. They have the ability to enhance anti-tumor activity and thus can be used as passive cancer treatments. Interferon-α is used in the treatment of hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and malignant melanoma. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma.

Interferon

Interferons are produced by the immune system. They are usually involved in anti-viral response, but also have use for cancer. They fall in three groups: type I (IFNα and IFNβ), type II (IFNγ) and type III (IFNλ). IFNα has been approved for use in hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and melanoma. Type I and II IFNs have been researched extensively and although both types promote anti-tumor immune system effects, only type I IFNs have been shown to be clinically effective. IFNλ shows promise for its anti-tumor effects in animal models.

Unlike type I IFNs, Interferon gamma is not approved yet for the treatment of any cancer. However, improved survival was observed when Interferon gamma was administrated to patients with bladder carcinoma and melanoma cancers. The most promising result was achieved in patients with stage 2 and 3 of ovarian carcinoma. The in vitro study of IFN-gamma in cancer cells is more extensive and results indicate anti-proliferative activity of IFN-gamma leading to the growth inhibition or cell death, generally induced by apoptosis but sometimes by autophagy.

Interleukin

Interleukins have an array of immune system effects. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. In normal physiology it promotes both effector T cells and T-regulatory cells, but its exact mechanism of action is unknown.

Combination immunotherapy

Combining various immunotherapies such as PD1 and CTLA4 inhibitors can enhance anti-tumor response leading to durable responses.

Combining ablation therapy of tumors with immunotherapy enhances the immunostimulating response and has synergistic effects for curative metastatic cancer treatment.

Combining checkpoint immunotherapies with pharmaceutical agents has the potential to improve response, and such combination therapies are a highly investigated area of clinical investigation. Immunostimulatory drugs such as CSF-1R inhibitors and TLR agonists have been particularly effective in this setting.

Polysaccharide-K

Japan's Ministry of Health, Labour and Welfare approved the use of polysaccharide-K extracted from the mushroom, Coriolus versicolor, in the 1980s, to stimulate the immune systems of patients undergoing chemotherapy. It is a dietary supplement in the US and other jurisdictions.

Genetic pre-testing for therapeutic significance

Because of the high cost of many of the immunotherapy medications and the reluctance of medical insurance companies to prepay for their prescriptions various test methods have been proposed, to attempt to forecast the effectiveness of these medications. The detection of PD-L1 protein seemed to be an indication of cancer susceptible to several immunotherapy medications, but research found that both the lack of this protein or its inclusion in the cancerous tissue was inconclusive, due to the little-understood varying quantities of the protein during different times and locations within the infected cells and tissue.

In 2018 some genetic indications such as Tumor Mutational Burden (TMB, the number of mutations within a targeted genetic region in the cancerous cell's DNA), and Microsatellite instability (MSI, the quantity of impaired DNA mismatch leading to probable mutations), have been approved by the FDA as good indicators for the probability of effective treatment of immunotherapy medication for certain cancers, but research is still in progress.

In some cases the FDA has approved genetic tests for medication that is specific to certain genetic markers. For example, the FDA approved BRAF associated medication for metastatic melanoma, to be administered to patients after testing for the BRAF genetic mutation.

Tests of this sort are being widely advertised for general cancer treatment and are expensive. In the past, some genetic testing for cancer treatment has been involved in scams such as the Duke University Cancer Fraud scandal, or claimed to be hoaxes.

Research

Adoptive T-cell therapy

Cancer specific T-cells can be obtained by fragmentation and isolation of tumour infiltrating lymphocytes, or by genetically engineering cells from peripheral blood. The cells are activated and grown prior to transfusion into the recipient (tumor bearer).

 

Adoptive T cell therapy is a form of passive immunization by the transfusion of T-cells (adoptive cell transfer). They are found in blood and tissue and usually activate when they find foreign pathogens. Specifically they activate when the T-cell's surface receptors encounter cells that display parts of foreign proteins on their surface antigens. These can be either infected cells, or Antigen-presenting cells (APCs). They are found in normal tissue and in tumor tissue, where they are known as tumor infiltrating lymphocytes (TILs). They are activated by the presence of APCs such as dendritic cells that present tumor antigens. Although these cells can attack the tumor, the environment within the tumor is highly immunosuppressive, preventing immune-mediated tumour death.

Multiple ways of producing and obtaining tumour targeted T-cells have been developed. T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. Subsequent activation and culturing is performed ex vivo, with the results reinfused. Activation can take place through gene therapy, or by exposing the T cells to tumor antigens. 

As of 2014, multiple ACT clinical trials were underway. Importantly, one study from 2018 showed that clinical responses can be obtained in patients with metastatic melanoma resistant to multiple previous immunotherapies.

The first 2 adoptive T-cell therapies, tisagenlecleucel and axicabtagene ciloleucel, were approved by the FDA in 2017.

Another approach is adoptive transfer of haploidentical γδ T cells or NK cells from a healthy donor. The major advantage of this approach is that these cells do not cause GVHD. The disadvantage is frequently impaired function of the transferred cells.

Anti-CD47 therapy

Many tumor cells overexpress CD47 to escape immunosurveilance of host immune system. CD47 binds to its receptor signal regulatory protein alpha (SIRPα) and downregulate phagocytosis of tumor cell. Therefore, anti-CD47 therapy aims to restore clearance of tumor cells. Additionally, growing evidence supports the employment of tumor antigen-specific T cell response in response to anti-CD47 therapy. A number of therapeutics is being developed, including anti-CD47 antibodies, engineered decoy receptors, anti-SIRPα antibodies and bispecific agents. As of 2017, wide range of solid and hematologic malignancies were being clinically tested.

Anti-GD2 antibodies

The GD2 ganglioside

Carbohydrate antigens on the surface of cells can be used as targets for immunotherapy. GD2 is a ganglioside found on the surface of many types of cancer cell including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas. It is not usually expressed on the surface of normal tissues, making it a good target for immunotherapy. As of 2014, clinical trials were underway.

