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Cancer immunotherapy

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Peptide epitope of CD20 bound to Rituximab's FAB

Cancer immunotherapy is the use of the immune system to treat cancer. Immunotherapies are often categorized as active, passive, or combinatory (active and passive). These immunotherapeutic approaches exploit the fact that cancer cells often have subtly different molecules on their surface that can be detected by the immune system known as cancer antigens; cancer antigens are often proteins or other macromolecules (e.g. carbohydrates).

Active immunotherapy is used to provoke the immune system into attacking the tumor cells by targeting tumour-associated antigens (TAAs). Passive immunotherapies are intrinsically functional and include monoclonal antibodies, lymphocytes, and cytokines. Among these, antibody therapies are the most successful to date and treat a wide range of cancers. Antibodies are proteins produced by the immune system that bind to a target antigen on the cell surface. In normal physiology the immune system uses them to fight pathogens. Each antibody is specific to one or a few proteins. Those that bind to cancer antigens are used to treat cancer. Cell surface receptors are common targets for antibody therapies and include the CD20, CD274, and CD279. 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. Multiple antibodies are approved to treat cancer, including Alemtuzumab, Ipilimumab, Nivolumab, Ofatumumab, and Rituximab.

Active cellular therapies usually involve the removal of immune cells from the blood or from a tumor. Immune cells specific for the tumor are activated, cultured and returned to the patient where the immune cells attack the cancer. Cell types that can be used in this way are natural killer cells, lymphokine-activated killer cells, cytotoxic T cells and dendritic cells. The only cell-based therapy approved in the US is Dendreon's Provenge, for the treatment of prostate cancer.

Interleukin-2 and interferon-α are cytokines, proteins that regulate and coordinate the behaviour 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.

History

Cancer immunotherapy arose from advances in oncology and immunology. Immunotherapy began in 1796 when Edward Jenner produced the first vaccine involving immunisation with cowpox to prevent smallpox. Towards the end of the 19th century Emil von Behring and Shibasaburō Kitasato discovered that injecting animals with diphtheria toxin produced blood serum with antitoxins to it.

Paul Ehrlich's research gave rise to the "magic bullet" concept; using antibodies to specifically target a disease. The production of pure monoclonal antibodies for therapeutic use became available in 1975 when Georges J. F. Köhler and Cesar Milstein produced the hybridoma technology.

In 1987, researchers identified cytotoxic T-lymphocyte antigen 4, or CTLA-4. James Allison found that CTLA-4 prevents T cells from attacking tumor cells. He wondered whether blocking CTLA-4 would allow the immune system to make those attacks. In 1996, Allison showed that antibodies against CTLA-4 destroyed tumors in mice.[1]

In 1999, biotech firm Medarex acquired rights to the antibody. In 2010, Medarex acquirer Bristol-Myers Squibb reported that patients with metastatic melanoma lived an average of 10 months on the antibody, versus 6 months without it. It was the first time any treatment had extended life in advanced melanoma in a randomized trial.[1]

In the early 1990s, a biologist discovered a molecule expressed in dying T cells, which he called programmed death 1, or PD-1, and which he recognized as another disabler of T cells. An antibody that targeted PD-1 was developed and by 2008 produced remission in multiple subjects across multiple cancer types. In 2013, clinicians reported that across 300 patients tumors shrunk by about half or more in 31% of those with melanoma, 29% with kidney cancer and 17% with lung cancer.[1]

However, with both anti–CTLA-4 and anti–PD-1, some tumors continued to grow before vanishing months later. Some patients kept responding after the antibody had been discontinued. Some patients, developed side effects including inflammation of the colon or of the pituitary gland.[1]

After success harvesting T cells from tumors, expanding them in the lab, and reinfusing them into patients reduced tumors, in 2010, Steven Rosenberg announced chimeric antigen receptor therapy, or CAR therapy. This technique is a personalized treatment that involves genetically modifying each patient's T cells to target tumor cells. It produced complete remission in a majority of leukemia patients, although some later relapsed.[1]

In 1997 Rituximab, the first antibody treatment for cancer, was approved by the FDA for treatment of follicular lymphoma. Since this approval, 11 other antibodies have been approved for cancer; Alemtuzumab (2001), Ofatumumab (2009), and Ipilimumab (2011).

