Cancer immunotherapy

Peptide epitope of CD20 bound to rituximab's

FAB

Cancer immunotherapyCancer immunotherapy (sometimes called

immuno-oncology, abbreviated IO) is the use of the

immune system to treat cancer.[1] Immunotherapies

can be categorized as active, passive or hybrid (active

and passive). These approaches exploit the fact that

cancer cells often have molecules on their surface that

can be detected by the immune system, known as

tumour-associated antigens (TAAs); they are often

proteins or other macromolecules (e.g. carbohydrates).

Active immunotherapy directs the immune system to

attack tumor cells by targeting TAAs. Passive

immunotherapies enhance existing anti-tumor

responses and include the use of monoclonal

antibodies, lymphocytes and cytokines.

Among these, multiple antibody therapies are approved in various jurisdictions to treat a wide range of

cancers.[2] Antibodies are proteins produced by the immune system that bind to a target antigen on the

cell surface. The immune system normally uses them to fight pathogens. Each antibody is specific to one

or a few proteins. Those that bind to tumor antigens treat cancer. Cell surface receptors are common

targets for antibody therapies and include CD20, CD27 4 and CD27 9. Once bound to a cancer antigen,

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

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 cultured 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. However, a newer study

conducted by Stanford University scientists has created a method of treating tumors that does not

require a patient's immune cells to be removed from their body. Their method uses the combination of

two immune-enhancing agents that are injected into a tumor to trigger a T cell immune response that then

eradicates the tumor.[3]

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.

Contents

Cellu lar immunotherapyDendritic cell therapy

CAR-T cell therapy

Antibody therapyAntibody types

Cell death mechanisms

FDA-approved antibodies

Cytokine therapyInterferon

Interleukin

Combinat ion immunotherapy

Polysacchar ide-K

ResearchAdoptive T-cell therapy

Anti-CD47 therapy

Anti-GD2 antibodies

Immune checkpoints

Oncolytic virus

Polysaccharides

Neoantigens

See also

References

External l inks

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.[4] In cancer treatment they aid cancer

antigen targeting.[5] 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[6] 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.

Cellular immunotherapy

Dendritic cell therapy

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.[5]

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.[7][8][9][10]

Tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR-T) therapy, was approved by FDA in 2017

to treat acute lymphoblastic leukemia.[11] This treatment removes CD19 positive cells (B-cells) from the

body (including the diseased cells, but also normal antibody producing cells).

Axicabtagene ciloleucel (Y escarta) is another CAR-T therapeutic, approved in 2017 for treatment of

diffuse large B-cell lymphoma.[12]

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

Approved drugs

CAR-T cell therapy

Approved drugs

Antibody therapy

Many forms of antibodies can be

engineered.

Antibody types

Two types are used in cancer treatments:[13]

Naked monoclonal antibodies are antibodies without added elements. Most antibody therapies use this antibodytype.

Conjugated monoclonal antibodies are joined to another molecule, which is either cytotoxic or radioactive. Thetoxic chemicals are those typically used as chemotherapy drugs, but other toxins can be used. The antibodybinds 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 withchemotherapeutic molecules or toxins, respectively.[14]

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.[15] 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.[16] 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.[17] 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.[18] Furthermore, antibodies targeting the co-

stimulatory protein CD40 require engagement with selective Fc receptors for optimal therapeutic

efficacy.[19] Together, these studies underscore the importance of Fc status in antibody-based immune

checkpoint targeting strategies.

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.[14]

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,

Conjugat ion

Fc Regions

Human/non-human balance

Cell death mechanisms

Antibody-dependent cel l-mediated cytotoxic ity (ADCC)

Cancer immunotherapy:Monoclonal ant ibodies[13][23]

Antibody Brandname

Type Target Approvaldate

Approved treatment(s)

Alemtuzumab Campath humanized CD52 2001B-cell chronic lymphocyticleukemia (CLL)[24]

Atezolizumab Tecentriq humanized PD-L1 2016 bladder cancer [25]

Avelumab Bavencio human PD-L1 2017metastatic Merkel cellcarcinoma[26]

Ipilimumab Yervoy human CTLA4 2011 metastatic melanoma[27]

Ofatumumab Arzerra human CD20 2009 refractory CLL[28]

Nivolumab Opdivo human PD-1 2014

unresectable or metastaticmelanoma, squamous non-smallcell lung cancer, Renal cellcarcinoma, colorectal cancer,hepatocellular carcinoma, classicalhodgkin lymphoma[29][30]

Pembrolizumab Keytruda humanized PD-1 2014 metastatic melanoma[29]

Rituximab Rituxan,Mabthera

chimeric CD20 1997 non-Hodgkin lymphoma[31]

Durvalumab Imfinzi human PD-L1 2017 bladder cancer[32] non-small celllung cancer[33]

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.[20][21]

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.[22]

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.

