Immunotherapeutics

By Peter J. Delves, PhD, University College London, London, UK

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Biology of the Immune System
Overview of the Immune System
Cellular Components of the Immune System
Molecular Components of the Immune System
Human Leukocyte Antigen (HLA) System
Complement System
Immunotherapeutics

Immunotherapeutic agents use or modify immune mechanisms. Use of these agents is rapidly evolving; new classes, new agents, and new uses of current agents are certain to be developed. A number of different classes of immunotherapeutic agents have been developed (see Table: Some Immunotherapeutic Agents in Clinical Use):

Monoclonal antibodies
Fusion proteins
Soluble cytokine receptors
Recombinant cytokines
Small-molecule mimetics
Cellular therapies

Some Immunotherapeutic Agents in Clinical Use

Agent	Effects	Indications
Monoclonal antibodies
Adalimumab	Anti–TNF-alpha	Moderate to severe RA Plaque psoriasis Moderate to severe Crohn disease refractory to standard treatments Ulcerative colitis Ankylosing spondylitis Psoriatic arthritis Moderate to severe polyarticular juvenile idiopathic arthritis Hidradenitis suppurativa
Alemtuzumab	Anti–B cell (CD52)	B-cell chronic lymphocytic leukemia refractory to standard treatments
Atezolizumab	Anti–PD-L1	Locally advanced or metastatic transitional cell urothelial carcinoma if it progresses during or after platinum-based chemotherapy
Basiliximab	Anti–IL-2 receptor	Prevention of acute kidney rejection
Belimumab	Anti–B-lymphocyte stimulator protein (anti-BLyS)	Autoantibody-positive SLE in adults receiving standard treatment
Bevacizumab	Anti–VEGF-A	Metastatic colorectal cancer (used with IV 5-fluorouracil–based chemotherapy as first- or 2nd-line treatment) Metastatic colorectal cancer (used with fluoropyrimidine-, irinotecan-, or fluoropyrimidine-oxaliplatin–based chemotherapy as 2nd-line treatment) if the cancer progressed during treatment with a first-line regimen that contains bevacizumab Unresectable, locally advanced, recurrent, or metastatic nonsquamous non–small cell lung cancer (used with carboplatin and paclitaxel as first-line treatment) Glioblastoma in adults if the disorder progresses after other treatments have been tried Metastatic renal cell carcinoma (used with IFN-alpha) Persistent, recurrent, or metastatic cervical cancer (used with paclitaxel and cisplatin or paclitaxel and topotecan) Platinum-resistant, recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (used with paclitaxel, pegylated liposomal doxorubicin, or topotecan)
Blinatumomab	Bispecific: Anti-CD19 and anti-CD3	Philadelphia chromosome–negative relapsed or refractory B-cell precursor ALL
Brentuximab vedotin	Anti-CD30 (linked to the antimitotic agent monomethyl auristatin E)	Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or of at least 2 multidrug chemotherapy regimens in patients who are not candidates for ASCT Systemic anaplastic large cell lymphoma after failure of at least one multidrug chemotherapy regimen
Canakinumab	Anti–IL-1 beta	Cryopyrin-associated periodic syndromes (cryopyrinopathies) in patients ≥ 4 yr Juvenile idiopathic arthritis in patients ≥ 2 yr
Certolizumab (pegylated Fab’ fragment)	Anti–TNF-alpha	Moderate to severe RA in adults Moderate to severe Crohn disease if response to conventional treatments is inadequate Psoriatic arthritis Ankylosing spondylitis
Cetuximab	Anti-EGFR	Locally or regionally advanced squamous cell carcinoma of the head and neck (used with radiation therapy) Recurrent locoregional or metastatic squamous cell carcinoma of the head and neck (used with platinum-based therapy and 5-fluorouracil) Recurrent or metastatic squamous cell carcinoma of the head and neck if it progresses after platinum-based therapy Wild-type KRAS, EGFR-expressing, metastatic colorectal cancer, given as follows: With FOLFIRI as first-line treatment With irinotecan if the cancer is refractory to irinotecan-based chemotherapy As a single agent if oxaliplatin- and irinotecan-based chemotherapy is ineffective or patients cannot tolerate irinotecan
Daclizumab	Anti–IL-2 receptor	Prevention of acute kidney rejection
Daratumumab	Anti-CD 38	Multiple myeloma if Patients have received ≥ 3 prior drug regimens that included a proteasome inhibitor and an immunomodulatory drug. or The cancer is refractory to both a proteasome inhibitor and an immunomodulatory drug.