Immune checkpoints

Cancer therapy by inhibition of negative immune regulation (CTLA4, PD1)

Immune checkpoints affect immune system function. Immune checkpoints can be stimulatory or inhibitory. Tumors can use these checkpoints to protect themselves from immune system attacks. Currently approved checkpoint therapies block inhibitory checkpoint receptors. Blockade of negative feedback signaling to immune cells thus results in an enhanced immune response against tumors.

One ligand-receptor interaction under investigation is the interaction between the transmembrane programmed cell death 1 protein (PDCD1, PD-1; also known as CD279) and its ligand, PD-1 ligand 1 (PD-L1, CD274). PD-L1 on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T cell activities. It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack. PD-L1 on cancer cells also inhibits FAS- and interferon-dependent apoptosis, protecting cells from cytotoxic molecules produced by T cells. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor.

CTLA-4 blockade

The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 for treatment of melanoma. It blocks the immune checkpoint molecule CTLA-4. Clinical trials have also shown some benefits of anti-CTLA-4 therapy on lung cancer or pancreatic cancer, specifically in combination with other drugs. In on-going trials the combination of CTLA-4 blockade with PD-1 or PD-L1 inhibitors is tested on different types of cancer.

However, patients treated with check-point blockade (specifically CTLA-4 blocking antibodies), or a combination of check-point blocking antibodies, are at high risk of suffering from immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions. These are most likely due to the breadth of the induced T-cell activation when anti-CTLA-4 antibodies are administered by injection in the blood stream.

Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood. At the same time the levels of circulating antibodies were lower, suggesting that local administration of the anti-CTLA-4 therapy might result in fewer adverse events.

PD-1 inhibitors

Initial clinical trial results with IgG4 PD1 antibody Nivolumab were published in 2010. It was approved in 2014. Nivolumab is approved to treat melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin's lymphoma. A 2016 clinical trial for non-small cell lung cancer failed to meet its primary endpoint for treatment in the first line setting, but is FDA approved in subsequent lines of therapy.

Pembrolizumab is another PD1 inhibitor that was approved by the FDA in 2014. Keytruda (Pembrolizumab) is approved to treat melanoma and lung cancer.

Antibody BGB-A317 is a PD-1 inhibitor (designed to not bind Fc gamma receptor I) in early clinical trials.

PD-L1 inhibitors

In May 2016, PD-L1 inhibitor atezolizumab was approved for treating bladder cancer. 

Anti-PD-L1 antibodies currently in development include avelumab and durvalumab, in addition to an affimer biotherapeutic.

Other

Other modes of enhancing [adoptive] immuno-therapy include targeting so-called intrinsic checkpoint blockades e.g. CISH. A number of cancer patients do not respond to immune checkpoint blockade. Response rate may be improved by combining immune checkpoint blockade with additional rationally selected anticancer therapies (out of which some may stimulate T cell infiltration into tumors). For example, targeted therapies such, radiotherapy, vasculature targeting agents, and immunogenic chemotherapy can improve immune checkpoint blockade response in animal models of cancer. 

Oncolytic virus

An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune responses for long-term immunotherapy.

The potential of viruses as anti-cancer agents was first realized in the early twentieth century, although coordinated research efforts did not begin until the 1960s. A number of viruses including adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia have now been clinically tested as oncolytic agents. T-Vec is the first FDA-approved oncolytic virus for the treatment of melanoma. A number of other oncolytic viruses are in Phase II-III development.

Polysaccharides

Certain compounds found in mushrooms, primarily polysaccharides, can up-regulate the immune system and may have anti-cancer properties. For example, beta-glucans such as lentinan have been shown in laboratory studies to stimulate macrophage, NK cells, T cells and immune system cytokines and have been investigated in clinical trials as immunologic adjuvants.

Neoantigens

Many tumors express mutations. These mutations potentially create new targetable antigens (neoantigens) for use in T cell immunotherapy. The presence of CD8+ T cells in cancer lesions, as identified using RNA sequencing data, is higher in tumors with a high mutational burden. The level of transcripts associated with cytolytic activity of natural killer cells and T cells positively correlates with mutational load in many human tumors. In non–small cell lung cancer patients treated with lambrolizumab, mutational load shows a strong correlation with clinical response. In melanoma patients treated with ipilimumab, long-term benefit is also associated with a higher mutational load, although less significantly. The predicted MHC binding neoantigens in patients with a long-term clinical benefit were enriched for a series of tetrapeptide motifs that were not found in tumors of patients with no or minimal clinical benefit. However, human neoantigens identified in other studies do not show the bias toward tetrapeptide signatures.

Phenomenalism

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Phenomenalism

Phenomenalism is the view that physical objects cannot justifiably be said to exist in themselves, but only as perceptual phenomena or sensory stimuli (e.g. redness, hardness, softness, sweetness, etc.) situated in time and in space. In particular, some forms of phenomenalism reduce talk about physical objects in the external world to talk about bundles of sense-data.

History

Phenomenalism is a radical form of empiricism. Its roots as an ontological view of the nature of existence can be traced back to George Berkeley and his subjective idealism, upon which David Hume further elaborated. John Stuart Mill had a theory of perception which is commonly referred to as classical phenomenalism. This differs from Berkeley's idealism in its account of how objects continue to exist when no one is perceiving them (this view is also known as "local realism"). Berkeley claimed that an omniscient God perceived all objects and that this was what kept them in existence, whereas Mill claimed that permanent possibilities of experience were sufficient for an object's existence. These permanent possibilities could be analysed into counterfactual conditionals, such as "if I were to have y-type sensations, then I would also have x-type sensations".

As an epistemological theory about the possibility of knowledge of objects in the external world, however, it is probable that the most easily understandable formulation of phenomenalism is to be found in the transcendental aesthetics of Immanuel Kant. According to Kant, space and time, which are the a priori forms and preconditions of all sensory experience, "refer to objects only to the extent that these are considered as phenomena, but do not represent the things in themselves". While Kant insisted that knowledge is limited to phenomena, he never denied or excluded the existence of objects which were not knowable by way of experience, the things-in-themselves or noumena, though he never proved them.

