Cancer immunotherapy is the use of the immune system to treat cancer. 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. 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, 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. 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. 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 US-approved cell-based therapy 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.
- 1 History
- 2 Cellular immunotherapy
- 3 Antibody therapy
- 3.1 Antibody types
- 3.2 Cell death mechanisms
- 3.3 FDA-approved antibodies
- 4 Cytokine therapy
- 5 Polysaccharide-K
- 6 Research
- 7 See also
- 8 References
- 9 External links
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 hybridoma technology.
Immuno cell therapy for cancer was introduced by Rosenberg and colleagues. In the late 1980s, they reported a low tumor regression rate (2.6–3.3%) in 1205 patients with metastatic cancer who underwent different types of active specific immunotherapy.
In 1987, researchers identified cytotoxic T-lymphocyte antigen 4, or CTLA-4. 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 allowed the immune system to destroy tumors in mice. 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.
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.
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).
In 2003 cytokines such as interleukin were administered. The adverse effects of intravenously administered cytokines led to the extraction, in vitro expansion against a tumour antigen and reinjection of the cells with appropriate stimulatory cytokines.
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.
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.
Dendritic cell therapy
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. In cancer treatment they aid cancer antigen targeting. The only approved cellular cancer therapy 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 tumour 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.
Sipuleucel-T (Provenge) is the only 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 prostate-specific prostatic acid phosphatase (PAP) and reinfused. This process is repeated three times.
Antibodies are a key component of the adaptive immune response, playing a central role in both recognizing foreign antigens and stimulating an immune response. Many immunotherapeutic regimens involve antibodies. Monoclonal antibody technology raises antibodies against specific antigens, such as those present on tumor surfaces.
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.
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 completely human DNA.
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 natural killer cells. When natural killer 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.
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.
|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 |
|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|
|Pembrolizumab||Keytruda||humanized||programmed cell death 1 (PD-1) receptor||2014||metastatic melanoma|
|Rituximab||Rituxan, Mabthera||chimeric||CD20||1997||non-Hodgkin lymphoma|
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.
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 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.
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 leukaemias such as B-cell chronic lymphocytic leukaemia. 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[clarification needed] and cellular growth arrest. Rituximab also increases the sensitivity of cancerous B-cells to chemotherapy.
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.
Interferons are produced by the immune system. They are usually involved in anti-viral response, but also have use for cancer. The 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.
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.
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.
Adoptive T-cell therapy
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 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. Although research has made major advances in this form of therapy, no adoptive T-cell therapy is as yet approved.
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 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 multiple 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 tumor and attack it.
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.
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Immune checkpoints affect immune system functioning. Immune checkpoints can be stimulatory or inhibitory. Tumors can use these checkpoints to protect themselves from immune system attacks. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function. 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. 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 IgG4 PD1 antibody Nivolumab were published in 2010. It was approved in 2014. Nivolumab is approved to treat melanoma, lung cancer, kidney cancer and Hodgkin's lymphoma.
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.
Agaricus subrufescens, (often mistakenly called Agaricus blazei), Lentinula edodes (shitake mushroom), Grifola frondosa and Hericium erinaceus are fungi that produce beta-glucans and have been tested for anti-cancer potential.
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.
- Rosenberg SA (January 1984). "Adoptive immunotherapy of cancer: accomplishments and prospects". Cancer Treat Rep 68 (1): 233–55. PMID 6362866.
- Couzin-Frankel, J. (2013-12-20). "Cancer Immunotherapy". Science 342 (6165): 1432–1433. doi:10.1126/science.342.6165.1432.
- Yang Q, Hokland ME, Bryant JL, Zhang Y, Nannmark U, Watkins SC, Goldfarb RH, Herberman RB, Basse PH (July 2003). "Tumor-localization by adoptively transferred, interleukin-2-activated NK cells leads to destruction of well-established lung metastases". Int. J. Cancer 105 (4): 512–9. doi:10.1002/ijc.11119. PMID 12712443.
- Egawa K (2004). "Immuno-cell therapy of cancer in Japan". Anticancer Res. 24 (5C): 3321–6. PMID 15515427.
- Li K, Li CK, Chuen CK, Tsang KS, Fok TF, James AE, Lee SM, Shing MM, Chik KW, Yuen PM (February 2005). "Preclinical ex vivo expansion of G-CSF-mobilized peripheral blood stem cells: effects of serum-free media, cytokine combinations and chemotherapy". Eur. J. Haematol. 74 (2): 128–35. doi:10.1111/j.1600-0609.2004.00343.x. PMID 15654904.
