Cancer immunotherapy

From Wikipedia, the free encyclopedia

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 system's natural ability to fight cancer. It is an application of the fundamental research of cancer immunology and a growing subspecialty 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.

Immunotherapy 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. 

Approved immunotherapy antibodies include alemtuzumab, ipilimumab, nivolumab, ofatumumab 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). 

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.

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 are also referred to as murine, chimeric, humanized and human. Murine antibodies are from a different species 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 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
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	metastatic melanoma
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.

Atezolizumab

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.

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.

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 2017, 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).

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.

Pathology

From Wikipedia, the free encyclopedia

Pathology

A pathologist examines a tissue section for evidence of cancerous cells while a surgeon observes.
Focus	Disease
Subdivisions	Anatomical pathology, clinical pathology, dermatopathology, forensic pathology, hematopathology, histopathology, molecular pathology, surgical pathology
Significant diseases	All infectious and organic diseases and physiological disorders.
Significant tests	All medical diagnostic tests, particular biopsy, blood analysis, dissection, and other applications of medical microscopy
Specialist	Pathologist
Glossary	Glossary of medicine

Pathology (from the Ancient Greek roots of pathos (πάθος), meaning "experience" or "suffering" and -logia (-λογία), "study of") is concerned mainly with the causal study of disease.

The word pathology itself may be broadly refer to the study of disease in general, incorporating a wide range of bioscience research fields and medical practices. However, when used in the context of modern medical treatment, the term is often used in a more narrow fashion to refer to processes and tests which fall within the contemporary medical field of "general pathology," an area which includes a number of distinct but inter-related medical specialties that diagnose disease, mostly through analysis of tissue, cell, and body fluid samples. Idiomatically, "a pathology" may also refer to the predicted or actual progression of particular diseases (as in the statement "the many different forms of cancer have diverse pathologies"), and the affix path is sometimes used to indicate a state of disease in cases of both physical ailment (as in cardiomyopathy) and psychological conditions (such as psychopathy). A physician practicing pathology is called a pathologist.

As a field of general inquiry and research, pathology addresses four components of disease: cause, mechanisms of development (pathogenesis), structural alterations of cells (morphologic changes), and the consequences of changes (clinical manifestations). In common medical practice, general pathology is mostly concerned with analyzing known clinical abnormalities that are markers or precursors for both infectious and non-infectious disease and is conducted by experts in one of two major specialties, anatomical pathology and clinical pathology. Further divisions in specialty exist on the basis of the involved sample types (comparing, for example, cytopathology, hematopathology, and histopathology), organs (as in renal pathology), and physiological systems (oral pathology), as well as on the basis of the focus of the examination (as with forensic pathology).

Pathology is a significant field in modern medical diagnosis and medical research.

General medical pathology

The modern practice of pathology is divided into a number of subdisciplines within the discrete but deeply interconnected aims of biological research and medical practice. Biomedical research into disease incorporates the work of a vast variety of life science specialists, whereas, in most parts of the world, to be licensed to practice pathology as medical specialty, one has to complete medical school and secure a license to practice medicine. Structurally, the study of disease is divided into many different fields that study or diagnose markers for disease using methods and technologies particular to specific scales, organs, and tissue types. The information in this section mostly concerns pathology as it regards common medical practice in these systems, but each of these specialties is also the subject of voluminous pathology research as regards the disease pathways of specific pathogens and disorders that affect the tissues of these discrete organs or structures.

Anatomical pathology

Anatomical pathology (Commonwealth) or anatomic pathology (United States) is a medical specialty that is concerned with the diagnosis of disease based on the gross, microscopic, chemical, immunologic and molecular examination of organs, tissues, and whole bodies (as in a general examination or an autopsy). Anatomical pathology is itself divided into subfields, the main divisions being surgical pathology, cytopathology, and forensic pathology. Anatomical pathology is one of two main divisions of the medical practice of pathology, the other being clinical pathology, the diagnosis of disease through the laboratory analysis of bodily fluids and tissues. Sometimes, pathologists practice both anatomical and clinical pathology, a combination known as general pathology. 

