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Saturday, February 1, 2020

Cancer immunotherapy

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Cancer_immunotherapy
 
Cancer immunotherapy
Peptide bound to Rituximab FAB.png

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

Accelerating change

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