- Strebhardt K, Ullrich A (Jun 2008). "Paul Ehrlich's magic bullet concept: 100 years of progress". Nature Reviews. Cancer 8 (6): 473–80. doi:10.1038/nrc2394. PMID 18469827.
- Waldmann TA (Mar 2003). "Immunotherapy: past, present and future". Nature Medicine 9 (3): 269–77. doi:10.1038/nm0303-269. PMID 12612576.
- Palucka K, Banchereau J (Jul 2013). "Dendritic-cell-based therapeutic cancer vaccines". Immunity 39 (1): 38–48. doi:10.1016/j.immuni.2013.07.004. PMID 23890062.
- Hirayama M, Nishimura Y (2016). "The present status and future prospects of peptide-based cancer vaccines". International Immunology. doi:10.1093/intimm/dxw027. PMID 27235694.
- Gardner TA, Elzey BD, Hahn NM (Apr 2012). "Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer". Human Vaccines & Immunotherapeutics 8 (4): 534–9. doi:10.4161/hv.19795. PMID 22832254.
- Oudard S (May 2013). "Progress in emerging therapies for advanced prostate cancer". Cancer Treatment Reviews 39 (3): 275–89. doi:10.1016/j.ctrv.2012.09.005. PMID 23107383.
- Sims RB (Jun 2012). "Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer". Vaccine 30 (29): 4394–7. doi:10.1016/j.vaccine.2011.11.058. PMID 22122856.
- Shore ND, Mantz CA, Dosoretz DE, Fernandez E, Myslicki FA, McCoy C, Finkelstein SE, Fishman MN (Jan 2013). "Building on sipuleucel-T for immunologic treatment of castration-resistant prostate cancer". Cancer Control 20 (1): 7–16. PMID 23302902.
- Scott AM, Wolchok JD, Old LJ (Apr 2012). "Antibody therapy of cancer". Nature Reviews. Cancer 12 (4): 278–87. doi:10.1038/nrc3236. PMID 22437872.
- Harding FA, Stickler MM, Razo J, DuBridge RB (May–Jun 2010). "The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions". mAbs 2 (3): 256–65. doi:10.4161/mabs.2.3.11641. PMID 20400861.
- Weiner LM, Surana R, Wang S (May 2010). "Monoclonal antibodies: versatile platforms for cancer immunotherapy". Nature Reviews. Immunology 10 (5): 317–27. doi:10.1038/nri2744. PMID 20414205.
- Seidel UJ, Schlegel P, Lang P (2013). "Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies". Frontiers in Immunology 4: 76. doi:10.3389/fimmu.2013.00076. PMID 23543707.
- Gelderman KA, Tomlinson S, Ross GD, Gorter A (Mar 2004). "Complement function in mAb-mediated cancer immunotherapy". Trends in Immunology 25 (3): 158–64. doi:10.1016/j.it.2004.01.008. PMID 15036044.
- Waldmann TA (Mar 2003). "Immunotherapy: past, present and future". Nature Medicine 9 (3): 269–77. doi:10.1038/nm0303-269. PMID 12612576.
- Demko S, Summers J, Keegan P, Pazdur R (Feb 2008). "FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia". The Oncologist 13 (2): 167–74. doi:10.1634/theoncologist.2007-0218. PMID 18305062.
- "FDA approves new, targeted treatment for bladder cancer". FDA. 18 May 2016. Retrieved 20 May 2016.
- Pazdur R. "FDA approval for Ipilimumab". Retrieved 7 November 2013.
- Lemery SJ, Zhang J, Rothmann MD, Yang J, Earp J, Zhao H, McDougal A, Pilaro A, Chiang R, Gootenberg JE, Keegan P, Pazdur R (Sep 2010). "U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab". Clinical Cancer Research 16 (17): 4331–8. doi:10.1158/1078-0432.CCR-10-0570. PMID 20601446.
- Sharma P, Allison JP (Apr 2015). "The future of immune checkpoint therapy". Science 348 (6230): 56–61. doi:10.1126/science.aaa8172. PMID 25838373.
- James JS, Dubs G (Dec 1997). "FDA approves new kind of lymphoma treatment. Food and Drug Administration". AIDS Treatment News (284): 2–3. PMID 11364912.
- Casak SJ, Lemery SJ, Shen YL, Rothmann MD, Khandelwal A, Zhao H, Davis G, Jarral V, Keegan P, Pazdur R (2011). "U.S. Food and drug administration approval: rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with chronic lymphocytic leukemia". The Oncologist 16 (1): 97–104. doi:10.1634/theoncologist.2010-0306. PMID 21212432.