A bone marrow smear from a case of erythroleukemia. The large cell in the top center is an abnormal erythroblast: it is multinucleated, with megaloblastoid nuclear chromatin This is diagnostic of erythroleukemia.

Cytopathology

Cytopathology (sometimes referred to as "cytology") is a branch of pathology that studies and diagnoses diseases on the cellular level. It is usually used to aid in the diagnosis of cancer, but also helps in the diagnosis of certain infectious diseases and other inflammatory conditions as well as thyroid lesions, diseases involving sterile body cavities (peritoneal, pleural, and cerebrospinal), and a wide range of other body sites. Cytopathology is generally used on samples of free cells or tissue fragments (in contrast to histopathology, which studies whole tissues) and cytopathologic tests are sometimes called smear tests because the samples may be smeared across a glass microscope slide for subsequent staining and microscopic examination. However, cytology samples may be prepared in other ways, including cytocentrifugation.

Dermatopathology

A malignant melanoma can often be suspected from sight, but confirmation of the diagnosis or outright removal requires an excisional biopsy.

Dermatopathology is a subspecialty of anatomic pathology that focuses on the skin and the rest of the integumentary system as an organ. It is unique, in that there are two paths a physician can take to obtain the specialization. All general pathologists and general dermatologists train in the pathology of the skin, so the term dermatopathologist denotes either of these who has reached a certainly level of accreditation and experience; in the USA, either a general pathologist or a dermatologist can undergo a 1 to 2 year fellowship in the field of dermatopathology. The completion of this fellowship allows one to take a subspecialty board examination, and becomes a board certified dermatopathologist. Dermatologists are able to recognize most skin diseases based on their appearances, anatomic distributions, and behavior. Sometimes, however, those criteria do not lead to a conclusive diagnosis, and a skin biopsy is taken to be examined under the microscope using usual histological tests. In some cases, additional specialized testing needs to be performed on biopsies, including immunofluorescence, immunohistochemistry, electron microscopy, flow cytometry, and molecular-pathologic analysis. One of the greatest challenges of dermatopathology is its scope. More than 1500 different disorders of the skin exist, including cutaneous eruptions ("rashes") and neoplasms. Therefore, dermatopathologists must maintain a broad base of knowledge in clinical dermatology, and be familiar with several other specialty areas in medicine.

Forensic pathology

Pathologist performing a human dissection of the abdominal and thoracic organs in an autopsy room.

Forensic pathology focuses on determining the cause of death by post-mortem examination of a corpse or partial remains. An autopsy is typically performed by a coroner or medical examiner, often during criminal investigations; in this role, coroners and medical examiners are also frequently asked to confirm the identity of a corpse. The requirements for becoming a licensed practitioner of forensic pathology varies from country to country (and even within a given nation) but typically a minimal requirement is a medical doctorate with a specialty in general or anatomical pathology with subsequent study in forensic medicine. The methods forensic scientists use to determine death include examination of tissue specimens to identify the presence or absence of natural disease and other microscopic findings, interpretations of toxicology on body tissues and fluids to determine the chemical cause of overdoses, poisonings or other cases involving toxic agents, and examinations of physical trauma. Forensic pathology is a major component in the trans-disciplinary field of forensic science.

Histopathology

An instance of diagnosis via histopathology, this high-magnification micrograph of a section of cardiac tissue reveals advanced cardiac amyloidosis. This sample was attained through an autopsy.

Histopathology refers to the microscopic examination of various forms of human tissue. Specifically, in clinical medicine, histopathology refers to the examination of a biopsy or surgical specimen by a pathologist, after the specimen has been processed and histological sections have been placed onto glass slides. This contrasts with the methods of cytopathology, which uses free cells or tissue fragments. Histopathological examination of tissues starts with surgery, biopsy, or autopsy. The tissue is removed from the body of an organism and then placed in a fixative that stabilizes the tissues to prevent decay. The most common fixative is formalin, although frozen section fixing is also common. To see the tissue under a microscope, the sections are stained with one or more pigments. The aim of staining is to reveal cellular components; counterstains are used to provide contrast. Histochemistry refers to the science of using chemical reactions between laboratory chemicals and components within tissue. The histological slides are then interpreted diagnostically and the resulting pathology report describes the histological findings and the opinion of the pathologist. In the case of cancer, this represents the tissue diagnosis required for most treatment protocols.