Kant's "epistemological phenomenalism", as it has been called, is therefore quite distinct from Berkeley's earlier ontological version. In Berkeley's view, the so-called "things-in-themselves" do not exist except as subjectively perceived bundles of sensations which are guaranteed consistency and permanence because they are constantly perceived by the mind of God. Hence, while Berkeley holds that objects are merely bundles of sensations (see bundle theory), Kant holds (unlike other bundle theorists) that objects do not cease to exist when they are no longer perceived by some merely human subject or mind. 

In the late 19th century, an even more extreme form of phenomenalism was formulated by Ernst Mach, later developed and refined by Russell, Ayer and the logical positivists. Mach rejected the existence of God and also denied that phenomena were data experienced by the mind or consciousness of subjects. Instead, Mach held sensory phenomena to be "pure data" whose existence was to be considered anterior to any arbitrary distinction between mental and physical categories of phenomena. In this way, it was Mach who formulated the key thesis of phenomenalism, which separates it from bundle theories of objects: objects are logical constructions out of sense-data or ideas; whereas according to bundle theories, objects are made up of sets, or bundles, of actual ideas or perceptions. 

That is, according to bundle theory, to say that the pear before me exists is simply to say that certain properties (greenness, hardness, etc.) are being perceived at this moment. When these characteristics are no longer perceived or experienced by anyone, then the object (pear, in this case) no longer exists. Phenomenalism as formulated by Mach, in contrast, is the view that objects are logical constructions out of perceptual properties. On this view, to say there is a table in the other room when there is no one in that room to perceive it, is to say that if there were someone in that room, then that person would perceive the table. It is not the actual perception that counts, but the conditional possibility of perceiving.

Logical positivism, a movement begun as a small circle which grew around the philosopher Moritz Schlick in Vienna, inspired many philosophers in the English speaking world from the 1930s through the 1950s. Important influences on their brand of empiricism included Ernst Mach — himself holding the Chair of Inductive Sciences at the University of Vienna, a position Schlick would later hold — and the Cambridge philosopher Bertrand Russell. The idea of the logical positivists, such as A.J. Ayer and Rudolf Carnap, was to formulate the doctrine of phenomenalism in linguistic terms, so as to define out of existence references to such entities as physical objects in the external world. Sentences which contained terms such as "table" were to be translated into sentences which referred exclusively to either actual or possible sensory experiences.

20th century American philosopher Arthur Danto asserted that "a phenomenalist, believ[es] that whatever is finally meaningful can be expressed in terms of our own [sense] experience.". He claimed that "The phenomenalist really is committed to the most radical kind of empiricism: For him reference to objects is always finally a reference to sense-experience ... ."

To the phenomenalist, objects of any kind must be related to experience. "John Stuart Mill once spoke of physical objects as but the 'permanent possibility of experience' and this, by and large, is what the phenomenalist exploits: All we can mean, in talking about physical objects — or nonphysical objects, if there are any — is what experiences we would have in dealing with them ... ." However, phenomenalism is based on mental operations. These operations, themselves, are not known from sense experience. Such non-empirical, non-sensual operations are the "...nonempirical matters of space, time, and continuity that empiricism in all its forms and despite its structures seems to require ... ."

See for comparison Sensualism, to which phenomenalism is closely related.

Criticisms

Roderick Chisholm criticized the logical positivist version of phenomenalism in 1948. C.I. Lewis had previously suggested that the physical claim "There is a doorknob in front of me" necessarily entails the sensory conditional "If I should seem to see a doorknob and if I should seem to myself to be initiating a grasping motion, then in all probability the sensation of contacting a doorknob should follow". Chisholm objected that the statement "There is a doorknob..." does not entail the counterfactual statement, for if it were to do so, then it must do so without regard to the truth or falsity of any other statement; but suppose the following statement was true: "I am paralyzed from the neck down and experience hallucinations such that I seem to see myself moving toward the door". If this were true, Chisholm objected, then there could be a doorknob in front of me, I could seem to myself to see a doorknob, and I could seem to myself to be performing the correct sort of grasping motion, but with absolutely no chance of having a sensation of contacting the doorknob. Likewise, he objected that the statement that "The only book in front of me is red" does not entail the sensory statement "Redness would probably appear to me were I to seem to myself to see a book", because redness is not likely to appear under a blue light-bulb. Some have tried to avoid this problem by extending the conditions in the analysandum: instead of "There is a doorknob in front of me" one could have it that "There is a doorknob, and I am not paralyzed, etc." In response, Chisholm objects that if one complicates the analysandum, one must also complicate the analysans; in this particular case, that one must analyse in purely sensory terms what it means not to be paralyzed and so on, with respect to which the same problems would arise leading to an infinite regress. 

Another common objection to phenomenalism is that in the process of eliminating material objects from language and replacing them with hypothetical propositions about observers and experiences, it seems to commit us to the existence of a new class of ontological object altogether: the sensibilia or sense-data which can exist independently of experience. Indeed, sense-data have been dismissed by some philosophers of mind, such as Donald Davidson, as mythological entities that are more troublesome than the entities that they were intended to replace.

A third common objection in the literature is that phenomenalism, in attempting to convert propositions about material objects into hypothetical propositions about sensibilia, postulates the existence of an irreducibly material observer in the antecedent of the conditional. In attempting to overcome this, some phenomenalists suggested that the first observer could be reduced by constructing a second proposition in terms of a second observer, who actually or potentially observes the body of the first observer. A third observer would observe the second and so on. In this manner we would end up with a "Chinese box series of propositions" of ever decreasing material content ascribed to the original observer. But if the final result is not the complete elimination of the materiality of the first observer, then the translational reductions that are proposed by phenomenalists cannot, even in principle, be carried out.

Another criticism is that the phenomenalist can give no satisfactory explanation of the permanent possibilities of experience. The question can be asked, "What are the counterfactual conditionals which ground the existence of objects true in virtue of?" One answer given by phenomenalists is that the conditionals are true in virtue of past regularities of experience. However, critics object that this answer leads to circularity: first our actual experience was meant to be explained by the possibility of experience, and now the possibility of experience is meant to be explained by our actual past experience. A further objection to the phenomenalist answer is that generally speaking, conditionals are not true in virtue of their past occurrences. This is because it seems that a conditional could be true even if it never actually obtained, and also past occurrences only confirm that a conditional is true, but never make it so.