Denosumab	Anti-RANKL	Prevention of skeletal-related events (eg, fractures, bone pain) in patients with bone metastases from solid tumors Treatment of adults and skeletally mature adolescents with a giant cell tumor of bone if the tumor is unresectable or if surgical resection is likely to result in severe morbidity Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy
Dinutuximab	Anti-GD2 glycolipid	High-risk pediatric neuroblastoma that has at least partially responded to prior first-line multidrug, multimodality therapy (used with GM-CSF, IL-2, and isotretinoin [13-cis-retinoic acid])
Eculizumab	Anti–complement component C5	Paroxysmal nocturnal hemoglobinuria Atypical hemolytic-uremic syndrome
Efalizumab^†	Anti-CD11a	Chronic moderate to severe plaque psoriasis
Elotuzumab	Anti-SLAMF7	Multiple myeloma in patients who have received 1 to 3 prior therapies (used with lenalidomide and dexamethasone)
Golimumab	Anti–TNF-alpha	Moderate to severe RA (used with methotrexate) Psoriatic arthritis Ankylosing spondylitis Moderate to severe ulcerative colitis if Patients have an inadequate response to or are intolerant of prior treatments. or They require continuous corticosteroid therapy.
Ibritumomab	Anti–B cell (CD20; linked to the radioactive agent yttrium 90)	Relapsed or refractory low-grade follicular or transformed B-cell non-Hodgkin lymphoma
Infliximab	Anti–TNF-alpha	Moderate to severe Crohn disease or ulcerative colitis if response to conventional treatments is inadequate Moderate to severe RA (used with methotrexate) Active ankylosing spondylitis Active psoriatic arthritis Chronic severe plaque psoriasis when other treatments are less appropriate
Ipilimumab	Anti–CTLA-4	Inoperable or metastatic advanced melanoma Melanoma with pathologic involvement of regional lymph nodes of > 1 mm in patients who have had complete resection, including total lymphadenectomy
Natalizumab	Anti–alpha-4 integrin subunit	Relapsing multiple sclerosis or Crohn disease when other treatments are inadequate
Necitumumab	EGFR1	Metastatic squamous non–small cell lung cancer as first-line treatment (used with gemcitabine and cisplatin)
Nivolumab	Anti–PD-1	Unresectable or metastatic melanoma (used with ipilimumab and, if the melanoma is BRAF V600 mutation–positive, with a BRAF inhibitor) Metastatic non–small cell lung cancer if it progresses during or after platinum-based chemotherapy Advanced renal cell cancer in patients who have received prior antiangiogenesis therapy Hodgkin lymphoma that recurs or progresses after autologous hematopoietic stem cell transplantation and post-transplantation treatment with brentuximab vedotin
Obinutuzumab	Anti-CD20	Follicular lymphoma that recurred after or is refractory to a regimen that contains rituximab (used first with bendamustine, then given as monotherapy) Previously untreated CLL (used with chlorambucil)
Ofatumumab	Anti‒B cell (CD20)	Extended treatment of CLL in patients with complete or partial response after ≥ 2-drug regimens for recurrent or progressive disease CLL refractory to fludarabine and alemtuzumab
Omalizumab	Anti-IgE	Moderate to severe asthma in patients > 12 yr with documented allergic disorders inadequately controlled by inhaled corticosteroids Chronic idiopathic urticaria in patients ≥ 12 yr who remain symptomatic despite H₁antihistamine treatment
Panitumumab	Anti-EGFR	Wild-type KRAS metastatic colorectal cancer as first-line treatment (used with FOLFOX or as monotherapy) if cancer progresses after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan
Pembrolizumab	Anti–PD-1	Inoperable or metastatic advanced melanoma PD-L1+ non–small lung cell carcinoma if it progresses during or after platinum-based chemotherapy
Pertuzumab	Anti-HER2	HER2+ metastatic breast cancer in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic cancer (used with trastuzumab and docetaxel) HER2+, locally advanced, inflammatory, or early-stage breast cancer (either > 2 cm in diameter or node-positive) for neoadjuvant treatment (used with trastuzumab and docetaxel) as part of a complete treatment regimen for early breast cancer
Ramucirumab	Anti–VEGFR-2	Metastatic colorectal cancer that has progressed during or after a first-line drug regimen that contains bevacizumab, oxaliplatin, and a fluoropyrimidine (used with FOLFIRI) Metastatic non–small cell lung cancer that progressed during or after platinum-based chemotherapy (used with docetaxel) Advanced or metastatic gastric or gastroesophageal junction adenocarcinoma if it progresses during or after prior chemotherapy that contains a fluoropyrimidine or platinum-based drug