Neuropathology

This coronal cross-section of a brain reveals a significant arteriovenous malformation that occupies much of the parietal lobe.

Neuropathology is the study of disease of nervous system tissue, usually in the form of either surgical biopsies or sometimes whole brains in the case of autopsy. Neuropathology is a subspecialty of anatomic pathology, neurology, and neurosurgery. In many English-speaking countries, neuropathology is considered a subfield of anatomical pathology. A physician who specializes in neuropathology, usually by completing a fellowship after a residency in anatomical or general pathology, is called a neuropathologist. In day-to-day clinical practice, a neuropathologist is a consultant for other physicians. If a disease of the nervous system is suspected, and the diagnosis cannot be made by less invasive methods, a biopsy of nervous tissue is taken from the brain or spinal cord to aid in diagnosis. Biopsy is usually requested after a mass is detected by medical imaging. With autopsies, the principal work of the neuropathologist is to help in the post-mortem diagnosis of various conditions that affect the central nervous system. Biopsies can also consist of the skin. Epidermal nerve fiber density testing (ENFD) is a more recently developed neuropathology test in which a punch skin biopsy is taken to identify small fiber neuropathies by analyzing the nerve fibers of the skin. This test is becoming available in select labs as well as many universities; it replaces the traditional nerve biopsy test as less invasive.

Pulmonary pathology

Pulmonary pathology is a subspecialty of anatomic (and especially surgical) pathology that deals with diagnosis and characterization of neoplastic and non-neoplastic diseases of the lungs and thoracic pleura. Diagnostic specimens are often obtained via bronchoscopic transbronchial biopsy, CT-guided percutaneous biopsy, or video-assisted thoracic surgery. These tests can be necessary to diagnose between infection, inflammation, or fibrotic conditions. 

This tissue cross-section demonstrates the gross pathology of polycystic kidneys.

Renal pathology

Renal pathology is a subspecialty of anatomic pathology that deals with the diagnosis and characterization of disease of the kidneys. In a medical setting, renal pathologists work closely with nephrologists and transplant surgeons, who typically obtain diagnostic specimens via percutaneous renal biopsy. The renal pathologist must synthesize findings from traditional microscope histology, electron microscopy, and immunofluorescence to obtain a definitive diagnosis. Medical renal diseases may affect the glomerulus, the tubules and interstitium, the vessels, or a combination of these compartments.

Surgical pathology

Surgical pathology is one of the primary areas of practice for most anatomical pathologists. Surgical pathology involves the gross and microscopic examination of surgical specimens, as well as biopsies submitted by surgeons and non-surgeons such as general internists, medical subspecialists, dermatologists, and interventional radiologists. Often an excised tissue sample is the best and most definitive evidence of disease (or lack thereof) in cases where tissue is surgically removed from a patient. These determinations are usually accomplished by a combination of gross (i.e., macroscopic) and histologic (i.e., microscopic) examination of the tissue, and may involve evaluations of molecular properties of the tissue by immunohistochemistry or other laboratory tests. 

Brain biopsy under stereotaxy. A small part of the tumor is taken via a needle with a vacuum system.

