Immunopotentiation Immunopotentiation can be defined as the process which directly augments one or more specific immune functions or indirectly enhance it through modulating one or more of the complex regulatory networks that control the immune system. The process is generally manifested by an increase in the velocity and intensity of the immune response to different antigens, bacteria, viruses and tumor cells in particular.

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Basic concepts in the understanding of the different strategies used to stimulate the immune response

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Immunopotentiation can be defined as the process which directly augments one or more specific immune functions or indirectly enhance it through modulating one or more of the complex regulatory networks that control the immune system. The process is generally manifested by an increase in the velocity and intensity of the immune response to different antigens, bacteria, viruses and tumor cells in particular.

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Prof. Dr. Mohammed-Samy AfifiHead Immunology and Allergy Department

Medical Research Institute, Alexandria University

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From the clinical point of view, immunopotentiation is mainly important for:

Enhancement of the immune responses during immunization through the use of immunological adjuvants.

Immunotherapy, directed at pathogenic microorganisms, malignant cells.

Treatment of immunodefiecency and autoimmune diseases

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SPECIFIC IMMUNOPOTENTIATION:Active Specific Immunopotentiation

a. Infectious agent’s Vaccine

The objective of vaccination is to provide effective immunity by establishing adequate levels of specific antibodies and a primed population of cells which can clonally expand on renewed contact with the antigen.

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Prophylactic vaccination against infectious diseases remains the single most clear cut success of immunopotentiation in practical application of immunological principals to improvement of human and animal health

surprisingly, most of the highly successful vaccines currently available were developed before 1970.

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1. Use of improved adjuvants suitable for clinical use.

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2. Use of delivery systems which allow for sustained or controlled release of antigens and which induce prolonged immunity following a single dose. The delivery system has been modulated to potentiate the immune response either by delivering the antigen over a prolonged period of time or in a predetermined sequence or by incorporating substances with immunoadjuvant properties e.g..., lecithin and biodegradable polymers.

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a. Microencapsulation

Involves the coating of the vaccine in a protective wall material that usually polymeric in nature e.g. poly DL-lactide-coglycolide (DL-PLG)

Advantages:Substantial potentiation of the immune responseAbility to construct formulations that release multiple discrete pulses of vaccineEffectively deliver vaccines to mucosal immune inductive tissues.

b. Liposomes:Act as an agents for the presentation of antigen.Stimulate production of IL-2.

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3. Live vector vaccine

Vectors are organisms into whose genome has been introduced a foreign gene that codes for an antigen of the vaccine of interest. e.g.,. Vaccinia, Fowlpox, Adeno-and picornaviruses.

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The ideal approach to immunologic therapy for cancer would be surgical resection of the primary lesion and immunization of patient with their own tumor cells. The concept of memory is critical for this approach because it requires the development of antigen specific recognition by cells of the immune system.

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Difficulties with this approach:

•Tumor associated or tumor specific antigens.

•Antigen heterogeneity

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Strategies used in clinical trials of tumor vaccine therapy:

Gene therapy : Uses established cell lines, either cancerous or normal derived into which genes of interest are transfected, this can be achieved by direct DNA transfer or by virus infection using for instance, retroviral or adenoviral gene expression vectors. The gene transfected cell lines are then inactivated, most frequently by gamma irradiation, and injected either alone or together with autologous patient derived cancer cells as a vaccine back into the patient in order to achieve an active specific immunization and immunotherapy effect.•In 1993, Hoover et al.,: immunized patient with resected colon carcinoma with their autologous tumor cells +BCG.

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Rational: T cells from tumor bearing patients were observed to exhibit abnormalities in signal transduction that render them unresponsive to appropriate activation signals. Cytokines were observed to be capable of bypassing such defect and to enhance the anti-tumor vaccine effect. Therefore, it is used in conjunction with either viral or oncolysate-based vaccine.

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•Direct inhibition of tumor cells•Delivery of immune effectors to tumor sites (IL-2)•Overcoming anergy-inducing effects and allowing induction of new effectors•Augmenting the effector function of T cells recognizing MHC-presented peptide epitope on tumor cells.•Counteracting the myelosuppressive effect of chemo- or radiotherapy (hematopoeitic growth factors,IL-1).

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Routes of administration:

• Systemic: R/ advanced renal cell carcinoma, malignant lymphoma and

hairy cell leukemia.

• Local:a. Isolated limb perfusion. b. Peritumoral or intratumoral.

• Gene Transfection

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Generally, this strategy is used for:

• Temporary protection against infection.

• Removal or blocking of tumor cell antigens

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Hetrologous antibodies: Now, only restricted to treatment of envenomation.

Hyperimmune globulin therapy: Immune serum globulin(ISG)are available for HBV,

Vaccinia, Varicella, Tetanus and Rabies.

Therapeutic monoclonal antibodies.

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problems that limited the use of mab in immunotherapy

Limited delivery to target tissue.