Roderick Firth formulated another objection in 1950, stemming from perceptual relativity: White wallpaper looks white under white light and red under red light, etc. Any possible course of experience resulting from a possible course of action will apparently underdetermine our surroundings: it would determine, for example, that there is either white wallpaper under red light or red wallpaper under white light, and so on. On what basis are we to decide which of the hypotheses is the correct one if we are constrained to rely exclusively on sensibilia?

Notable proponents

• Johannes Nikolaus Tetens
• John Foster (phenomenalistic idealist)

Sadomasochism

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Sadomasochism

This article is about the general historical concept of sadomasochism. For consenting partners engaging in sexual play behavior, see BDSM. For the medical condition involving unwilling victims, see Sexual sadism disorder. For the medical condition where pain or humiliation is required for sexual arousal and causes distress or impairment, see Sexual masochism disorder.

Joe Shuster (1950s), co-creator of Superman, from Nights of Horror

 

A male dominant whipping a female submissive while another woman watches (Paris, 1930)

Sadomasochism (/ˌseɪdoʊˈmæsəkɪzəm/ SAY-doh-MASS-ə-kiz-əm) is the giving or receiving of pleasure from acts involving the receipt or infliction of pain or humiliation. Practitioners of sadomasochism may seek sexual gratification from their acts. While the terms sadist and masochist refer respectively to one who enjoys giving and receiving pain, practitioners of sadomasochism may switch between activity and passivity. 

The word sadomasochism is a portmanteau of the words sadism (/ˈseɪdɪzəm/) and masochism. The abbreviation S&M is often used for Sadomasochism (or Sadism & Masochism), although practitioners themselves normally remove the ampersand and use the acronym S-M or SM or S/M when written throughout the literature. Sadomasochism is not considered a clinical paraphilia unless such practices lead to clinically significant distress or impairment for a diagnosis. Similarly, sexual sadism within the context of mutual consent, generally known under the heading BDSM, is distinguished from non-consensual acts of sexual violence or aggression.

Definition and etymology

Portrait of Marquis de Sade by Charles-Amédée-Philippe van Loo (1761)

 

The term sadomasochism is used in a variety of different ways. It can refer to cruel individuals or those who brought misfortunes onto themselves and psychiatrists define it as pathological. However, recent research suggests that sadomasochism is mostly simply a sexual interest, and not a pathological symptom of past abuse, or a sexual problem, and that people with sadomasochistic sexual interest are in general neither damaged nor dangerous.

The two words incorporated into this compound, "sadism" and "masochism", were originally derived from the names of two authors. The term "Sadism" has its origin in the name of the Marquis de Sade (1740–1814), who not only practiced sexual sadism, but also wrote novels about these practices, of which the best known is Justine. "Masochism" is named after Leopold von Sacher-Masoch, who wrote novels expressing his masochistic fantasies. These terms were first selected for identifying human behavioural phenomena and for the classification of psychological illnesses or deviant behaviour. The German psychiatrist Richard von Krafft-Ebing introduced the terms "Sadism" and "Masochism"' into medical terminology in his work Neue Forschungen auf dem Gebiet der Psychopathia sexualis ("New research in the area of Psychopathology of Sex") in 1890.

In 1905, Sigmund Freud described sadism and masochism in his Drei Abhandlungen zur Sexualtheorie ("Three papers on Sexual Theory") as stemming from aberrant psychological development from early childhood. He also laid the groundwork for the widely accepted medical perspective on the subject in the following decades. This led to the first compound usage of the terminology in Sado-Masochism (Loureiroian "Sado-Masochismus") by the Viennese Psychoanalyst Isidor Isaak Sadger in his work Über den sado-masochistischen Komplex ("Regarding the sadomasochistic complex") in 1913.

In the later 20th century, BDSM activists have protested against these ideas, because, they argue, they are based on the philosophies of the two psychiatrists, Freud and Krafft-Ebing, whose theories were built on the assumption of psychopathology and their observations of psychiatric patients. The DSM nomenclature referring to sexual psychopathology has been criticized as lacking scientific veracity, and advocates of sadomasochism have sought to separate themselves from psychiatric theory by the adoption of the term BDSM instead of the common psychological abbreviation, "S&M".^{[citation needed]} However, the term BDSM also includes B&D (bondage and discipline), D/s (dominance and submission), and S&M (sadism and masochism). The terms bondage and discipline usually refer to the use of either physical or psychological restraint or punishment, and sometimes involves sexual role playing, including the use of costumes.

Autosadism is inflicting of pain or humiliation on oneself. The photo shows pornographic actress Felicia Fox pouring hot wax over herself in front of an audience (U.S. 2005). Her nipples and genitals are also clamped.

 

In contrast to frameworks seeking to explain sadomasochism through psychological, psychoanalytic, medical or forensic approaches, which seek to categorize behavior and desires, and find a root cause, Romana Byrne suggests that such practices can be seen as examples of "aesthetic sexuality", in which a founding physiological or psychological impulse is irrelevant. Rather, according to Byrne, sadism and masochism may be practiced through choice and deliberation, driven by certain aesthetic goals tied to style, pleasure, and identity, which in certain circumstances, she claims can be compared with the creation of art.

Psychology

Historical perspective

Both terms were introduced to the medical field by German psychiatrist Richard von Krafft-Ebing in his 1886 compilation of case studies Psychopathia Sexualis. Pain and physical violence are not essential in Krafft-Ebing's conception, and he defined "masochism" (German Masochismus) entirely in terms of control. Sigmund Freud, a psychoanalyst and a contemporary of Krafft-Ebing, noted that both were often found in the same individuals, and combined the two into a single dichotomous entity known as "sadomasochism" (German Sadomasochismus, often abbreviated as S&M or S/M). This observation is commonly verified in both literature and practice; many practitioners, both sadists and masochists, define themselves as switches and "switchable" — capable of taking and deriving pleasure in either role. However, French philosopher Gilles Deleuze argued that the concurrence of sadism and masochism proposed in Freud's model is the result of "careless reasoning," and should not be taken for granted.