Ranibizumab	Anti-VEGF	Neovascular (wet) age- related macular degeneration Macular edema after retinal vein occlusion Diabetic macular edema Diabetic retinopathy in patients with diabetic macular edema
Rituximab	Anti–B cell (CD20)	Relapsed or refractory CD20+, low-grade or follicular B-cell non-Hodgkin lymphoma CD20+ CLL (used with fludarabine and cyclophosphamide) Moderate to severe RA (used with methotrexate) when response to TNF-antagonists is inadequate Granulomatosis with polyangiitis (Wegener granulomatosis) Microscopic polyangiitis
Secukinumab	Anti–IL-17A	Ankylosing spondylitis Psoriatic arthritis Moderate to severe plaque psoriasis
Siltuximab	Anti–IL-6	Multicentric Castleman disease in patients who are HIV- and HHV-8–negative
Tocilizumab	Anti–IL-6 receptor (anti–IL-6R)	Moderate to severe RA when response to TNF-antagonists is inadequate Polyarticular or systemic juvenile idiopathic arthritis in patients ≥ 2 yr
Tositumomab	Anti–B cell (CD20; linked to radioactive iodine [¹³¹I])	Refractory and relapsed CD20+ low-grade follicular or transformed non-Hodgkin lymphoma
Trastuzumab	Anti–HER2	HER2+ breast cancer HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma
Ustekinumab	Anti–IL-12 and –IL-23	Moderate to severe plaque psoriasis Psoriatic arthritis
Vedolizumab	Anti–alpha-4 beta-7 integrin	Moderate to severe active ulcerative colitis if response to conventional therapy or TNF-antagonists is inadequate Moderate to severe Crohn disease if response to conventional therapy or TNF-antagonists is inadequate
Fusion proteins
Abatacept (CTLA-4 extracellular domain fused to the Fc region of IgG1)	Inhibition of T-cell activation	Moderate to severe RA
Denileukin diftitox (fusion of IL-2 to diphtheria toxin)	Delivery of toxin to CD25 component of IL-2 receptor	CD25+ cutaneous T-cell lymphoma
Etanercept (fusion of 2 CD120b TNF-alpha receptors to Fc region of IgG1)	Decrease in TNF levels	RA Polyarticular juvenile idiopathic arthritis in patients ≥ 2 yr Psoriatic arthritis Ankylosing spondylitis Plaque psoriasis
Soluble cytokine receptor
Anakinra (IL-1 receptor antagonist, sometimes pegylated for longer half-life)	Competitive inhibition of IL-1 alpha and IL-1 beta activities	In patients ≥ 18 yr: Moderate to severe RA, cryopyrin-associated periodic syndromes
Cytokines
IFN-alpha	Antiproliferative and antiviral	In patients ≥ 18 yr: Chronic hepatitis C, AIDS-related Kaposi sarcoma, hairy cell leukemia, chronic myelogenous leukemia, metastatic melanoma
IFN-beta	Antiproliferative and antiviral	Reduction of number of flare-ups in relapsing multiple sclerosis
IFN-gamma	Immunostimulatory and antiviral	Control of infection in chronic granulomatous disease, delay of progression in severe malignant osteopetrosis
IL-2	Immunostimulatory	Metastatic renal cell carcinoma and metastatic melanoma
IL-11	Thrombopoietic growth factor	Prevention of thrombocytopenia after myelosuppressive chemotherapy
G-CSF	Stimulation of granulocyte production	Reversal of neutropenia after chemotherapy, radiation therapy, or both
GM-CSF	Stimulation of granulocyte and monocyte/macrophage production	Reversal of neutropenia after chemotherapy, radiation therapy, or both
Cellular therapy
Sipuleucel-T	Autologous circulating ICAM-1+ peripheral blood mononuclear cells activated with prostatic acid phosphatase and GM-CSF	Asymptomatic or minimally symptomatic metastatic prostate cancer refractory to castration (hormone therapy)
*mAbs used for diagnostic testing and radiologic imaging are not included.
^†Efalizumab is not available in the US.
ALL = acute lymphocytic leukemia; ANCA = antineutrophil cytoplasmic antibodies; CD = cluster of differentiation; CLL = chronic lymphocytic leukemia; CTLA = cytotoxic T-lymphocyte antigen; EGFR = epidermal growth factor receptor; Fc = crystallizable fragment; FOLFIRI = leucovorin (folinic acid), fluorouracil, plus irinotecan; FOLFOX = leucovorin (folinic acid), fluorouracil, plus oxaliplatin; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; HER2 = human epidermal growth factor receptor 2; HHV-8 = human herpesvirus 8; ICAM = intercellular adhesion molecule; IFN = interferon; mAb = monoclonal antibody; PD-L1 = programmed death–ligand 1; RANKL = receptor activator of nuclear factor kappa beta ligand; SLAMF7 = signaling lymphocyte activation molecule family member 7; TNF = tumor necrosis factor; VEGF-A = vascular endothelial growth factor A; VEGFR = VEGF receptor.