The first cell-based immunotherapy cancer vaccine, Sipuleucel-T, was approved in 2010 for the treatment of prostate cancer.[2][3]

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. Dendritic cells present antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. In cancer treatment they aid cancer antigen targeting.[4] The only approved cellular therapy for cancer is Sipuleucel-T.

One method of inducing dendritic cells to present tumor antigens is by vaccination with short peptides (small parts of protein that correspond to the protein antigens on cancer cells). These peptides on their own do not stimulate a strong immune response and may be given in combination with adjuvants (highly immunogenic substances). This provokes a strong response, while also producing a (sometimes) robust anti-tumor response by the immune system. 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 within the body (in vivo) by making tumour cells express (GM-CSF). This can be achieved by either genetically engineering tumor cells that 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 (ex vivo). 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 activated dendritic cells are put back into the body where they provoke an immune response to the cancer cells. Adjuvants are sometimes used systemically to increase the anti-tumor response provided by ex vivo activated dendritic cells. More modern 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 targets by antibodies to produce immune responses.[4]

Sipuleucel-T

Sipuleucel-T (Provenge) is the first approved cancer vaccine. It was approved for treatment of asymptomatic or minimally symptomatic metastatic castrate 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 prostatic acid phosphatase (PAP). These cells are infused back into the patient to induce an immune response because PAP protein is prostate specific. This process is repeated three times.[5][6][7][8]

Antibody therapy

Many forms of antibodies can be engineered.
Main article: Monoclonal antibody therapy

Antibodies are a key component of the adaptive immune response, playing a central role in both the recognition of foreign antigens and the stimulation of an immune response to them. It is not surprising therefore, that many immunotherapeutic approaches involve the use of antibodies. The advent of monoclonal antibody technology has made it possible to raise antibodies against specific antigens, such as the unusual antigens present on tumor surfaces.

Types of monoclonal antibodies

Two types of monoclonal antibodies are used in cancer treatments:[9]

  • Naked monoclonal antibodies are antibodies without modification. Most of the currently used antibodies therapies are naked.
  • Conjugated monoclonal antibodies are joined to another molecule, which is either toxic to cells 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. If the antibodies are labelled with chemotherapy or toxins, they are known as chemolabelled or immunotoxins, respectively.[10]

Antibodies are also referred to as murine, chimeric, humanized and human. Murine antibodies were the first to be produced, and carry a great risk of immune reaction, because the antibodies are from a different species. Chimeric antibodies were the first attempt to reduce the immunogenicity of these antibodies. They are murine antibodies with a specific part of the antibody replaced 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 antibodies. Human antibodies have completely human DNA.[10]

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) is a mechanism of attack by the immune system that 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 cells via their Fc surface receptors. Fc receptors are found on many immune system cells, including natural killer cells. When natural killer cells encounter antibody-coated cells, the latter's Fc regions interact with their Fc receptors, leading to the release of perforin and granzyme B to cause tumor cell death (apoptosis). Effective antibodies include Rituximab, Ofatumumab, and Alemtuzumab. Third generation antibodies under development have altered Fc regions that have higher affinity for a specific type of Fc receptor, FcγRIIIA, which can dramatically increase ADCC.[11][12]

Complement

The complement system includes blood proteins that can cause cell death after an antibody binds to the cell surface (this is 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.[13]

