Immunotherapy


Article Author:
Angel Justiz Vaillant


Article Editor:
Patrick Zito


Editors In Chief:
David Wood
Andrew Wilt
Mary Cataletto


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/18/2019 6:32:34 PM

Indications

Immunotherapy is the use of drugs (e.g., immunosuppressors), biologicals (e.g., cytokines, monoclonal antibodies, and antisera), vitamins and minerals (e.g., zinc, vitamin C, and vitamin B6), transplantation (e.g., bone marrow) and immunizations (e.g., prophylactic and therapeutic vaccines) to control immune responses in diverse direction. For example, immunotherapy is used to upregulate or downregulate the immune system to achieve a therapeutic effect in immunological mediated disorders including immunodeficiencies, hypersensitivity reactions, autoimmune diseases, tissue and organ transplantations, malignancies, inflammatory disorders, infectious diseases, and any other disease, where immunotherapy can improve the quality and life expectancy.[1][2][3][4][5]

Clinicians describe the use of immunotherapy in some essential disorders of the immune system. The use of immunoglobulins, transfer factor, immunosuppressors, monoclonal antibodies, cytokines, nutritional supplements, transplantation, among other therapies is listed below.

Immunoglobulin Therapy 

  • X- linked agammaglobulinemia
  • Transient hypogammaglobulinemia of infancy
  • Variable common immunodeficiency
  • Selective immunoglobulin deficiencies, except for IgA
  • Hyper-IgM syndrome
  • Lupus-like syndromes

 Use of Transfer Factor (Dialysable Leukocyte Extract)

  • Interstitial pneumonia in acquired immunodeficient states
  • Recurrent viral infections in immunodeficiency syndromes
  • Chronic mucocutaneous candidiasis
  • Primary tuberculosis with immunodeficiency
  • Wiskott-Aldrich syndrome
  • Severe combined immunodeficiency disease
  • Chronic active hepatitis
  • Coccidioidomycosis
  • Behcet disease
  • Aphthous stomatitis
  • Familial keratoacanthoma 
  • Malignancy  

Use of Immunosuppressors 

  • Systemic lupus erythematosus (SLE)  
  • Wiskott-Aldrich syndrome  
  • Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy   
  • Autoimmune lymphoproliferative syndrome
  • Idiopathic CD4+ lymphocytopenia
  • Complement system deficiencies
  • Various malignancies

Transplantation

Bone marrow transplant  

  • RAG-1/RAG-2 SCID
  • ADA-SCID  
  • Artemis SCID
  • Wiskott-Aldrich syndrome
  • X-linked agammaglobulinemia
  • Acute leukemia

Thymus transplant    

  • DiGeorge syndrome

Immunizations   

  • Diphtheria, tetanus, and pertussis (DTP)
  • Inactivated Polio vaccine
  • Measles, Mumps, and Rubella
  • Pneumococcal conjugate
  • Hemophilus B conjugate
  • Hepatitis B
  • Varicella
  • Bacille Calmette-Guerin (BCG)
  • Human Papillomavirus (HPV)
  • Meningococcal vaccine
  • Cholera vaccine
  • Rotavirus vaccine
  • Yellow fever vaccine
  • Dengue vaccine 

Use of Cytokines in the Immunotherapy of Advanced Malignancies   

  • Interleukin-2
  • Interleukin-7
  • Interleukin-12
  • Interleukin-18
  • Interleukin-21

Use of Nutritional Supplements (Vitamins A, C, E and B6, Iron, Zinc, Selenium, and Copper)  

  • Primary immunodeficiency with malnutrition
  • Lymphoma
  • Malignancies in general 
  • Graft-versus-host reaction
  • Diseases with impaired cell-mediated immunity 
  • Recurrent and chronic bacterial infections
  • SCID
  • HIV/AIDS
  • Burns  

Phase III Clinical Trials of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib   