Development of human antimurine Ab response.

Lack of cytocidal properties

Failure to develop mab with absolute specificity to tumor cells.

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Strategies developed to potentiate the therapeutic efficacy of mab

•Production of genetically engineered antibodies constructed to have the murine variable regions and the human constant region. Unfortunately, this strategy was associated with reduced binding affinity.

•Production of bifunctional antibodies with two distinct binding activities. One is directed for the tumor target while the other toward the CD3 receptor (T cell retargetting).

•Production of monoclonal anti-idiotypic antibodies. an approach which were claimed to be effective in treatment of B cell lymphomas that express surface Ig.

•Conjugation with enzymatically active toxin (Immunotoxin). The toxins most commonly used are those of diphtheria, shigella, Pseudomonas aeroginosa exotoxin A, and the plant toxin ricin. •Modifying antibody delivery by liposomal encapsulation

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Monoclonal antibodies in development for treatment of NHL

Antibody or Immunotoxin Target

Rituximab (Rituxan) CD20Tositumomab(Bexxar) CD20Ibritumomab tiuxetan (Zevalin) CD20CAMPATH 1H CD25HulD10 HLA-DR variantApratuzumab (hLL2) CD22LMB-2 (TAC) CD25 receptorBL22 CD22HuM291 CD3HeFi-1 CD30CTLA4-Ig B7/CD28

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Several clinical trials have shown that rituximto be an effective and relatively nontoxic therapy for patients with relapsed low-grade or follicular lymphomas. However, the data on its use in aggressive non-Hodgkin’s lymphoma histologic types are limited and do not allow definitive conclusions.

As a single agent, rituximab appears to have significant activity in phase II and III trials in low- grade or follicular lymphoma.

Beyond lymphoma, rituximab is being used in treatment of immunosuppression, multiple myeloma, immunethrombocytopeniaa, and HIV-NHL.

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HuID10 is a humanized antibody that binds to a variant of an HLA-DR antigen expressed in B-cell malignancies. Benign toxicity profile, induce apoptosis and depletes B cells.

Used in a variety of hematologic malignancies with variable response rates.

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Refer to the transfer of immunologically active cells that can mediate immune enhancement. This strategy is mainly used in tumor immunotherapy.

Tumor infiltrating lymphocytes (TIL):

Could be isolated from all human tumors. However, 1/3 exhibit specific cytolytic activity.

Rosenberg’s group at NCI observed that TILs + IL-2 are more effective than LAK.

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Purified (synthetic) antigen determinants relevant for induction of protective immunity against virulent organisms display only poor immunogenecity.

Existence of a state of anergy in tumor bearing patients (defects in signal transduction).

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ImmunoadjuvantsRefer to compounds which act in nonspecific manner to augment specific immunity to antigen.

Mechanisms of action:activation of macrophages, improvement of antigen presentation , formation of depot ( delay Ag release, modyfing phagocytosis of particulate Ag), and selective activation of T cell subpopulation.

Non-specific stimulation of host resistance against infections and cancer.•Potentiation of vaccine immunogenecity. They serve to reduce the antigen dose required, the number of injections, and achieve an enhanced immune response.

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Surface active agents:Saponins, liposomes, lysolecithins, polyols, lipophilic amines, retenoids

Anionic polymers:polynucleotid, and dextran sulphate

Miscellaneous:Immunostimulating complexes (ISCOMs), bacterial products or derivatives, Schif-base forming compounds, vector adjuvant, and cytokines

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Bacillus Calmette-Guerin (BCG)

Systemic administration of BCG or its methanol extractable residue (MER) had been disappointing. Promising data obtained in early trial could not reproduced. the main limitation of this form of therapy appears to be its inability to induce meaningful systemic immune stimulation.

Local administration: Intralesional injection of BCG and MER into cutaneous metastasis of malignant melanoma resulted in a significant clinical regression of the lesion in 70-90% of the cases, but recurrence in non injected areas was frequently observed.Intravesical administration of BCG in superficial bladder cancer resulted in about 80% of complete response. Recurrence was not observed in 70% of the responder cases after 5 years.

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LevamisoleAntihelminthic drug with immunomodulatory and anticancer effect.

Isoprinosine:Act through a receptor for an inosin like compound on pre-T cells.

Licensed for use in HSV, rhinovirus, early HIV, Measles- related


Schiff-base forming drugs

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Passive nonspecific immunopotentiation

Immunoglobulin Therapy (IVIG):

•Functional blockade of Fc receptor on splenic macrophages

•Inhibition of C- mediated damage (binding to C4b & C8b)

•Modulation of cytokines and anti-cytokine antagonists.

•Neutralization of circulating autoantibodies by anti-idiotypic antibodies in IVIG.

•Selection of immune repertoires, a complex set of effects that may be observed in individuals receiving IVIG far beyond the half- life of the infused Ig.

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Adoptive non specific Immunotherapy

Lymphokine activated killer cells