Freud introduced the terms "primary" and "secondary" masochism. Though this idea has come under a number of interpretations, in a primary masochism the masochist undergoes a complete, rather than partial, rejection by the model or courted object (or sadist), possibly involving the model taking a rival as a preferred mate. This complete rejection is related to the death drive (Todestrieb) in Freud's psychoanalysis. In a secondary masochism, by contrast, the masochist experiences a less serious, more feigned rejection and punishment by the model. Secondary masochism, in other words, is the relatively casual version, more akin to a charade, and most commentators are quick to point out its contrivedness.

Rejection is not desired by a primary masochist in quite the same sense as the feigned rejection occurring within a mutually consensual relationship—or even where the masochist happens to be the one having actual initiative power. In Things Hidden Since the Foundation of the World, René Girard attempts to resuscitate and reinterpret Freud's distinction of primary and secondary masochism, in connection with his own philosophy.

Both Krafft-Ebing and Freud assumed that sadism in men resulted from the distortion of the aggressive component of the male sexual instinct. Masochism in men, however, was seen as a more significant aberration, contrary to the nature of male sexuality. Freud doubted that masochism in men was ever a primary tendency, and speculated that it may exist only as a transformation of sadism. Sadomasochism in women received comparatively little discussion, as it was believed that it occurred primarily in men. Both also assumed that masochism was so inherent to female sexuality that it would be difficult to distinguish as a separate inclination.

A submissive woman bound to a Saint Andrew's Cross being whipped at the Folsom Street Fair. The red marks on her body are from the whipping.

 

Havelock Ellis, in Studies in the Psychology of Sex, argued that there is no clear distinction between the aspects of sadism and masochism, and that they may be regarded as complementary emotional states. He also made the important point that sadomasochism is concerned only with pain in regard to sexual pleasure, and not in regard to cruelty, as Freud had suggested. In other words, the sadomasochist generally desires that the pain be inflicted or received in love, not in abuse, for the pleasure of either one or both participants. This mutual pleasure may even be essential for the satisfaction of those involved.

Here, Ellis touches upon the often paradoxical nature of widely reported consensual S&M practices. It is described as not simply pain to initiate pleasure, but violence—"or the simulation of involuntary violent acts"—said to express love. This irony is highly evident in the observation by many, that not only are popularly practiced sadomasochistic activities usually performed at the express request of the masochist, but that it is often the designated masochist who may direct such activities, through subtle emotional cues perceived or mutually understood and consensually recognized by the designated sadist.

In his essay Coldness and Cruelty, (originally Présentation de Sacher-Masoch, 1967) Gilles Deleuze rejects the term "sadomasochism" as artificial, especially in the context of the quintessentially modern masochistic work, Sacher-Masoch's Venus In Furs. Deleuze's counterargument is that the tendency toward masochism is based on intensified desire brought on or enhanced by the acting out of frustration at the delay of gratification. Taken to its extreme, an intolerably indefinite delay is 'rewarded' by punitive perpetual delay, manifested as unwavering coldness. The masochist derives pleasure from, as Deleuze puts it, the "Contract": the process by which he can control another individual and turn the individual into someone cold and callous. The sadist, in contrast, derives pleasure from the "Law": the unavoidable power that places one person below another. The sadist attempts to destroy the ego in an effort to unify the id and super-ego, in effect gratifying the most base desires the sadist can express while ignoring or completely suppressing the will of the ego, or of the conscience. Thus, Deleuze attempts to argue that masochism and sadism arise from such different impulses that the combination of the two terms is meaningless and misleading. A masochist's perception of their own self-subjugating sadistic desires and capacities are treated by Deleuze as reactions to prior experience of sadistic objectification. (For example, in terms of psychology, compulsively defensive appeasement of pathological guilt feelings as opposed to the volition of a strong free will.) The epilogue of Venus In Furs shows the character of Severin has become embittered by his experiment in the alleged control of masochism, and advocates instead the domination of women.

Before Deleuze, however, Sartre had presented his own theory of sadism and masochism, at which Deleuze's deconstructive argument, which took away the symmetry of the two roles, was probably directed. Because the pleasure or power in looking at the victim figures prominently in sadism and masochism, Sartre was able to link these phenomena to his famous philosophy of the "Look of the Other". Sartre argued that masochism is an attempt by the "For-itself" (consciousness) to reduce itself to nothing, becoming an object that is drowned out by the "abyss of the Other's subjectivity". By this Sartre means that, given that the "For-itself" desires to attain a point of view in which it is both subject and object, one possible strategy is to gather and intensify every feeling and posture in which the self appears as an object to be rejected, tested, and humiliated; and in this way the For-itself strives toward a point of view in which there is only one subjectivity in the relationship, which would be both that of the abuser and the abused. Conversely, Sartre held sadism to be the effort to annihilate the subjectivity of the victim. That means that the sadist is exhilarated by the emotional distress of the victim because they seek a subjectivity that views the victim as both subject and object.

This argument may appear stronger if it is understood that this "Look of the Other" theory is either only an aspect of the faculties of desire, or somehow its primary faculty. This does not account for the turn that Deleuze took for his own theory of these matters, but the premise of "desire as 'Look'" is associated with theoretical distinctions always detracted by Deleuze, in what he regarded as its essential error to recognize "desire as lack"—which he identified in the philosophical temperament of Plato, Socrates, and Lacan. For Deleuze, insofar as desire is a lack it is reducible to the "Look".

Finally, after Deleuze, René Girard included his account of sado-masochism in Things Hidden Since the Foundation of The World (1978), making the chapter on masochism a coherent part of his theory of mimetic desire. In this view of sado-masochism, the violence of the practices are an expression of a peripheral rivalry that has developed around the actual love-object. There is clearly a similarity to Deleuze, since both in the violence surrounding the memory of mimetic crisis and its avoidance, and in the resistance to affection that is focused on by Deleuze, there is an understanding of the value of the love object in terms of the processes of its valuation, acquisition and the test it imposes on the suitor.

S&M may involve painful acts such as cock and ball torture. Image shows a dominatrix, holding a bound man's penis, applying electricity to his balls at the Folsom Street Fair.

