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Immunotherapeutics

By Peter J. Delves, PhD, Professor of Immunology, Division of Infection & Immunity, Faculty of Medical Sciences, University College London, London, UK

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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

Moderate to severe polyarticular juvenile idiopathic arthritis

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

  • 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

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

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)

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.

Small-molecule mimetics

Small linear peptides, cyclicized peptides, and small organic molecules are being developed as agonists or antagonists for various applications. Screening libraries of peptides and organic compounds can identify potential mimetics (eg, agonists for receptors for erythropoietin, thrombopoietin, and G-CSF).

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.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • EMPLICITI
  • DARZALEX
  • SOLIRIS
  • ENTYVIO
  • LEUKERAN
  • ENBREL
  • REMICADE
  • HUMIRA
  • OZURDEX
  • OPDIVO
  • PERJETA
  • No US brand name
  • HERCEPTIN
  • ELOXATIN
  • XOLAIR
  • TAXOTERE
  • OTREXUP
  • TREANDA
  • CARAC
  • HYCAMTIN
  • BLINCYTO
  • KEYTRUDA
  • AVASTIN
  • PLATINOL
  • STELARA
  • CAMPTOSAR
  • ZEVALIN
  • TYSABRI
  • SIMULECT
  • ERBITUX
  • UNITUXIN
  • GEMZAR
  • KINERET
  • CAMPATH
  • CYRAMZA
  • RITUXAN
  • TAXOL
  • VECTIBIX
  • ACTEMRA
  • PROLIA
  • CYTOXAN (LYOPHILIZED)
  • SIMPONI
  • PORTRAZZA
  • SOTRET
  • ORENCIA
  • REVLIMID
  • LUCENTIS