Continuing Education Activity

Immunotherapy is a pivotal intervention in managing a spectrum of immunological disorders, from immunodeficiencies to malignancies. This activity discusses the diverse modalities of immunotherapy, their mechanisms of action, potential adverse events, and crucial considerations such as dosing and monitoring. Participants will explore the conditions amenable to immunotherapeutic interventions to better comprehend immunotherapy's role in enhancing the quality of life and longevity of afflicted individuals. Attendees will gain additional insights into immunotherapeutic agents by discussing their pharmacodynamics, pharmacokinetics, and pertinent interactions. By fostering a comprehensive understanding of immunotherapeutic principles, this program empowers healthcare teams to deliver personalized, efficacious care to patients navigating immunological challenges, thereby advancing the frontier of modern medicine.

Objectives:

• Identify different categories of immunotherapy.
• Determine indicated conditions for each type of immunotherapy.
• Identify some of the contraindications of various forms of immunotherapy.
• Select interprofessional team strategies for improving care coordination and communication to advance immunotherapy, improve outcomes, and minimize adverse events.

Indications

Immunotherapy is the use of drugs (eg, immunosuppressors), biologicals (eg, cytokines, monoclonal antibodies, and antisera), vitamins and minerals (eg, zinc, vitamin C, and vitamin B6), transplantation (eg, bone marrow), and immunizations (eg, prophylactic and therapeutic vaccines) to control immune responses. For example, immunotherapy works to upregulate or downregulate the immune system to achieve a therapeutic effect in immunologically 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][6]

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, and transplantation 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 (SCID)
• Chronic active hepatitis
• Coccidioidomycosis
• Behçet 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-Guérin (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 syndrome 

CAR T-cell therapy

CAR T-cell therapy has primarily been investigated and approved for certain hematological malignancies, particularly B-cell malignancies. These include:

• B-cell Acute Lymphoblastic Leukemia (B-ALL): CAR T-cell therapy has demonstrated remarkable efficacy in treating relapsed or refractory B-ALL, particularly in pediatric and young adult patients.
• Diffuse Large B-cell Lymphoma (DLBCL): CAR T-cell therapy has been approved for certain subtypes of DLBCL, including relapsed or refractory DLBCL after 2 or more lines of systemic therapy.
• Follicular Lymphoma (FL): CAR T-cell therapy has demonstrated promising results in treating relapsed or refractory FL, especially in patients who have failed multiple lines of therapy.
• Mantle Cell Lymphoma (MCL): CAR T-cell therapy has shown efficacy in treating relapsed or refractory MCL, particularly in patients who have failed prior therapies.
• Chronic Lymphocytic Leukemia (CLL): While still investigational, CAR T-cell therapy is being studied in CLL, particularly in patients with high-risk disease or those who have relapsed after multiple lines of therapy.

In addition to these hematological malignancies, CAR T-cell therapy is also being investigated for certain types of solid tumors, although progress in this area has been more limited. Solid tumors being targeted with CAR T-cell therapy include:

• Multiple Myeloma: CAR T-cell therapy targeting BCMA (B-cell maturation antigen) has shown promise in treating relapsed or refractory multiple myeloma.
• Glioblastoma: CAR T-cell therapy targeting EGFRvIII (epidermal growth factor receptor variant III) has been investigated in glioblastoma, although results have been mixed.
• Sarcomas: CAR T-cell therapy is being explored in certain types of sarcomas, including osteosarcoma and synovial sarcoma, although research is still in the early stages.

While CAR T-cell therapy has shown significant promise in treating certain types of cancer, particularly B-cell malignancies, ongoing research is needed to expand its applicability to other cancer types and improve its efficacy and safety profile.