Modern psychology

There are a number of reasons commonly given for why a sadomasochist finds the practice of S&M enjoyable, and the answer is largely dependent on the individual. For some, taking on a role of compliance or helplessness offers a form of therapeutic escape; from the stresses of life, from responsibility, or from guilt. For others, being under the power of a strong, controlling presence may evoke the feelings of safety and protection associated with childhood. They likewise may derive satisfaction from earning the approval of that figure. A sadist, on the other hand, may enjoy the feeling of power and authority that comes from playing the dominant role, or receive pleasure vicariously through the suffering of the masochist. It is poorly understood, though, what ultimately connects these emotional experiences to sexual gratification, or how that connection initially forms. Dr. Joseph Merlino, author and psychiatry adviser to the New York Daily News, said in an interview that a sadomasochistic relationship, as long as it is consensual, is not a psychological problem: 

“	It's a problem only if it is getting that individual into difficulties, if he or she is not happy with it, or it's causing problems in their personal or professional lives. If it's not, I'm not seeing that as a problem. But assuming that it did, what I would wonder about is what is his or her biology that would cause a tendency toward a problem, and dynamically, what were the experiences this individual had that led him or her toward one of the ends of the spectrum.	”
— Joseph Merlino

It is usually agreed on by psychologists that experiences during early sexual development can have a profound effect on the character of sexuality later in life. Sadomasochistic desires, however, seem to form at a variety of ages. Some individuals report having had them before puberty, while others do not discover them until well into adulthood. According to one study, the majority of male sadomasochists (53%) developed their interest before the age of 15, while the majority of females (78%) developed their interest afterwards (Breslow, Evans, and Langley 1985). The prevalence of sadomasochism within the general population is unknown. Despite female sadists being less visible than males, some surveys have resulted in comparable amounts of sadistic fantasies between females and males. The results of such studies demonstrate that one's sex does not determine preference for sadism.

Medical and forensic classification

Medical categorization

BDSM

Medical opinion of sadomasochistic activities has changed over time. The classification of sadism and masochism in the Diagnostic and Statistical Manual of Mental Disorders (DSM) has always been separate; sadism was included in the DSM-I in 1952, while masochism was added in the DSM-II in 1968. Contemporary psychology continues to identify sadism and masochism separately, and categorizes them as either practised as a life style, or as a medical condition.

The current version of the American Psychiatric Association's manual, DSM-5, excludes consensual BDSM from diagnosis as a disorder when the sexual interests cause no harm or distress.

The DSM‐5 Sexual sadism disorder, however, do not distinguish between arousal patterns involving consenting and non‐consenting others.

ICD

June 18, 2018 WHO, The World Health Organization, published ICD-11, and Sadomasochism, together with Fetishism and Transvestic Fetishism, are now removed as psychiatric diagnoses. Moreover, discrimination of fetish- and BDSM individuals is considered inconsistent with human rights principles endorsed by the United Nations and The World Health Organization.

The classifications of sexual disorders reflect contemporary sexual norms and have moved from a model of pathologization or criminalization of non-reproductive sexual behaviors to a model which reflects sexual well-being and pathologizes the absence or limitation of consent in sexual relations.

The ICD-11 classification, contrary to ICD-10 and DSM-5, clearly distinguishes consensual sadomasochistic behaviours (BDSM) that do not involve inherent harm to self or others, from harmful violence on non‐consenting persons (Coercive sexual sadism disorder).

In this regard, ”ICD-11 go further than the changes made for DSM-5 … in the removal of disorders diagnosed based on consenting behaviors that are not in and of themselves associated with distress or functional impairment.” 

In Europe, an organization called ReviseF65 has worked to remove sadomasochism from the ICD. On commission from the WHO ICD-11 Working Group on Sexual Disorders and Sexual Health, ReviseF65 in 2009 and 2011 delivered reports documenting that sadomasochism and sexual violence are two different phenomena. The report concluded that the Sadomasochism diagnosis were outdated, non scientific, and stigmatizing. In 1995, Denmark became the first European Union country to have completely removed sadomasochism from its national classification of diseases. This was followed by Sweden in 2009, Norway in 2010, Finland in 2011 and Iceland in 2015.

"Based on advances in research and clinical practice, and major shifts in social attitudes and in relevant policies, laws, and human rights standards”, the World Health Organization June 18, 2018, removed Fetishism, Transvestic Fetishism and Sadomasochism as psychiatric diagnoses.

The ICD-11 classification consider Sadomasochism as a variant in sexual arousal and private behaviour without appreciable public health impact and for which treatment is neither indicated nor sought.” 

Further the ICD-11 guidelines ”respect the rights of individuals whose atypical sexual behavior is consensual and not harmful.” 

WHO’s ICD-11 Working Group admits that psychiatric diagnoses has been abused to harass, silence, or imprison sadomasochists. Labeling them as such may create harm, convey social judgment, and exacerbate existing stigma and violence to individuals so labeled.

According to ICD-11, psychiatric diagnoses can no longer be used to discriminate against BDSM people and fetishists.

Recent surveys on the spread of BDSM fantasies and practices show strong variations in the range of their results. Nonetheless, researchers assume that 5 to 25 percent of the population practices sexual behavior related to pain or dominance and submission. The population with related fantasies is believed to be even larger.

Forensic classification

According to Anil Aggrawal, in forensic science, levels of sexual sadism and masochism are classified as follows:

Sexual masochists:

• Class I: Bothered by, but not seeking out, fantasies. May be preponderantly sadists with minimal masochistic tendencies or non-sadomasochistic with minimal masochistic tendencies
• Class II: Equal mix of sadistic and masochistic tendencies. Like to receive pain but also like to be dominant partner (in this case, sadists). Sexual orgasm is achieved without pain or humiliation.
• Class III: Masochists with minimal to no sadistic tendencies. Preference for pain or humiliation (which facilitates orgasm), but not necessary to orgasm. Capable of romantic attachment.
• Class IV: Exclusive masochists (i.e. cannot form typical romantic relationships, cannot achieve orgasm without pain or humiliation).

Sexual sadists:

• Class I: Bothered by sexual fantasies but do not act on them.
• Class II: Act on sadistic urges with consenting sexual partners (masochists or otherwise). Categorization as leptosadism is outdated.
• Class III: Act on sadistic urges with non-consenting victims, but do not seriously injure or kill. May coincide with sadistic rapists.
• Class IV: Only act with non-consenting victims and will seriously injure or kill them.