  • Relapsed or refractory chronic lymphocytic leukemia
  • Small lymphocytic lymphoma
  • Relapsed or refractory Mantle cell lymphoma
  • Newly diagnosed non-germinal center B-cell subtype of diffuse large B-cell lymphoma

Use of Interferon Gamma    

  • Chronic granulomatous disease
  • Bladder carcinoma
  • Melanoma
  • Chagas disease
  • Lepromatous leprosy
  • HIV/AIDS 
  • Cryptococcal meningitis

Immune checkpoint inhibitors

  • Ipilimumab 
  • Nivolumab 
  • Pembrolizumab 
  • Atezolizumab 
  • Avelumab  
  • Durvalumab

Cytokine antagonists (IL-1RA)

  • Septic shock
  • Inflammatory bowel disease
  • Ischemia-reperfusion injury
  • Adult respiratory distress syndrome
  • Osteoporosis
  • Polyarteritis nodosa
  • Glomerulonephritis

Granulocyte-macrophage colony-stimulating factor (GM-CSF)

  • Accelerate marrow recovery after autologous bone marrow transplantation
  • Primary neutropenia
  • Myelodysplasia
  • Myeloproliferative disorders
  • AIDS
  • Aplastic anemia
  • Neutropenia associated with Felty's syndrome 

Mechanism of Action

Intravenous Immunoglobulins (IVIG)

IVIG is a product made from fractionation of pools of thousands of plasma donations collected in blood transfusion services. Traces of IgM and IgA and cytokines are present in IVIG.  IVIGs have several mechanisms of actions that have been proposed to achieve their therapeutic effects including[6][7][8]:

  • Effects of IVIG on activated B lymphocytes                   
  • Infusion of IVIG results in auto-IgG suppression          
  • Interaction of Fc fragment with Fc receptors        
  • Interaction of infused IgG with complement proteins           
  • Modulation of synthesis of cytokines         
  • Modulation of cell proliferation and apoptosis      
  • Remyelinisation     
  • Neutralizes pathogenic autoantibodies          
  • Interferes with antigen presentation       
  • Functional blockade of Fc receptors on splenic macrophages      
  • Selection of immune repertoires       
  • Neutralization of bacterial toxins and superantigens       
  • Hindrance of natural killer cell activity    
  • Inhibition of matrix metalloproteinase-9      
  • Suppression of NF-kB activation and IkB degradation   
  • G1 cell cycle arrest      
  • Prevention of tumor growth            
  • Enhances the expansion of Tregs 

IVIG has been used with some success to improve the symptoms and clinical signs of immune thrombocytopenic purpura (ITP), Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, Systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies, ANCA-associated vasculitis, multiple motor neuropathy, multiple sclerosis, Myasthenia gravis, Kawasaki disease, autoimmune uveitis, dermatomyositis, systemic sclerosis, Sjogren syndrome, antiphospholipid antibody syndrome, Still's disease, acute disseminated encephalomyelitis, diabetic neuropathy, Lambert-Eaton myasthenic syndrome, Opsoclonus-myoclonus, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, polymyositis, Rasmussen's encephalitis, Stiff person syndrome, primary immunodeficiency disorders, secondary immunodeficiency disorder, chronic lymphocytic leukemia, bone marrow transplantation, Treatment-induced neutropenia and thrombocytopenia, AIDS, autoimmune thyroiditis, inclusion-body myositis, graft versus host disease, recurrent pregnancy loss, cancer, severe infections, toxic epidermal necrolysis, Stevens-Johnson syndrome, and neonatal hemochromatosis.