Complement

FDA-approved antibodies

Alemtuzumab

Alemtuzumab (Campeth-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.[34][35][36]

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-containingchemotherapy.

Ipilimumab (Y ervoy) 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.[37][38][39][40]

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.[37][38][39][40]

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 .[41][42]

Pembrolizumab is approved for the first-line treatment of patients with metastatic non-small cell lung

cancer whose tumors have high PD-L1 expression as determined by an FDA-approved test.

Atezolizumab

Ipi l imumab

Nivolumab

Ofatumumab

Pembrol izumab

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.[43][44][44][45][46][47]

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.[48]

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.[49][50]

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.[51]

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.[48][52]

Combining various immunotherapies such as PD1 and CTLA4 inhibitors can enhance anti-tumor response

leading to durable responses.[53][54][1]

Combining ablation therapy of tumors with immunotherapy enhances the immunostimulating response

and has synergistic effects for curative metastatic cancer treatment.[55]

Rituximab

Cytokine therapy

Interferon

Interleukin

Combination immunotherapy

Combining checkpoint immunotherapies with pharmaceutical agents has the potential to improve

response, and such combination therapies are a highly investigated area of clinical investigation.[56]

Immunostimulatory drugs such as CSF-1R inhibitors and TLR agonists have been particularly effective in

this setting.[57][58]

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.[59]

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.[60]

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.[61][62][63][64][65] Importantly , one study from

2018 showed that clinical responses can be obtained in patients with metastatic melanoma resistant to

multiple previous immunotherapies.[66]

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

FDA in 2017 .[67][12]

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.[68]

Polysaccharide-K

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 (tumour bearer).

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.[69]

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.[70][71] A number of therapeutics is being developed, including anti-CD47 antibodies, engineered

decoy receptors, anti-SIRPα antibodies and bispecific agents.[70] As of 2017 , wide range of solid and

hematologic malignancies were being clinically tested.[70][72]

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.[73]

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.[1][74]

One ligand-receptor interaction under investigation is the interaction between the transmembrane

programmed cell death 1 protein (PDCD1, PD-1; also known as CD27 9) and its ligand, PD-1 ligand 1 (PD-L1,

CD27 4). 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.[1] Antibodies that bind to either PD-1 or PD-L1 and therefore block the

interaction may allow the T-cells to attack the tumor.[1][75]

The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 for treatment of

melanoma.[76] 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.[77][78] In on-going trials the combination of CTLA-4 blockade with PD-1 or PD-L1 inhibitors is

tested on different types of cancer.[1][79]

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.[80] These are

Anti-GD2 antibodies

The GD2 ganglioside

Immune checkpoints

CTLA-4 blockade

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.[81] 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.[81]

Initial clinical trial results with IgG4 PD1 antibody Nivolumab were published in 2010.[74] 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.[1][82] 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.[83]

Pembrolizumab is another PD1 inhibitor that was approved by the FDA in 2014. Keytruda

(Pembrolizumab) is approved to treat melanoma and lung cancer.[82]

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

trials.[84]

In May 2016, PD-L1 inhibitor atezolizumab[85] was approved for treating bladder cancer.

Anti-PD-L1 antibodies currently in development include avelumab[86] and durvalumab,[87] in addition to

an affimer biotherapeutic.[88]

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 [89] can improve immune checkpoint blockade response in animal models of cancer.

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.[90][91][92]

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

PD-1 inhibitors

PD-L1 inhibitors

Other

Oncolytic virus

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.

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.[93]

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.[94] However, human neoantigens identified in other studies do not show the bias toward

tetrapeptide signatures.[95]

Cancer vaccine

Antigen 5T4

Coley's Toxins

Combinatorial ablation and immunotherapy

Cryoimmunotherapy

Photoimmunotherapy

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External links

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"Immuno-Oncology: Investigating Cancer Therapies Powered by the Immune System" (http://www.merckserono.com/en/research_development/therapeutic_focus/immuno_oncology/immuno_oncology.html;jsessionid=B776F4E8CCC023654F278E890F95B80D). Merck Serono. Retrieved 13 March 2014.

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