Approved antibodies

Cancer immunotherapy:Monoclonal antibodies[9][14]
Antibody Brand name Type Target Approval date Approved treatment(s)
Alemtuzumab Campath humanized CD52 2001 B-cell Chronic lymphocytic leukemia (CLL)[15]
Ipilimumab Yervoy human CTLA4 2011 metastatic melanoma[16]
Ofatumumab Arzerra human CD20 2009 refractory CLL[17]
Nivolumab Opdivo human ligand activation of the programmed cell death 1 (PD-1) receptor on activated T cells 2014 unresectable or metastatic melanoma, squamous non-small cell lung cancer[18]
Pembrolizumab Keytruda humanized programmed cell death 1 (PD-1) receptor 2014 metastatic melanoma[18]
Rituximab Rituxan, Mabthera chimeric CD20 1997 non-Hodgkin lymphoma[19]
2010 CLL[20]

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. Upon binding to CD52, alemtuzumab initiates its cytotoxic effect by complement fixation and antibody-dependent cell-mediated cytotoxicity mechanisms. Due to the antibody target (cells of the immune system) common complications of alemtuzumab therapy are infection, toxicity and myelosuppression.[21][22][23]

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 on the surface of antigen presenting cells. CTLA4 binds to CD80 or CD86, preventing the binding of CD28 to these surface proteins and therefore negatively regulating the activation of T-cells.[24][25][26][27]

Active cytotoxic T-cells are required for the immune system to attack melanoma cells. Active melanoma-specific cytotoxic T-cells that would normally be inhibited can produce an effective anti-tumor response. Also, ipilumumab can cause a shift in the ratio of regulatory T-cells to cytotoxic T-cells. Regulatory T-cells inhibit other T-cells, which may benefit the tumor. Increasing the amount of cytotoxic T-cells and decreasing the regulatory T-cells is another mechanism by which ipilumumab increases the anti-tumor response.[24][25][26][27]

Nivolumab

Main article: Nivolumab

Ofatumumab

Ofatumumab is a second generation human IgG1 antibody that binds to CD20. It is used in the treatment of chronic lymphocytic leukemia (CLL) because the cancerous cells of CLL are usually CD20-expressing B-cells. Unlike Rituximab, which binds to a large loop of the CD20 protein, Ofatumumab binds to a separate small loop. This may be the reason for the two drugs' different characteristics. Compared to Rituximab, Ofatumumab induces complement-dependent cytotoxicity at a lower dose with less immunogenicity.[28][29]

Pembrolizumab

Main article: Pembrolizumab

Rituximab

Rituximab is a chimeric monoclonal IgG1 antibody specific for CD20, developed from its parent antibody Ibritumomab. As with Ibritumomab, Rituximab targets CD20. For this reason it is effective in treating certain types of malignancies that are formed from cancerous B-cells. These include aggressive and indolent lymphomas such as diffuse large B-cell lymphoma and follicular lymphoma, and leukaemias such as B-cell chronic lymphocytic leukaemia. Although the function of CD20 is relatively unknown it has been suggested that CD20 could be a calcium channel involved in B-cell activation. The antibody's mode of action is primarily through the induction of antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity. Other mechanisms include apoptosis and cellular growth arrest. Rituximab also increases the sensitivity of cancerous B-cells to chemotherapy.[30][31][31][32][33][34]

Cytokine therapy

Cytokines are a broad group of proteins produced by many types of cells present within a tumor. They have the ability to modulate immune responses. The tumor often employs it to allow it to grow and manipulate the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response. Two commonly used groups of cytokines are interferons and interleukins.[35]

Interferon

Interferons are cytokines produced by the immune system. They are usually involved in anti-viral response, but also have use for cancer. The three groups of interferons (IFNs) are 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.[36][37]

Interleukin

Interleukins are a group of cytokines with a wide 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 in the treatment of cancer is unknown.[35][38]

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.[39]

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).
Main article: Adoptive cell transfer