The difference between I–II and III–IV is consent.

BDSM

Woman's buttocks turned red as a result of a paddling

 

Play piercing on a woman's back using multiple needles

 

Pussy torture: wax play done on a bound nude woman's genitals at Wave-Gotik-Treffen festival, Germany, 2014.

 

A submissive man is consoled by his dominatrix after she has made his back bloody by beating.

 

The term BDSM is commonly used to describe consensual activities that contain sadistic and masochistic elements. Masochists tend to be very specific about the types of pain they enjoy, preferring some and disliking others. Many behaviors such as spanking, tickling, and love-bites contain elements of sadomasochism. Even if both parties legally consent to such acts this may not be accepted as a defense against criminal charges. Very few jurisdictions will permit consent as a legitimate defense if serious bodily injuries are caused. It has been argued that in many countries, the law disregards the sexual nature of sadomasochism - or the fact that participants enter these relationships voluntarily because they enjoy the experience. Instead, the criminal justice system focuses on what it views as dangerous or violent behavior. What this essentially means is that instead of attempting to understand and accommodate for voluntary sadomasochism, the law typically views these incidences as cases of assault. This can be seen with the well-known case in Great Britain, where 15 men were trialed for a range of offences relating to sadomasochism. Samois, the earliest known lesbian S/M organization in the United States, was founded in San Francisco in 1978.

Harsh acts of S&M may include consensual torture of the sensitive parts of body, such as cock and ball torture for males, and breast torture and pussy torture for females. Acts common for both genders may include ass torture (ex. using speculum), face torture (ex. nose torture), etc. In extreme cases, sadism and masochism can include fantasies, sexual urges or behavior which cause observably significant distress or impairment in social, occupational, or other important areas of functioning, to the point that they can be considered part of a mental disorder. However, this is widely considered to be rare, as psychiatrists now regard such behaviors as clinically aberrant only if they are identifiable as symptoms or associated with other problems such as personality disorder or neurosis. There is some controversy in the psychology professions regarding a personality disorder referred to alternately as "self-defeating personality disorder" or "masochistic personality disorder", where masochistic behavior may not be in relation to other diagnosed mental disease. Ernulf and Innala (1995) observed discussions among individuals with such interests, one of whom described the goal of hyperdominance.

The Fifty Shades trilogy is a series of very popular erotic romance novels by E. L. James which involve S/M. These have been criticized for their inaccurate and harmful depiction of S/M. Their film adaptations have been similarly criticized.

Pain and pleasure

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Pain_and_pleasure

Some philosophers, such as Jeremy Bentham, Baruch Spinoza, and Descartes, have hypothesized that the feelings of pain (or suffering) and pleasure are part of a continuum.

There is strong evidence of biological connections between the neurochemical pathways used for the perception of both pain and pleasure, as well as other psychological rewards.

Perception of pain

Sensory input system

From a stimulus-response perspective, the perception of physical pain starts with the nociceptors, a type of physiological receptor that transmits neural signals to the brain when activated. These receptors are commonly found in the skin, membranes, deep fascias, mucosa, connective tissues of visceral organs, ligaments and articular capsules, muscles, tendons, periosteum, and arterial vessels. Once stimuli are received, the various afferent action potentials are triggered and pass along various fibers and axons of these nociceptive nerve cells into the dorsal horn of the spinal cord through the dorsal roots. A neuroanatomical review of the pain pathway, "Afferent pain pathways" by Almeida, describes various specific nociceptive pathways of the spinal cord: spinothalamic tract, spinoreticular tract, spinomesencephalic tract, spinoparabrachial tract, spinohypothalamic tract, spinocervical tract, postsynaptic pathway of the spinal column.

Neural coding and modulation

Activity in many parts of the brain is associated with pain perception. Some of the known parts for the ascending pathway include the thalamus, hypothalamus, midbrain, lentiform nucleus, somatosensory cortices, insular, prefrontal, anterior and parietal cingulum. Then, there are also the descending pathways for the modulation of pain sensation. One of the brainstem regions responsible for this is the periaqueductal gray of the midbrain, which both relieves pain by behavior as well as inhibits the activity of the nociceptive neurons in the dorsal horn of the spinal cord. Other brainstem sites, such as the parabrachial nucleus, the dorsal raphe, locus coeruleus, and the medullary reticular formation also mediate pain relief and use many different neurotransmitters to either facilitate or inhibit activity of the neurons in the dorsal horn. These neurotransmitters include noradrenaline, serotonin, dopamine, histamine, and acetylcholine. 

Perception of pleasure

Pleasure can be considered from many different perspectives, from physiological (such as the hedonic hotspots that are activated during the experience) to psychological (such as the study of behavioral responses towards reward). Pleasure has also often been compared to, or even defined by many neuroscientists as, a form of alleviation of pain.

Neural coding and modulation

Pleasure has been studied in the systems of taste, olfaction, auditory (musical), visual (art), and sexual activity. Well known hedonic hotspots involved in the processing of pleasure include the nucleus accumbens, posterior ventral pallidum, amygdala, other cortical and subcortical regions. The prefrontal and limbic regions of the neocortex, particularly the orbitofrontal region of the prefrontal cortex, anterior cingulate cortex, and the insular cortex have all been suggested to be pleasure causing substrates in the brain.

Psychology of pain and pleasure (reward-punishment system)

One approach to evaluating the relationship between pain and pleasure is to consider these two systems as a reward-punishment based system. When pleasure is perceived, one associates it with reward. When pain is perceived, one associates with punishment. Evolutionarily, this makes sense, because often, actions that result in pleasure or chemicals that induce pleasure work towards restoring homeostasis in the body. For example, when the body is hungry, the pleasure of rewarding food to one-self restores the body back to a balanced state of replenished energy. Like so, this can also be applied to pain, because the ability to perceive pain enhances both avoidance and defensive mechanisms that were, and still are, necessary for survival.