Transfer Factor

It is a dialysable extract of leukocytes and can transfer cell-mediated immunity from one individual to another. It may use in several pathologies including immunodeficiencies, viral infections, malignancies, and recurrent fungal infections. Some patients with type I hypersensitivity disorders have reacted to this product.[9][10][11]

Immunosuppressors

Steroids inhibit cytokine synthesis, affect cell migration and inhibit the production of leukocytes. Cyclophosphamide acts by covalent alkylation, together with chlorambucil exert an immunomodulatory effect. They inhibit strand separation of DNA during replication. Methotrexate is an analog of folic acid and blocks pathways essential for DNA synthesis. Azathioprine is a drug that can convert to 6-mercaptopurine, and its effect is incorporation into DNA as a fraudulent base.[12]

Transplantation

It is a promising solution for many rare diseases that can manifest as primary immunodeficiencies including severe-combined immunodeficiency disorder (SCID), DiGeorge syndrome, Wiskott-Aldrich syndrome, and X-linked agammaglobulinemia.[13][14]

Several Immunotherapy Modalities Used in Cancer Treatment

The use of monoclonal antibodies can use in the cancer immunotherapy, for example, immune checkpoint inhibitors (ICIs) including pembrolizumab and atezolizumab. These ICI unlock the immune system, which is then able to recognize tumors and kill them.[4]The use of cytokines to successfully treat certain malignancies is a reality, for example, the use of IL-2 in combination with interferon-gamma for renal carcinoma; use of interferon alpha and beta for hairy leukemia; and TNF-alpha used in various tumors caused a notable reduction of the mass. These cytokines upregulated the immune system through stimulation of T cell and NK cell activation and increased MHC class I expression.

Administration

IVIG can administer intravenously in the dosage of 0.4g/kg for 5 days to treat Guillain–Barre Syndrome, but the dose varies depending on the pathology. Cyclophosphamide low dose has had a more significant impact on cell-mediated immunity. In humans, a low-dose bolus 600 mg/m B cells decrease more than T cells, and among T cells the CD8 subset diminishes more than CD4 cells.

Adverse Effects

  • Cyclophosphamide and chlorambucil include bone marrow toxicity, and therefore, leukopenia must be monitored.
  • Azathioprine produces reductions of both T and B lymphocytes. 
  • Transfer factor must be given with caution in patients with Type I hypersensitivity reactions to the prevention of anaphylaxis.
  • Interleukins must be given in a low dose to prevent side effects and decrease morbidity.
  • Glucocorticoid therapy causes negative calcium balance leading to osteoporosis, increased appetite, centripetal obesity, impaired wound healing, increased risk of infection, suppression of hypothalamic-pituitary-adrenal axis and growth arrest in children. Other side effects seen are myopathy, avascular necrosis, hypertension, plethora, hyperlipidemia, and edema.
  • Side effects of NSAID therapy include gastritis, duodenal and gastric ulcer, decreased creatinine clearance, acute renal failure, interstitial nephritis, confusion, memory loss, and personality changes, especially in the elderly.

Contraindications

Patients with T-cell deficiencies including SCID should not vaccinate with the live-attenuated vaccine, because there is a danger that the antigen reverses its pathogenicity and causes physical illness. Patients with IgA deficiency should not be given IgG preparations that are not highly purified, because there is a danger of a hypersensitivity reaction, If the immune system does not recognize the IgA in the preparation, this can be life-threatening. Patients with DiGeorge syndrome should not be transplanted with a thymus older than 14 weeks, because a graft-versus-host reaction may occur. The donor can be one of the siblings or a parent if genetic compatibility exists. Blood group compatibility for major antigens such as the ABO system and Rh system must match.[13][15]

Enhancing Healthcare Team Outcomes

The use of IVIG has expanded significantly over the past 3 decades. In general patients with immune deficits are best managed by a multidisciplinary team that includes hematology nurses and pharmacists. While iVIG is effective, patients need to be informed that the therapy is not benign and is associated with adverse effects. Close monitoring of patients is necessary because of allergies, anaphylaxis and graft versus host reactions.


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Immunotherapy - Questions

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Which of the following statements regarding allergen immunotherapy is false?