Adoptive T-cell therapy is a form of passive immunization by the transfusion of T-cells. 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 other cells that display small parts of foreign proteins on their surface antigens. These can be either infected cells, or specialised immune cells known as 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 have the capability of attacking the tumor, the environment within the tumor is highly immunosuppressive, preventing immune-mediated tumour death.[40]

Multiple ways of producing and obtaining tumour targeted T-cells have been discovered. 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 outside the body (ex vivo) and then they are transfused into the patient. Activation can take place through gene therapy, or by exposing the T cells to tumor antigens. Although research has made major advances in this form of therapy, no adoptive T-cell therapy is as yet approved.[40][41]

As of 2014, several clinical trials for ACT were underway. Initial clinical trials showed complete remission of leukemia in some patients in two small clinical trials, announced in December 2013.[42][43][44][45][46]

Another approach is adoptive transfer of haploidentical γδ T cells or NK cells from a healthy donor. Major advantage of this approach is that these cells do not cause GVHD. The disadvantage is frequently impaired function of the transferred cells.[47]

Anti-CD47 antibodies

Anti-CD47 antibodies, which block the protein CD47 from telling the cancer host's immune system not to attack it, have been shown to eliminate or inhibit the growth of a wide range of cancers and tumors in laboratory tests on cells and mice. CD47 is present on many cancer cells and on many healthy cells. After the cancer cells have been engulfed by macrophages, the host immune system's CD8+ T Cells become mobilized against the cancer and attack it on their own in addition to the macrophages.[48]

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, Phase I, II, and III trials were underway for antibody treatments.[49]

Immune checkpoint blockade

Immune checkpoint blockade is a blockade of immune system inhibitory checkpoints.[50] Immune checkpoints can be stimulatory or inhibitory. Blockade of inhibitory immune checkpoint activates immune system function. One ligand-receptor interaction that was investigated as a target for cancer treatment 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). In normal physiology PD-L1 on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity. Although not exclusively, PD-L1 plays a key regulatory role on T cell activities.[51][52] It appears that upregulation of PD-L1 on the cancer cell surface may allow them to evade the host immune system by inhibiting T cells that might otherwise attack the tumor cell. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor. Initial clinical trial results with an IgG4 PD1 antibody called Nivolumab were published in 2010.[50] It has been approved in 2014. Pembrolizumab was also approved by the FDA in 2014.

The first monoclonal antibody approved by the FDA for immune checkpoint blockade was ipilimumab, approved in 2011. Ipilimumab blocks the inhibitory immune checkpoint CTLA-4.

Other modes of enhancing [adoptive] immuno-therapy include targeting so-called intrinsic checkpoint blockades e.g. CISH

Polysaccharides

Lentinula edodes (Shiitake mushrooom)

Certain compounds found in mushrooms, primarily polysaccharide compounds, 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 adjuvant therapies.[53]

Agaricus subrufescens, (often mistakenly called Agaricus blazei), Lentinula edodes (Shiitake mushrooom), Grifola frondosa and Hericium erinaceus are fungi known to produce beta-glucans and have been tested for their anti-cancer potential.[54]

Neoantigens

Main article: Neoantigen

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 read out 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 large 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 does not show the bias toward tetrapeptide signatures.[55]

Public awareness

Starting with the FDA approval in 2010 of the therapeutic vaccine sipuleucel-T (Provenge) for prostate cancer and, in 2011, of ipilimumab (Yervoy) for melanoma,[56] public awareness of cancer immunotherapy has increased thanks to mainstream news articles.[57][58][59]

In 2012, the U.S.-based nonprofit Cancer Research Institute launched Cancer Immunotherapy Month (originally Cancer Immunotherapy Awareness Month), an educational and awareness-building initiative taking place each year in June. The month features free webinars with leading experts in cancer immunotherapy, stories of hope and survival told in patients' own words, and social media events, all aimed at informing patients and caregivers about new treatment options as well as underscoring the need for continued research funding to realize immunotherapy's potential to treat and eventually cure all cancers.

See also

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