There are two major types of specimens submitted for surgical pathology analysis: biopsies and surgical resections. A biopsy is a small piece of tissue removed primarily for surgical pathology analysis, most often in order to render a definitive diagnosis. Types of biopsies include core biopsies, which are obtained through the use of large-bore needles, sometimes under the guidance of radiological techniques such as ultrasound, CT scan, or magnetic resonance imaging. Incisional biopsies are obtained through diagnostic surgical procedures that remove part of a suspicious lesion, whereas excisional biopsies remove the entire lesion, and are similar to therapeutic surgical resections. Excisional biopsies of skin lesions and gastrointestinal polyps are very common. The pathologist's interpretation of a biopsy is critical to establishing the diagnosis of a benign or malignant tumor, and can differentiate between different types and grades of cancer, as well as determining the activity of specific molecular pathways in the tumor. Surgical resection specimens are obtained by the therapeutic surgical removal of an entire diseased area or organ (and occasionally multiple organs). These procedures are often intended as definitive surgical treatment of a disease in which the diagnosis is already known or strongly suspected, but pathological analysis of these specimens remains important in confirming the previous diagnosis.

Clinical pathology

Clinical pathology is a medical specialty that is concerned with the diagnosis of disease based on the laboratory analysis of bodily fluids such as blood and urine, as well as tissues, using the tools of chemistry, clinical microbiology, hematology and molecular pathology. Clinical pathologists work in close collaboration with medical technologists, hospital administrations, and referring physicians. Clinical pathologists learn to administer a number of visual and microscopic tests and an especially large variety of tests of the biophysical properties of tissue samples involving Automated analysers and cultures. Sometimes the general term "laboratory medicine specialist" is used to refer to those working in clinical pathology, including medical doctors, Ph.D.s and doctors of pharmacology. Immunopathology, the study of an organism's immune response to infection, is sometimes considered to fall within the domain of clinical pathology.

Clinical chemistry: an automated blood chemistry analyzer

Hematopathology

Hematopathology is the study of diseases of blood cells (including constituents such as white blood cells, red blood cells, and platelets) and the tissues, and organs comprising the hematopoietic system. The term hematopoietic system refers to tissues and organs that produce and/or primarily host hematopoietic cells and includes bone marrow, the lymph nodes, thymus, spleen, and other lymphoid tissues. In the United States, hematopathology is a board certified subspecialty (licensed under the American Board of Pathology) practiced by those physicians who have completed a general pathology residency (anatomic, clinical, or combined) and an additional year of fellowship training in hematology. The hematopathologist reviews biopsies of lymph nodes, bone marrows and other tissues involved by an infiltrate of cells of the hematopoietic system. In addition, the hematopathologist may be in charge of flow cytometric and/or molecular hematopathology studies.

Immunopathology

Immunopathology is a branch of clinical pathology that deals with an organism’s immune response to a certain disease. When a foreign antigen enters the body, there is either an antigen specific or nonspecific response to it. These responses are the immune system fighting off the foreign antigens, whether they are deadly or not. Immunopathology could refer to how the foreign antigens cause the immune system to have a response or problems that can arise from an organism’s own immune response on itself. There are certain problems or faults in the immune system that can lead to more serious illness or disease. These diseases can come from one of the following problems. The first would be Hypersensitivity reactions, where there would be a stronger immune response than normal. There are four different types (type one, two, three and four), all with varying types and degrees of an immune response. The problems that arise from each type vary from small allergic reactions to more serious illnesses such as tuberculosis or arthritis. The second kind of complication in the immune system is Autoimmunity, where the immune system would attack itself rather than the antigen. Inflammation is a prime example of autoimmunity, as the immune cells used are self-reactive. A few examples of autoimmune diseases are Type 1 diabetes, Addison’s disease and Celiac disease. The third and final type of complication with the immune system is Immunodeficiency, where the immune system lacks the ability to fight off a certain disease. The immune system’s ability to combat it is either hindered or completely absent. The two types are Primary Immunodeficiency, where the immune system is either missing a key component or does not function properly, and Secondary Immunodeficiency, where disease is obtained from an outside source, like radiation or heat, and therefore cannot function properly. Diseases that can cause immunodeficiency include HIV, AIDS and leukemia.

Radiation pathology

Radiation pathology is study of the interaction between human tissues and radiation, as well as the problems and diseases that can arise from the use of radiation. When human tissue is exposed to radiation, it can be genetically altered and deformed; in turn, this could lead to a variety of illnesses that could be minor or deadly.