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Immunotherapy - References

References

Antiviral T Cells for Adenovirus in the Pretransplant Period: A Bridge Therapy for Severe Combined Immunodeficiency., Miller HK,Hanley PJ,Lang H,Lazarski CA,Chorvinsky EA,McCormack S,Roesch L,Albihani S,Dean M,Hoq F,Adams RH,Bollard CM,Keller MD,, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2018 May 9     [PubMed]
Interferon alpha as antiviral therapy in chronic active Epstein-Barr virus disease with interstitial pneumonia - case report., Roliński J,Grywalska E,Pyzik A,Dzik M,Opoka-Winiarska V,Surdacka A,Maj M,Burdan F,Pirożyński M,Grabarczyk P,Starosławska E,, BMC infectious diseases, 2018 Apr 20     [PubMed]
Increased risk of hematologic malignancies in primary immunodeficiency disorders: opportunities for immunotherapy., Verhoeven D,Stoppelenburg AJ,Meyer-Wentrup F,Boes M,, Clinical immunology (Orlando, Fla.), 2018 May     [PubMed]
The role of regulatory T cells in immunopathogenesis and immunotherapy of viral infections., Karkhah A,Javanian M,Ebrahimpour S,, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2018 Apr     [PubMed]
Immune checkpoint inhibitors and radiotherapy-concept and review of current literature., Thangamathesvaran L,Shah R,Verma R,Mahmoud O,, Annals of translational medicine, 2018 Apr     [PubMed]
Recombinant adenovirus expressing a dendritic cell-targeted melanoma surface antigen for tumor-specific immunotherapy in melanoma mice model., Guo LL,Wang GC,Li PJ,Wang CM,Liu LB,, Experimental and therapeutic medicine, 2018 Jun     [PubMed]
Immunosuppression minimization in kidney transplantation., Cantarovich D,Vistoli F,Soulillou JP,, Frontiers in bioscience : a journal and virtual library, 2008 Jan 1     [PubMed]
Immunodeficiency, Justiz Vaillant AA,Qurie A,,, 2018 Jan     [PubMed]
Querido S,Weigert A,Adragão T,Henriques J,Birne R,Matias P,Jorge C,Nascimento C,Bruges M,Machado D, Intravenous Immunoglobulin and Rituximab in HLA Highly Sensitized Kidney Transplant Recipients. Transplantation proceedings. 2018 Apr;     [PubMed]
Martínez T,Garcia-Robledo JE,Plata I,Urbano MA,Posso-Osorio I,Rios-Serna LJ,Barrera MC,Tobón GJ, Mechanisms of action and historical facts on the use of intravenous immunoglobulins in systemic lupus erythematosus. Autoimmunity reviews. 2019 Jan 11;     [PubMed]
Apte S,Navarro-Puerto J,Damodar S,Ramanan V,John J,Kato G,Ross C,Shah C,Torres M,Fu C',Rucker K,Pinciaro P,Barrera G,Aragonés ME,Ayguasanosa J, Safety and efficacy of intravenous immunoglobulin (Flebogamma{sup}®{/sup} 10% DIF) in patients with immune thrombocytopenic purpura. Immunotherapy. 2018 Nov 30;     [PubMed]
Xu Y,Zhang Q,Zhan X,Xie D,Dai G,Yang H, [Preparation and immunological evaluation of oral solution of egg yolk-derived hepatitis B virus-specific transfer factor]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University. 2013 Dec;     [PubMed]
Pizza G,Viza D,De Vinci C,Palareti A,Cuzzocrea D,Fornarola V,Baricordi R, Orally administered HSV-specific transfer factor (TF) prevents genital or labial herpes relapses. Biotherapy (Dordrecht, Netherlands). 1996;     [PubMed]
Mikula I,Pistl J,Rosocha J, Dialyzable leukocyte extract used in the prevention of Salmonella infection in calves. Veterinary immunology and immunopathology. 1992 Apr;     [PubMed]
Alexander KE,Tong PL,Macartney K,Beresford R,Sheppeard V,Gupta M, Live zoster vaccination in an immunocompromised patient leading to death secondary to disseminated varicella zoster virus infection. Vaccine. 2018 Jun 22     [PubMed]

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