- Byrd JC, Stilgenbauer S, Flinn IW. Chronic Lymphocytic Leukemia. Hematology (Am Soc Hematol Educ Program) 2004: 163-183. Date retrieved: 26/01/2006.
- Domagała A, Kurpisz M (Mar–Apr 2001). "CD52 antigen--a review". Medical Science Monitor 7 (2): 325–31. PMID 11257744.
- Dearden C (Jul 2012). "How I treat prolymphocytic leukemia". Blood 120 (3): 538–51. doi:10.1182/blood-2012-01-380139. PMID 22649104.
- Sondak VK, Smalley KS, Kudchadkar R, Grippon S, Kirkpatrick P (Jun 2011). "Ipilimumab". Nature Reviews. Drug Discovery 10 (6): 411–2. doi:10.1038/nrd3463. PMID 21629286.
- Lipson EJ, Drake CG (Nov 2011). "Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma". Clinical Cancer Research 17 (22): 6958–62. doi:10.1158/1078-0432.CCR-11-1595. PMID 21900389.
- Thumar JR, Kluger HM (Dec 2010). "Ipilimumab: a promising immunotherapy for melanoma". Oncology 24 (14): 1280–8. PMID 21294471.
- Chambers CA, Kuhns MS, Egen JG, Allison JP (2001). "CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy". Annual Review of Immunology 19: 565–94. doi:10.1146/annurev.immunol.19.1.565. PMID 11244047.
- Castillo J, Perez K (2010). "The role of ofatumumab in the treatment of chronic lymphocytic leukemia resistant to previous therapies". Journal of Blood Medicine 1: 1–8. doi:10.2147/jbm.s7284. PMC 3262337. PMID 22282677.
- Zhang B (Jul–Aug 2009). "Ofatumumab". mAbs 1 (4): 326–31. doi:10.4161/mabs.1.4.8895. PMC 2726602. PMID 20068404.
- Keating GM (Jul 2010). "Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or follicular lymphoma and diffuse large B-cell lymphoma". Drugs 70 (11): 1445–76. doi:10.2165/11201110-000000000-00000. PMID 20614951.
- Plosker GL, Figgitt DP (2003). "Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia". Drugs 63 (8): 803–43. doi:10.2165/00003495-200363080-00005. PMID 12662126.
- Cerny T, Borisch B, Introna M, Johnson P, Rose AL (Nov 2002). "Mechanism of action of rituximab". Anti-Cancer Drugs. 13 Suppl 2: S3–10. doi:10.1097/00001813-200211002-00002. PMID 12710585.
- Janeway C, Paul Travers, Mark Walport, Mark Shlomchik (2001). Immunobiology; Fifth Edition. New York and London: Garland Science. ISBN 0-8153-4101-6.
- Weiner GJ (Apr 2010). "Rituximab: mechanism of action". Seminars in Hematology 47 (2): 115–23. doi:10.1053/j.seminhematol.2010.01.011. PMC 2848172. PMID 20350658.
- Dranoff G (Jan 2004). "Cytokines in cancer pathogenesis and cancer therapy". Nature Reviews. Cancer 4 (1): 11–22. doi:10.1038/nrc1252. PMID 14708024.
- Dunn GP, Koebel CM, Schreiber RD (Nov 2006). "Interferons, immunity and cancer immunoediting". Nature Reviews. Immunology 6 (11): 836–48. doi:10.1038/nri1961. PMID 17063185.
- Lasfar A, Abushahba W, Balan M, Cohen-Solal KA (2011). "Interferon lambda: a new sword in cancer immunotherapy". Clinical & Developmental Immunology 2011: 349575. doi:10.1155/2011/349575. PMID 22190970.
- Coventry BJ, Ashdown ML (2012). "The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses". Cancer Management and Research 4: 215–21. doi:10.2147/cmar.s33979. PMC 3421468. PMID 22904643.
- American Cancer Society. Coriolus Versicolor Last Medical Review: 11/01/2008. Last Revised: 11/01/2008. Accessed May 10, 2014
- Restifo NP, Dudley ME, Rosenberg SA (Apr 2012). "Adoptive immunotherapy for cancer: harnessing the T cell response". Nature Reviews. Immunology 12 (4): 269–81. doi:10.1038/nri3191. PMID 22437939.