Molecular pathology

Molecular pathology is focused upon the study and diagnosis of disease through the examination of molecules within organs, tissues or bodily fluids. Molecular pathology is multidisciplinary by nature and shares some aspects of practice with both anatomic pathology and clinical pathology, molecular biology, biochemistry, proteomics and genetics. It is often applied in a context that is as much scientific as directly medical and encompasses the development of molecular and genetic approaches to the diagnosis and classification of human diseases, the design and validation of predictive biomarkers for treatment response and disease progression, and the susceptibility of individuals of different genetic constitution to particular disorders. The crossover between molecular pathology and epidemiology is represented by a related field "molecular pathological epidemiology". Molecular pathology is commonly used in diagnosis of cancer and infectious diseases. Molecular Pathology is primarily used to detect cancers such as melanoma, brainstem glioma, brain tumors as well as many other types of cancer and infectious diseases. Techniques are numerous but include quantitative polymerase chain reaction (qPCR), multiplex PCR, DNA microarray, in situ hybridization, DNA sequencing, antibody based immunofluorescence tissue assays, molecular profiling of pathogens, and analysis of bacterial genes for antimicrobial resistance. Techniques used are based on analyzing samples of DNA and RNA. Pathology is widely used for gene therapy and disease diagnosis.

Many conditions, such as this case of geographic tongue, can be diagnosed partly on gross examination, but may be confirmed with tissue pathology.

Oral and maxillofacial pathology

Oral and Maxillofacial Pathology is one of nine dental specialties recognized by the American Dental Association, and is sometimes considered a specialty of both dentistry and pathology. Oral Pathologists must complete three years of post doctoral training in an accredited program and subsequently obtain diplomate status from the American Board of Oral and Maxillofacial Pathology. The specialty focuses on the diagnosis, clinical management and investigation of diseases that affect the oral cavity and surrounding maxillofacial structures including but not limited to odontogenic, infectious, epithelial, salivary gland, bone and soft tissue pathologies. It also significantly intersects with the field of dental pathology. Although concerned with a broad variety of diseases of the oral cavity, they have roles distinct from otorhinolaryngologists ("ear, nose, and throat" specialists), and speech pathologists, the latter of which helps diagnose many neurological or neuromuscular conditions relevant to speech phonology or swallowing. Owing to the availability of the oral cavity to non-invasive examination, many conditions in the study of oral disease can be diagnosed, or at least suspected, from gross examination, but biopsies, cell smears, and other tissue analysis remain important diagnostic tools in oral pathology.

Medical training and accreditation

Individual nations vary some in the medical licensing required of pathologists. In the United States, pathologists are physicians (D.O. or M.D.) that have completed a four-year undergraduate program, four years of medical school training, and three to four years of postgraduate training in the form of a pathology residency. Training may be within two primary specialties, as recognized by the American Board of Pathology: anatomical Pathology and clinical Pathology, each of which requires separate board certification. The American Osteopathic Board of Pathology also recognizes four primary specialties: anatomic pathology, dermatopathology, forensic pathology, and laboratory medicine. Pathologists may pursue specialised fellowship training within one or more subspecialties of either anatomical or clinical pathology. Some of these subspecialties permit additional board certification, while others do not.

An anatomical pathology instructor uses a microscope with multiple eyepieces to instruct students in diagnostic microscopy.

In the United Kingdom, pathologists are physicians licensed by the UK General Medical Council. The training to become a pathologist is under the oversight of the Royal College of Pathologists. After four to six years of undergraduate medical study, trainees proceed to a two-year foundation program. Full-time training in histopathology currently lasts between five and five and a half years and includes specialist training in surgical pathology, cytopathology, and autopsy pathology. It is also possible to take a Royal College of Pathologists diploma in forensic pathology, dermatopathology, or cytopathology, recognising additional specialist training and expertise and to get specialist accreditation in forensic pathology, pediatric pathology, and neuropathology. All postgraduate medical training and education in the UK is overseen by the General Medical Council.

