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A. Overviewnavigator

  1. Immunotherapy has been used for many years in modifying allergic responses
  2. The field is growing enourmously as new pathways in immunology are discovered
  3. Autoimmune disease, transplantation, and cancer are targets of new approaches
  4. Radiolabelled antibodies showing good promise in cancer treatments
  5. Majority of cases use experimental protocols, many in clinical trials

B. Densensitization [1] navigator

  1. When particular allergens are identified, consider desensitization therapy
  2. Allergen desensitization therapy effective for 50-70% patients
    1. Classical desensitization involves subcutaneous injections
    2. Sublingual / oral immunotherapy is effective in patients with dust-mite allergies [9]
    3. Clear improvement in patients desensitized to grass-pollen antigens [13]
    4. Jack jumper ant allergies can be desensitized with venom immunotherapy with complete prevention of hypotensive episodes in a small study [31]
    5. After ~3 years, need for continued immunotherapy is questionable [13]
  3. May improve systemic as well as local symptoms
  4. Mechanisms of Action [20]
    1. Complex and multiple mechanisms
    2. Most allergic responses are IgE mediated (Type I Hypersensitivity)
    3. In general, these antibody responses require Type 2 T helper Cells
    4. IgG "blocking" Abs induced by subcutaneous injections of allergens
    5. These blocking Abs may also prevent aggregation of IgE complexes and IgE receptor
    6. Also appear to interfere with antigen trapping by IgE bound to antigen presenting cells
    7. Immunotherapy induces shift from Th2 type cytokines to Th1 type cytokines
    8. These T cell changes probably drive inhibition of late-phase reactions
    9. In addition, induction of interleukin 10 expression by T cells may be essential
  5. Effective for allergic rhinitis symptoms but less so for asthma symptoms
  6. Desensitization early in evolution of allergic responses may be beneficial [13]
  7. Anti-IgE can also reduce sensitivity to peanuts in highly allergic patients [30]

C. Anti-IgE Immunotherapy [22,23] navigator

  1. IgE involved in many allergic and some inflammatory responses
  2. Reduction in serum IgE causes reduction in IgE (FcE) receptors on mast cells, basophils
  3. Anti-IgE Antibody (omalizumab, Xolair®) [24,25]
    1. Recombinant humanized monoclonal anti-human IgE antibody (Ab)
    2. Recognizes human IgE specifically at the same part of Fc region as the Fc(E) receptor
    3. Attenutates early- and late-phase reactions to inhaled allergens
    4. Biweekly IV dosing for 20 weeks in patients with allergic asthma on some form of glucocorticoids led to improved asthma scores and reduced need for glucocorticoids
    5. Some reduction in need for daily ß-adrenergic agonist use seen in treated patients
    6. Serum IgE levels were reduced >95% with high and low dose anti-IgE treatments
    7. Subcutaneous dosing every 2-4 weeks for 16 weeks in children with allergic asthma reduced inhaled glucocorticoid use and number of asthma exacerbations
    8. Antibodies to the anti-IgE treatments developed in all patients
    9. Side effects no different in placebo versus treated
    10. Dose varies 150-300mg q4 weeks to 225-375mg q2 weeks
  4. TNX-901, another anti-IgE Ab, reduces sensitivity to peanuts and other food allergens [30]
  5. Immunotherapy with Ragweek-TLR-9 Agonist Vaccine [37]
    1. Toll-like receptor 9 (TLR-9) stimulates Th1 cytokines
    2. Amb a 1, ragweek-pollen allergen, conjugated to a TLR-9 stimulator
    3. Six weekly injections of conjugate vaccine versus placebo
    4. Vaccine reduced peak-seaon rhinitis scores and daily nasal symptoms
    5. Vaccine also prevented usual seasonal increase in ragweed specific IgE response
    6. Generally well tolerated