Opioid and dopamine systems in pain and pleasure

The neural systems to be explored when trying to look for a neurochemical relationship between pain and pleasure are the opioid and dopamine systems. The opioid system is responsible for the actual experience of the sensation, whereas the dopamine system is responsible for the anticipation or expectation of the experience. Opioids work in the modulation of pleasure or pain relief by either blocking neurotransmitter release or by hyperpolarizing neurons by opening up a potassium channel which effectively temporarily blocks the neuron.

Pain and pleasure on a continuum

Arguments for pain and pleasure on a continuum

It has been suggested as early as 4th century BC that pain and pleasure occurs on a continuum. Aristotle claims this antagonistic relationship in his Rhetoric:

"We may lay it down that Pleasure is a movement, a movement by which the soul as a whole is consciously brought into its normal state of being; and that Pain is the opposite."

He describes pain and pleasure very much like a push-pull concept; human beings will move towards something that causes pleasure and will move away from something that causes pain.

Common neuroanatomy

On an anatomical level, it can be shown the source for the modulation of both pain and pleasure originates from neurons in the same locations, including the amygdala, the pallidum, and the nucleus accumbens. Not only have Leknes and Tracey, two leading neuroscientists in the study of pain and pleasure, concluded that pain and reward processing involve many of the same regions of the brain, but also that the functional relationship lies in that pain decreases pleasure and rewards increase analgesia, which is the relief from pain.

Arguments against pain and pleasure on a continuum

Asymmetry between pain and pleasure

Thomas Szasz, the late Professor of Psychiatry Emeritus at the State University of New York Health Science Center in Syracuse, New York, explored how pain and pleasure are not opposites ends of a spectrum in his 1957 book, "Pain and Pleasure -a study of bodily feelings".

Szasz notes that although we often refer to pain and pleasure as opposites in such a way, that this is incorrect; we have receptors for pain, but none in the same way for pleasure; and so it makes sense to ask "where is the pain?" but not "where is the pleasure?". With this vantage point established, the author delves into the topics of metaphorical pain and of legitimacy, of power relations, and of communications, and of myriad others.

Evolutionary hypotheses for the relationship between pain and pleasure

Whether or not pain and pleasure are indeed on a continuum, it still remains scientifically supported that parts of the neural pathways for the two perceptions overlap. There is also scientific evidence that one may have opposing effects on the other. So why would it be evolutionarily advantageous to human beings to develop a relationship between the two perceptions at all?

South African neuroscientists presented evidence that there was a physiological link on a continuum between pain and pleasure in 1980. First, the Neuroscientists, Gillman and Lichtigfeld demonstrated that there were two endogenous endorphin systems, one pain producing and the other pain relieving. A short time later they showed that these two systems might also be involved in addiction, which is initially pursued, presumably for the pleasure generating or pain relieving actions of the addictive substance. Soon after they provided evidence that the endorphins system was involved in sexual pleasure.

Dr. Kringelbach suggests that this relationship between pain and pleasure would be evolutionarily efficient, because it was necessary to know whether or not to avoid or approach something for survival. According to Dr. Norman Doidge, the brain is limited in the sense that it tends to focus on the most used pathways. Therefore, having a common pathway for pain and pleasure could have simplified the way in which human beings have interacted with the environment (Dr. Morten Kringelbach, personal communication, October 24, 2011).

Leknes and Tracey offer two theoretical perspectives to why a relationship could be evolutionarily advantageous.

Opponent process theory

The opponent-process theory is a model that views two components as being pairs that are opposite to each other, such that if one component is experienced, the other component will be repressed. Therefore, an increase in pain should bring about a decrease in pleasure, and a decrease in pain should bring about an increase in pleasure or pain relief. This simple model serves the purpose of explaining the evolutionarily significant role of homeostasis in this relationship. This is evident since both seeking pleasure and avoiding pain are important for survival. Leknes and Tracey provide an example:

"In the face of a large food reward, which can only be obtained at the cost of a small amount of pain, for instance, it would be beneficial if the pleasurable food reduced pain unpleasantness."

They then suggest that perhaps a common currency for which human beings determine the importance of the motivation for each perception can allow them to be weighed against each other in order to make a decision best for survival.

Motivation-decision model

The Motivation-Decision Model, suggested by Fields, is centered around the concept that decision processes are driven by motivations of highest priority. The model predicts that in the case that there is anything more important than pain for survival will cause the human body to mediate pain by activating the descending pain modulation system described earlier. Thus, it is suggested that human beings have developed the unconscious ability to endure pain or sometimes, even relieve pain if it can be more important for survival to gain a larger reward. It may have been more advantageous to link the pain and pleasure perceptions together to be able to reduce pain to gain a reward necessary for fitness, such as childbirth. Like the opponent-process theory, if the body can induce pleasure or pain relief to decrease the effect of pain, it would allow human beings to be able to make the best evolutionary decisions for survival.

Clinical applications

Related diseases

The following neurological and/or mental diseases have been linked to forms of pain or anhedonia: schizophrenia, depression, addiction, cluster headache, chronic pain.

Animal trials

A great deal of what is known about pain and pleasure today primarily comes from studies conducted with rats and primates.

Insertion of electrode during Deep Brain Stimulation surgery using a stereotactic frame

 

Deep brain stimulation

Deep brain stimulation involves the electrical stimulation of deep brain structures by electrodes implanted into the brain. The effects of this neurosurgery has been studied in patients with Parkinson's disease, tremors, dystonia, epilepsy, depression, obsessive-compulsive disorder, Tourette's syndrome, cluster headache and chronic pain. A fine electrode is inserted into the targeted area of the brain and secured to the skull. This is attached to a pulse generator which is implanted elsewhere on the body under the skin. The surgeon then turns the frequency of the electrode to the voltage and frequency desired. Deep brain stimulation has been shown in several studies to both induce pleasure or even addiction as well as ameliorate pain. For chronic pain, lower frequencies (about 5–50 Hz) have produced analgesic effects, whereas higher frequencies (about 120–180 Hz) have alleviated or stopped pyramidal tremors in Parkinson's patients.

There is still further research necessary into how and why exactly DBS works. However, by understanding the relationship between pleasure and pain, procedures like these can be used to treat patients suffering from a high intensity or longevity of pain. So far, DBS has been recognized as a treatment for Parkinson's disease, tremors, and dystonia by the Food and Drug Administration (FDA).