In France, Pathology is separate in two distinct specialties, anatomical pathology and clinical pathology. Residencies for both lasts four years. Residency in anatomical pathology is open to physicians only, while clinical pathology is open to both physicians and pharmacists. At the end of the second year of clinical pathology residency, residents can choose between general clinical pathology and a specialization in one of the disciplines, but they can not practice anatomical pathology, nor can anatomical pathology residents practice clinical pathology.

Overlap with other diagnostic medicine

Though separate fields in terms of medical practice, a number of areas of inquiry in medicine and medical science either overlap greatly with general pathology, work in tandem with it, or contribute significantly to the understanding of the pathology of a given disease or its course in an individual. As a significant portion of all general pathology practice is concerned with cancer, the practice of oncology is deeply tied to, and dependent upon, the work of both anatomical and clinical pathologists. Biopsy, resection and blood tests are all examples of pathology work that is essential for the diagnoses of many kinds of cancer and for the staging of cancerous masses. In a similar fashion, the tissue and blood analysis techniques of general pathology are of central significance to the investigation of serious infectious disease and as such inform significantly upon the fields of epidemiology, etiology, immunology, and parasitology. General pathology methods are of great importance to biomedical research into disease, wherein they are sometimes referred to as "experimental" or "investigative" pathology. 

Medical imaging is the generating of visual representations of the interior of a body for clinical analysis and medical intervention. Medical imaging reveals details of internal physiology that help medical professionals plan appropriate treatments for tissue infection and trauma. Medical imaging is also central in supplying the biometric data necessary to establish baseline features of anatomy and physiology so as to increase the accuracy with which early or fine-detail abnormalities are detected. These diagnostic techniques are often performed in combination with general pathology procedures and are themselves often essential to developing new understanding of the pathogenesis of a given disease and tracking the progress of disease in specific medical cases. Examples of important subdivisions in medical imaging include radiology (which uses the imaging technologies of X-ray radiography) magnetic resonance imaging, medical ultrasonography (or ultrasound), endoscopy, elastography, tactile imaging, thermography, medical photography, nuclear medicine and functional imaging techniques such as positron emission tomography. Though they do not strictly relay images, readings from diagnostics tests involving electroencephalography, magnetoencephalography, and electrocardiography often give hints as to the state and function of certain tissues in the brain and heart respectively.

Psychopathology

Psychopathology is the study of mental illness, particularly of severe disorders. Informed heavily by both psychology and neurology, its purpose is to classify mental illness, elucidate its underlying causes, and guide clinical psychiatric treatment accordingly. Although diagnosis and classification of mental norms and disorders is largely the purview of psychiatry—the results of which are guidelines such as the Diagnostic and Statistical Manual of Mental Disorders, which attempt to classify mental disease mostly on behavioural evidence, though not without controversy—the field is also heavily, and increasingly, informed upon by neuroscience and other of the biological cognitive sciences. Mental or social disorders or behaviors seen as generally unhealthy or excessive in a given individual, to the point where they cause harm or severe disruption to the sufferer's lifestyle, are often called "pathological" (e.g., pathological gambling or pathological liar).

History

The advent of the microscope was one of the major developments in the history of pathology. Here researchers at the Centers for Disease Control in 1978 examine cultures containing Legionella pneumophila, the pathogen responsible for Legionnaire's disease.

The study of pathology, including the detailed examination of the body, including dissection and inquiry into specific maladies, dates back to antiquity. Rudimentary understanding of many conditions was present in most early societies and is attested to in the records of the earliest historical societies, including those of the Middle East, India, and China. By the Hellenic period of ancient Greece, a concerted causal study of disease was underway, with many notable early physicians (such as Hippocrates, for whom the modern Hippocratic Oath is named) having developed methods of diagnosis and prognosis for a number of diseases.The medical practices of the Romans and those of the Byzantines continued from these Greek roots, but, as with many areas of scientific inquiry, growth in understanding of medicine stagnated some after the Classical Era, but continued to slowly develop throughout numerous cultures. Notably, many advances were made in the medieval era of Islam, during which numerous texts of complex pathologies were developed, also based on the Greek tradition. Even so, growth in complex understanding of disease mostly languished until knowledge and experimentation again began to proliferate in the Renaissance, Enlightenment, and Baroque eras, following the resurgence of the empirical method at new centers of scholarship. By the 17th century, the study of microscopy was underway and examination of tissues had led British Royal Society member Robert Hooke to coin the word "cell", setting the stage for later germ theory. 