Mechanism of Action

Intravenous Immunoglobulins (IVIG)

IVIG is a product isolated from fractionation pools of thousands of plasma donations collected in blood transfusion services. Traces of IgM, IgA, and cytokines are present in IVIG. IVIGs have several proposed mechanisms of action including:[7][8][9]

• 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      
• Remyelination
• 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 conditions that include:

• 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
• Sjögren syndrome
• Antiphospholipid antibody syndrome
• Still disease
• Acute disseminated encephalomyelitis
• Diabetic neuropathy
• Lambert-Eaton myasthenic syndrome
• Opsoclonus-myoclonus
• Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections
• Polymyositis
• Rasmussen 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
• Neonatal hemochromatosis

Transfer Factor

Transfer factor is a dialysable extract of leukocytes that can transfer cell-mediated immunity from one individual to another. It may be used for several pathologies, including immunodeficiencies, viral infections, malignancies, and recurrent fungal infections. Some patients with type I hypersensitivity disorders have demonstrated a response to this product.[10][11][12]

Immunosuppressors

Steroids inhibit cytokine synthesis, affect cell migration, and inhibit the production of leukocytes. Together with chlorambucil, cyclophosphamide acts by covalent alkylation to exert an immunomodulatory effect. This combination inhibits the separation of DNA strands 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 to be incorporated into DNA as a fraudulent base.[13]

Transplantation

Transplantation 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.[14]

Several Immunotherapy Modalities Used in Cancer Treatment

The use of monoclonal antibodies can be used in cancer immunotherapy (eg, immune checkpoint inhibitors (ICIs). These drugs include pembrolizumab and atezolizumab. These ICIs unlock the immune system, which is then able to recognize tumors and kill them.[4]

Cytokines have successfully treated certain malignancies. For example, IL-2 combined with interferon-γ for renal carcinoma, interferon-α and β for hairy leukemia, and TNF-α used in various tumors caused a notable reduction of the mass. These cytokines upregulated the immune system by stimulating T-cell and NK cell activation and increased MHC class I expression.

CAR T-cell therapy, or Chimeric Antigen Receptor T-cell therapy, is a groundbreaking immunotherapy approach used to treat certain types of cancer. Here are the key principles:[15][6]

• CAR Structure: CARs are synthetic receptors that redirect T-cells to recognize and attack cancer cells. They consist of an extracellular antigen-binding domain, a transmembrane domain, and intracellular signaling domains.
• Antigen Recognition: The extracellular domain of the CAR is engineered to recognize a specific antigen present on the surface of cancer cells. This antigen is often a tumor-associated antigen (TAA) or a cancer-specific antigen.
• T-Cell Activation: Upon binding to the target antigen, the CAR activates the T-cell, leading to its proliferation, cytokine release, and cytotoxic activity against the cancer cell.
• Persistence and Memory: CAR T-cells are designed to persist in the body and form memory cells, providing long-term surveillance against cancer recurrence.
• Treatment Process: The CAR T-cell therapy process involves collecting a patient's T-cells through leukapheresis, genetically engineering them to express the CAR, expanding them in the laboratory, and then reinfusing them into the patient.
• Clinical Applications: CAR T-cell therapy has shown remarkable success in treating certain hematological malignancies, such as B-cell acute lymphoblastic leukemia (B-ALL) and certain types of non-Hodgkin lymphoma (NHL). It is also being investigated for solid tumors.
• Challenges and Side Effects: Despite its efficacy, CAR T-cell therapy can be associated with side effects such as cytokine release syndrome (CRS) and neurotoxicity. Managing these side effects and improving the therapy's safety profile are ongoing research areas.

Administration

IVIG can be administered intravenously with a dosage of 0.4 g/kg for 5 days to treat Guillain–Barré syndrome, but the dose varies depending on the pathology. Low-dose cyclophosphamide has had a more significant impact on cell-mediated immunity. In humans, a low-dose bolus of 600 mg/m B-cells decreases more than T-cells, and among T-cells, the CD8 subset diminishes more than CD4 cells.

Adverse Effects

Adverse effects of immunotherapy include:

• Cyclophosphamide and chlorambucil include bone marrow toxicity; therefore, leukopenia requires monitoring.
• Azathioprine produces reductions of both T and B-lymphocytes. 
• Giving transfer factor requires caution in patients with Type I hypersensitivity reactions to prevent 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, central obesity, impaired wound healing, increased risk of infection, suppression of the hypothalamic-pituitary-adrenal axis, and growth arrest in children. Other side effects include myopathy, avascular necrosis, hypertension, plethora, hyperlipidemia, and edema.
• Adverse effects of NSAID therapy include gastritis, duodenal and gastric ulcers, decreased creatinine clearance, acute renal failure, interstitial nephritis, confusion, memory loss, and personality changes, especially in older patients.