- June CH (Jun 2007). "Adoptive T cell therapy for cancer in the clinic". The Journal of Clinical Investigation 117 (6): 1466–76. doi:10.1172/JCI32446. PMC 1878537. PMID 17549249.
- Carroll J (December 2013). "Novartis/Penn's customized T cell wows ASH with stellar leukemia data". Fierce Biotech.
- Carroll, John (February 2014). "Servier stages an entry into high-stakes CAR-T showdown with Novartis". FierceBiotech.
- Regalado A (June 2015). "Biotech’s Coming Cancer Cure: Supercharge your immune cells to defeat cancer? Juno Therapeutics believes its treatments can do exactly that". MIT Technology Review.
- "CAR T-Cell Therapy: Engineering Patients’ Immune Cells to Treat Their Cancers". cancer.gov. 2013-12-06. Retrieved 2014-05-09.
- "NIH study demonstrates that a new cancer immunotherapy method could be effective against a wide range of cancers". nih.gov. 2014-05-08. Retrieved 2014-05-09.
- Wilhelm M, Smetak M, Schaefer-Eckart K, Kimmel B, Birkmann J, Einsele H, Kunzmann V (Feb 2014). "Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells". Journal of Translational Medicine 12: 45. doi:10.1186/1479-5876-12-45. PMC 3926263. PMID 24528541.
- Unanue ER (Jul 2013). "Perspectives on anti-CD47 antibody treatment for experimental cancer". Proceedings of the National Academy of Sciences of the United States of America 110 (27): 10886–7. doi:10.1073/pnas.1308463110. PMC 3704033. PMID 23784781.
- Ahmed M, Cheung NK (Jan 2014). "Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy". FEBS Letters 588 (2): 288–97. doi:10.1016/j.febslet.2013.11.030. PMID 24295643.
- Pardoll DM (Apr 2012). "The blockade of immune checkpoints in cancer immunotherapy". Nature Reviews. Cancer 12 (4): 252–64. doi:10.1038/nrc3239. PMID 22437870.
- Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (July 2007). "Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses". Immunity 27 (1): 111–22. doi:10.1016/j.immuni.2007.05.016. PMID 17629517.
- Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D (August 2011). "PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells". EMBO Molecular Medicine 3 (10): 581–92. doi:10.1002/emmm.201100165. PMID 21739608.
- Pollack, Andrew (2016-05-18). "F.D.A. Approves an Immunotherapy Drug for Bladder Cancer". The New York Times. ISSN 0362-4331. Retrieved 2016-05-21.
- BeiGene Presents Initial Clinical Data on PD-1 Antibody BGB-A317 at the 2016 American Society of Clinical Oncology Annual Meeting. June 2016
- Roche. "FDA grants priority review for Roche's cancer immunotherapy atezolizumab in specific type of lung cancer".
- Merck Group. "Immuno-oncology Avelumab".
- Cure today. "Durvalumab continues to progress in treatment of advanced bladder cancer.".
- Avacta Life Sciences. "Affimer biotherapeutics target cancer's off-switch with PD-L1 inhibitor".
- Aleem E (Jun 2013). "β-Glucans and their applications in cancer therapy: focus on human studies". Anti-Cancer Agents in Medicinal Chemistry 13 (5): 709–19. doi:10.2174/1871520611313050007. PMID 23140353.
- Patel S, Goyal A (Mar 2012). "Recent developments in mushrooms as anti-cancer therapeutics: a review". 3 Biotech 2 (1): 1–15. doi:10.1007/s13205-011-0036-2. PMC 3339609. PMID 22582152.
- Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. (December 2014). "Genetic basis for clinical response to CTLA-4 blockade in melanoma". The New England Journal of Medicine 371 (23): 2189–99. doi:10.1056/NEJMoa1406498. PMID 25409260.
- Schumacher TN, Schreiber RD (April 2015). "Neoantigens in cancer immunotherapy". Science 348 (6230): 69–74. doi:10.1126/science.aaa4971. PMID 25838375.
- Cancer Research Institute - What is Cancer Immunotherapy
- Association for Immunotherapy of Cancer
- Society for Immunotherapy of Cancer
- "And Then There Were Five". Economist. Retrieved June 2015.
- "Discover the Science of Immuno-Oncology". Bristol-Myers Squibb. Retrieved 13 March 2014.
- Eggermont A, Finn O. "Advances in immuno-oncology". Oxford University Press. Retrieved March 13, 2014.
- "Immuno-Oncology: Investigating Cancer Therapies Powered by the Immune System". Merck Serono. Retrieved 13 March 2014.