D. Autoimmune Disease Therapy [2,3] navigator

  1. Major focus on rheumatoid arthritis (RA) and inflammatory bowel disease
    1. Tumor Necrosis Factor alpha (TNFa) Blockade appears extremely promising
    2. TNFa blockade is highly effective in rheumatoid arthritis [3] and Crohn Disease
    3. TNFa blockade has shown efficacy in psoriasis and psoriatic arthritis
    4. Interleukin 1 (IL-1) blockade (IL1-RA) is also approved for RA
  2. Most new agents focus on CD4+ T helper Lymphocytes
    1. Direct Nonspecific Anti-T (CD4) Cell: Anti-CD3, Anti-CD2, Anti-Campath 1, Anti-CD5
    2. Accessory Molecule Targets: Anti-CD2, Anti-CD28 (CTLA4Ig), Anti-CD40L
    3. Adhesion Molecule Targets: Anti-VLA4, Anti-ICAM1, Anti-A4/B7 Integrin
  3. Campath 1H [15]
    1. Antibody to CD52 found on lymphocytes and monocytes
    2. Depletes these white cell populations (sustained effects)
    3. Evaluated in transplantation, rheumatoid arthritis, multiple sclerosis (MS)
    4. Single pulse of Campath 1H suppresses MRI markers of inflammation in MS
    5. CD4 and CD8 T cell populations are depleted for >18 months
    6. Converts T helper populations from Th1 to Th2 in MS patients
    7. About 35% of patients develop anti-thyroid hormone receptor antibodies [38]
    8. This autoimmune thyroid (Graves') disease was responsive to carbimazole
  4. Alefacept (LFA30IgG1 fusion protein, Amevive®) [26,32]
    1. Soluble LFA3-IgG1 binds to CD2+ expressing CD4 T lymphocytes
    2. Depletes CD4+ T cells in high doses
    3. In low and moderate doses, specifically depletes CD45RO (memory) CD4 or CD8 T cells
    4. Treatment with alefacept for 12 weeks led to complete clearance in 16%
    5. No rebound of psoriasis occurred after cessation of therapy
  5. Anti-alpha4 Integrin MAb (natalizumab, Tysabri®; formerly Antegren®) [34,35]
    1. Lymphocytes and monocytes express a4b1 integrin
    2. Six-month randomized study of monthly natalizumab in relapsing multiple sclerosis
    3. Reduced new MRI lesions by >90%
    4. Reduced clinical relapses by 50% during 6 months of treatment
    5. Adverse events similar to placebo
    6. Withdrawn from market in 2005 due to two cases of progressive multifocal leukoencephalopathy (PML) in patients on natalizumab+IFNß
  6. CTLA4I-g [33]
    1. Soluble fusion molecule of cytotoxic T clymphocyte antigen 4 with human IgG1 Fc
    2. Blocks costimulation of T cells through CD80 and CD86 binding to T lymphocyte CD28
    3. Activity in psoriasis and rheumatoid arthritis (RA)
    4. CTLA4-Ig 10mg/kg IV over 30 minutes on days 1,15, 30 and then monthly for 6 months
    5. Improved responses in RA patients with active disease on methotrexate
  7. Anti-alpha4/beta7-Integrin Antibody (MLN02) [36]
    1. Blocks lymphocyte migration into inflamed intestinal tissue
    2. Dose 0.5 - 2.0 mg/kg on days 1 and 29 induced remissions in 33% versus 14% placebo
    3. Very well tolerated
    4. Neutralizing antibodies appear in some patients
    5. Opportunistic infections have not been observed

E. Transplantation [4] navigator

  1. Major focus has been on Solid Organ Transplantation
  2. Goal has been improvement in acute and chronic rejection management
  3. Acute Rejection
    1. Originally managed mainly with anti-thymocyte globulin (ATG)
    2. OKT3 (Anti-CD3) Ab now used, nonspecifically binds and kills most mature T cells
    3. Leads to cytokine release syndrome, but is effective
    4. Newer agents developed to block activated T cells (including CTLA4Ig)
    5. Anti-IL2 Receptor (Anti-CD25) monoclonal Ab approved to reduce acute rejection [5]
  4. Chronic Rejection
    1. Likely mediated in part by antibodies and cell infiltration
    2. Endothelial damage ensues
    3. Progressive atherosclerosis often develops, particularly in cardiac transplants
    4. No currently approved agents block chronic rejection

F. Cytotoxic T Lymphocytes navigator

  1. CD8+ T cells may be expanded in vivo
  2. Usually by coculture with virally infected or tumor target cells
  3. Partly HLA-matched allogeneic cytoxic T cell lines [29]
    1. T cell lines specific for Epstein-Barr virus (EBV) have been produced
    2. Can induce regression and complete remissions in post-transplant EBV disease