Contraindications

Patients with T-cell deficiencies (including SCID) should not be vaccinated with the live-attenuated vaccine because there is a danger that the antigen will reverse its pathogenicity and cause illness. Patients with IgA deficiency should not receive 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 a sibling or a parent if genetic compatibility exists. Blood group compatibility for major antigens (such as the ABO system and Rh system) must match.[14][16]

Enhancing Healthcare Team Outcomes

The use of IVIG has expanded significantly over the past 3 decades. Providing care to patients with immune deficiencies is most effective with an interprofessional team that includes clinicians (MDs, DOs, NPs, PAs), specialists, hematology nurses, and pharmacists. While IVIG is effective, patients need to understand 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. Given the potential for adverse events with immunotherapy, the entire team must be vigilant for these reactions. The pharmacist must have close involvement with nursing and the clinician staff, with all members of the interprofessional team informed and communicating regarding the adverse event profile. This is so immunotherapy has the best chance to help the patient with minimal chance for adverse effects.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Roliński J, Grywalska E, Pyzik A, Dzik M, Opoka-Winiarska V, Surdacka A, Maj M, Burdan F, Pirożyński M, Grabarczyk P, Starosławska E. Interferon alpha as antiviral therapy in chronic active Epstein-Barr virus disease with interstitial pneumonia - case report. BMC Infect Dis. 2018 Apr 20;18(1):190. [PMC free article: PMC5910619] [PubMed: 29678144]

2.

Verhoeven D, Stoppelenburg AJ, Meyer-Wentrup F, Boes M. Increased risk of hematologic malignancies in primary immunodeficiency disorders: opportunities for immunotherapy. Clin Immunol. 2018 May;190:22-31. [PubMed: 29499421]

3.

Guo LL, Wang GC, Li PJ, Wang CM, Liu LB. Recombinant adenovirus expressing a dendritic cell-targeted melanoma surface antigen for tumor-specific immunotherapy in melanoma mice model. Exp Ther Med. 2018 Jun;15(6):5394-5402. [PMC free article: PMC5958800] [PubMed: 29844804]

4.

Thangamathesvaran L, Shah R, Verma R, Mahmoud O. Immune checkpoint inhibitors and radiotherapy-concept and review of current literature. Ann Transl Med. 2018 Apr;6(8):155. [PMC free article: PMC5952022] [PubMed: 29862244]

5.

Karkhah A, Javanian M, Ebrahimpour S. The role of regulatory T cells in immunopathogenesis and immunotherapy of viral infections. Infect Genet Evol. 2018 Apr;59:32-37. [PubMed: 29413883]

6.

Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. [PMC free article: PMC4267531] [PubMed: 25317870]

7.

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. Transplant Proc. 2018 Apr;50(3):723-727. [PubMed: 29661424]

8.

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. Autoimmun Rev. 2019 Mar;18(3):279-286. [PubMed: 30639648]

9.

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^® 10% DIF) in patients with immune thrombocytopenic purpura. Immunotherapy. 2019 Feb;11(2):81-89. [PubMed: 30499734]

10.

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. 2013 Dec;33(12):1827-30. [PubMed: 24369255]

11.

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. 1996;9(1-3):67-72. [PubMed: 8993760]

12.

Mikula I, Pistl J, Rosocha J. Dialyzable leukocyte extract used in the prevention of Salmonella infection in calves. Vet Immunol Immunopathol. 1992 Apr;32(1-2):113-24. [PubMed: 1604794]

13.

Cantarovich D, Vistoli F, Soulillou JP. Immunosuppression minimization in kidney transplantation. Front Biosci. 2008 Jan 01;13:1413-32. [PubMed: 17981639]

14.

Justiz Vaillant AA, Qurie A. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jun 26, 2023. Immunodeficiency. [PubMed: 29763203]

15.

Wang L, Zhang L, Dunmall LC, Wang YY, Fan Z, Cheng Z, Wang Y. The dilemmas and possible solutions for CAR-T cell therapy application in solid tumors. Cancer Lett. 2024 Apr 10;591:216871. [PubMed: 38604310]

16.

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;36(27):3890-3893. [PubMed: 29807711]

Disclosure: Angel Justiz Vaillant declares no relevant financial relationships with ineligible companies.

Disclosure: Trevor Nessel declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Patrick Zito declares no relevant financial relationships with ineligible companies.