Modern pathology began to develop as a distinct field of inquiry during the 19th Century through natural philosophers and physicians that studied disease and the informal study of what they termed “pathological anatomy” or “morbid anatomy”. However, pathology as a formal area of specialty was not fully developed until the late 19th and early 20th centuries, with the advent of detailed study of microbiology. In the 19th century, physicians had begun to understand that disease-causing pathogens, or "germs" (a catch-all for disease-causing, or pathogenic, microbes, such as bacteria, viruses, fungi, amoebae, molds, protists, and prions) existed and were capable of reproduction and multiplication, replacing earlier beliefs in humors or even spiritual agents, that had dominated for much of the previous 1,500 years in European medicine. With the new understanding of causative agents, physicians began to compare the characteristics of one germ’s symptoms as they developed within an affected individual to another germ’s characteristics and symptoms. This realization led to the foundational understanding that diseases are able to replicate themselves, and that they can have many profound and varied effects on the human host. To determine causes of diseases, medical experts used the most common and widely accepted assumptions or symptoms of their times, a general principal of approach that persists into modern medicine.

Modern medicine was particularly advanced by further developments of the microscope to analyze tissues, to which Rudolf Virchow gave a significant contribution, leading to a slew of research developments. By the late 1920s to early 1930s pathology was deemed a medical specialty. Combined with developments in the understanding of general physiology, by the beginning of the 20th century, the study of pathology had begun to split into a number of rarefied fields and resulting in the development of large number of modern specialties within pathology and related disciplines of diagnostic medicine.

Non-humans

This field post-mortem of a ewe has revealed lesions consistent with acute haemolytic pneumonia, possibly due to Pasteurella haemolytica.

Although the vast majority of lab work and research in pathology concerns the development of disease in humans, pathology is of significance throughout the biological sciences. Two main catch-all fields exist to represent most complex organisms capable of serving as host to a pathogen or other form of disease: veterinary pathology (concerned with all non-human species of kingdom of Animalia) and phytopathology, which studies disease in plants.

Veterinary

Veterinary pathology covers a vast array of species, but with a significantly smaller number of practitioners, so understanding of disease in non-human animals, especially as regards veterinary practice, varies considerably by species. Nonetheless, significant amounts of pathology research are conducted on animals, for two primary reasons: 1) The origins of diseases are typically zoonotic in nature, and many infectious pathogens have animal vectors and, as such, understanding the mechanisms of action for these pathogens in non-human hosts is essential to the understanding and application of epidemiology and 2) those animals that share physiological and genetic traits with humans can be used as surrogates for the study of the disease and potential treatments as well as the effects of various synthetic products. For this reason, as well as their roles as livestock and companion animals, mammals generally have the largest body of research in veterinary pathology. Animal testing remains a controversial practice, even in cases where it is used to research treatment for human disease. As in human medical pathology, the practice of veterinary pathology is customarily divided into the two main fields of anatomical and clinical pathology. 

A tobacco plant infected with the tobacco mosaic virus

Plants

Although the pathogens and their mechanics differ greatly from those of animals, plants are subject to a wide variety of diseases, including those caused by fungi, oomycetes, bacteria, viruses, viroids, virus-like organisms, phytoplasmas, protozoa, nematodes and parasitic plants. Damage caused by insects, mites, vertebrate, and other small herbivores is not considered a part of the domain of plant pathology. The field is deeply connected to plant disease epidemiology and the horticulture of species that are of high importance to the human diet or other uses.