G. Anti-Cancer Therapy [6,10] navigator

  1. Initial attempts to augment immune system with various non-specific agents [7]
    1. Bacillus-Calmutte-Guerune
    2. Levamisole
    3. In general, such attempts failed
  2. Killer Lymphocyte Generation [8]
    1. First generation killer cells were lymphokine (IL2) expanded activated killers (LAK)
    2. These cells, when infused with high dose IL2, showed efficacy in ~5% of patients
    3. Tumor infiltrating lymphocytes (TIL) were isolated from tumors and expanded in vitro
    4. These TIL have shown more activity against human tumors
    5. Activity of TIL is mainly in renal cell carcinoma and melanoma
  3. Allogeneic Peripheral Blood Cell Transplantation [19]
    1. Tested in patients with refractory renal adenocarcinoma
    2. Patients treated with nonmyeloablative chemotherapy to permit transplantation
    3. Allogeneic donor stem cell infusions from HLA-similar sibling
    4. Cyclosporine given to prevent graft-versus-host disease
    5. Ten of 19 patients had tumor regression (7 partial, 3 complete)
    6. Donor T cells were detected in all patients with regression
    7. The 3 complete responders remained in remission 16, 25, and 27 months after transplant
  4. Tumor Specific (Rejection) Antigens [9]
    1. Expanded TIL cells have been used to identify specific tumor associated antigens
    2. Other methods of using T cells or sera of cancer patients have been used to identify specific cancer antigens [6]
    3. A series of antigens expressed by tumors as well as by testes but not other tissues identified
    4. Melanoma antigens MAGE-1 and NY-ESO-1 belong to this cancer-testis antigen family
    5. Tumor antigens by such methods have been cloned and sequenced
    6. Some of these antigens belong to
    7. Vaccine development using these antigens as targets are underway
    8. Autologous CD4+ T cells expanded against NY-ESO-1 pulsed autologous dendritic cells with IL2 and IL7 and reinfused lead to complete remission in metastatic resistant melanoma [39]
  5. Cytokine Immunostimulants
    1. Interferon alpha has some activity against glioma, melanoma, myelocytic leukemias
    2. IFN alpha may act through direct effects on tumor, rather than on immune system
    3. IFN gamma has shown promise in vitro, but minimal efficacy (highly toxic) in humans
    4. IL-12 is being assessed as adjunctive therapy
    5. IL-2 with and without LAK/TIL therapy is best studied cytokine immune stimulant
  6. Interleukin 2 (IL-2) Therapy
    1. IL-2 is a major T cell growth factor which can induce T cell proliferation (with antigen)
    2. Can be used in vitro to expand T cell clones as well as LAK and TIL cells
    3. Also has effects on natural killer (NK) and B cells
    4. High dose infusions in humans - attempts to stimulate immune system against tumor
    5. In general, efficacy results are disappointing and drug is very toxic
    6. Toxicity is mainly a severe pulmonary capillary leak syndrome
  7. BCG Immunotherapy for Bladder Cancer [12]
    1. BCG is live Mycobactermium bovis which can become disseminated in some patients
    2. BCG stimulates poroduction of IL6, IL8 and TNFa
    3. Leads to CD4+ T cell activation and production of IL12, IL2 and IFN gamma
    4. Activated macrophages and killer T lymphocytes likely mediate anti-tumor response
    5. BCG treatment has shown ~55% effectiveness against small residual tumors
    6. BCG treatment shows 70-75% complete response rate for cacinoma in situ (CIS)
    7. Remissions are generally sustained at ~70% over 5 years
  8. Interleukin 12 is in development for treatment of cancer
  9. Monoclonal Antibodies (mAb)
    1. Tumor selective antibodies have been developed
    2. These are often directed at clonotype specific surface molecules
    3. Radiolabelled monoclonals are available against some tumors, particularly lymphomas
  10. Approved mAb in Cancer [6]
    1. Alemtuzumab (Campath®): anti-CD52 on lymphocytes
    2. Bevacizumab (Avastin®): anti-VEGF on breast, lung, colorectal (and other) carcinomas
    3. Cetuxumab (Erbitux®): anti-EGF-R on colorectal (and other) cancers
    4. Gemtuzumab ozogamicin (Mylotarg®): anti-CD33 with colicheamicin derived toxin for AML [17]
    5. Ibritumomab tiuxetan (Zevalin®, see below)
    6. Panitumumab (ABX-EGF): anti-EGF-R
    7. Rituximab (Rituxan®, see below)
    8. Tositumomab (Bexxar®, see below)
    9. Trastuzumab (Herceptin®) - anti-her2/neu McAb for breast cancer treatment [16]
  11. Rituximab (Rituxan®) [14]
    1. Anti-CD20 mAb for treatment of various low-grade NHL
    2. Unlabelled (non-radioactive) Ab showed 9% complete and 50% partial responses
    3. Good activity in refractory autoimmune thrombocytopenia [27]
    4. Also may be used for graft-versus-host disease [28]
    5. Excellent activity when combined with IVIg in refractory pemphigus vulgaris [38]
  12. Radiolabeled Anti-CD20 mAb
    1. Yttrium-90 (ibritumomab, Zevalin®) and 131-Iodine (tositumomab, Bexxar®)
    2. Show ~50% complete and 79% partial responses
    3. Using myeloablative levels of radiolabelled Ab, 79% complete and 86% partial responses were observed
    4. Radiolabelled anti-CD20 MAbs have improved response rates but increased side effects (thrombocytopenia) compared with naked anti-CD20 MAb
  13. Toxin Conjugated Immunotherapy: Denileukin Difitox (Ontak®) - IL2-diphtheria toxin [21]
  14. Adoptive Immunotherapy [18]
    1. Objective response rates to adoptive immunotherapy in liver ca have been documented
    2. Adoptive immunotherpay analyzed in post-surgical patients (Stages I, II, IIIa, IVa)
    3. Autologous mononuclear cells from 50mL of peripheral blood expanded in IL2 and CD3 Ab
    4. Cells cultured for 2 weeks and shown to have anti-tumor activity
    5. Immunotherapy group had longer disease free survival and reduced recurrence 18%
    6. Adoptive immunotherapy should be studied further in liver cancer, melanoma, renal cancers
  15. Tumor Vaccines
    1. Certain tumors such as melanoma and colon cancer appear to be immunogenic
    2. Melanoma vaccine trials are ongoing
    3. Colon cancer vaccine may be beneficial in patient with localized disease [11]
    4. In general, these vaccines are well tolerated

References navigator

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