Immunotherapy

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.