Monoclonal antibodies

Monoclonal antibodies (mAbs) are manufactured in vitro to recognize specific targeted antigens (Ags); they are used to treat solid and hematopoietic tumors and inflammatory disorders. The mAbs that are currently in clinical use include

Murine
Chimeric
Humanized
Fully human

Murine mAbs are produced by injecting a mouse with an Ag, harvesting its spleen to obtain B-cells that are producing Ab specific to that Ag, fusing those cells with immortal mouse myeloma cells, growing these hybridoma cells (eg, in cell culture), and harvesting the Ab. Although mouse antibodies are similar to human antibodies, clinical use of murine mAbs is limited because they induce human anti-mouse Ab production, can cause immune complex serum sickness (a type III hypersensitivity reaction), and are rapidly cleared.

To minimize the problems due to use of pure mouse Ab, researchers have used recombinant DNA techniques to create monoclonal Abs that are part human and part mouse. Depending on the proportion of the Ab molecule that is human, the resultant product is termed one of the following:

Chimeric
Humanized

In both cases, the process usually begins as above with production of mouse hybridoma cells that make Ab to the desired Ag. Then the DNA for some or all of the variable portion of the mouse Ab is merged with DNA for human immunoglobulin. The resultant DNA is placed in a mammalian cell culture, which then expresses the resultant gene, producing the desired Ab. If the mouse gene for the whole variable region is spliced next to the human constant region, the product is termed "chimeric." If the mouse gene for only the Ag-binding hypervariable regions of the variable region is used, the product is termed "humanized."

Chimeric mAbs activate Ag-presenting cells (APCs) and T cells more effectively than murine mAbs but can still induce production of human anti-chimeric Ab.

Humanized mAbs against various antigens (Ags) have been approved for the treatment of colorectal and breast cancer, leukemia, allergy, autoimmune disease, transplant rejection, and respiratory syncytial virus infection.

Fully human mAbs are produced using transgenic mice that contain human immunoglobulin genes or using phage display (ie, a bacteriophage-based cloning method) of immunoglobulin genes isolated from human B cells. Fully human mAbs have decreased immunogenicity and therefore may have fewer adverse effects in patients.

Fusion proteins

These hybrid proteins are created by linking together the gene sequences encoding all or part of 2 different proteins to generate a chimeric polypeptide that incorporates desirable attributes from the parent molecules (eg, a cell-targeting component combined with a cell toxin). The circulating half-life of therapeutic proteins can also often be improved by fusing them to another protein that naturally has a longer serum half-life (eg, the Fc region of IgG).

Soluble cytokine receptors

Soluble versions of cytokine receptors are used as therapeutic reagents. They can block the action of cytokines by binding with them before they attach to their normal cell surface receptor.

Etanercept, a fusion protein, consists of 2 identical chains from the CD120b receptor for tumor necrosis factor (TNF)-alpha. This agent thus blocks TNF-alpha and is used to treat RA refractory to other treatments, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.

Soluble IL receptors (eg, those for IL-1, IL-2, IL-4, IL-5, and IL-6) are being developed for treatment of inflammatory and allergic disorders and cancer.

Recombinant cytokines

Colony-stimulating factors (CSF), such as erythropoietin, granulocyte CSF (G-CSF), and granulocyte-macrophage CSF (GM-CSF), are used in patients undergoing chemotherapy or transplantation for hematologic disorders and cancers (see Table: Some Immunotherapeutic Agents in Clinical Use). Interferon-alpha (IFN-alpha) and IFN-gamma are used to treat cancer, immunodeficiency disorders, and viral infections; IFN-beta is used to treat relapsing multiple sclerosis. Many other cytokines are being studied.

Anakinra, used to treat RA, is a recombinant, slightly modified form of the naturally occurring IL-1R antagonist; this drug attaches to the IL-1 receptor and thus prevents binding of IL-1, but unlike IL-1, it does not activate the receptor.

Cells expressing cytokine receptors can be targeted by modified versions of the relevant cytokine (eg, denileukin diftitox, which is a fusion protein containing sequences from IL-2 and from diphtheria toxin). Denileukin is used in cutaneous T-cell lymphoma to target the toxin to cells expressing the CD25 component of the IL-2 receptor.

Cellular therapies

Immune system cells are harvested (eg, by leukapheresis) and activated in vitro before they are returned to the patient. The aim is to amplify the normally inadequate natural immune response to cancer. Methods of activating immune cells include using cytokines to stimulate and increase numbers of antitumor cytotoxic T cells and using pulsed exposure to antigen-presenting cells such as dendritic cells with tumor antigens.

Last full review/revision January 2017 by Peter J. Delves, PhD