immunological surveillance

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Immunological surveillance:

Immunological surveillance Dr.Preethi.k

Immunological Surveillance Ehrlich, Burnet & Thomas:

Immunological Surveillance Ehrlich, Burnet & Thomas Paul Ehrlich (1909) First to conceive of the concept of Cancer Immunosurveillance. Predicted that cancer would occur at “incredible frequency” if host defenses did not prevent the outgrowth of continuously arising cancer cells. Lewis Thomas (1957) “primary function of cellular immunity….is to protect from neoplastic disease” Macfarland Burnet (1957) “It is by no means inconceivable that small accumulations of tumour cells may develop and because of their possession of new antigenic potentialities provide an effective immunological reaction with regression of this tumor and no clinical hint of its existence”

Evidence for immune surveillance in humans:

Evidence for immune surveillance in humans Increased incidence of EBV+ B cell lymphomas in transplant patients treated with immunosuppressive drugs Increased incidence of Kaposi’s sarcoma & EBV+ B cell lymphomas in AIDS patients Gastric cancer associated with H. pylori infection Cervical cancer caused by HPV Liver cancer caused by hepatitis B & C

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Immunosurveillance & “ Immunoediting ” Tumor Antigens - definition & discovery Passive Immunotherapy anti-tumor CTL anti-tumor antibodies inhibitory receptor blockade Active Immunotherapy Vaccination Tumor Evasion Strategies

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Anti-Tumor Effector Mechanisms CD4 + T cells, CD8 + CTL, and NK cells - direct cytotoxicity or ADCC (NK cells) via perforin & granzymes - cytokine release (e.g., TNF, IFN  , GM-CSF) leading to: a) lysis of tumor cells b) disruption of angiogenesis c) recruitment and activation of DC, macrophages, & granulocytes

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B cells - production of tumor-specific antibodies leading to: a) lysis by complement-mediated killing b) lysis by ADCC c) antibody-mediated apoptosis by disrupting oncogenic signals Macrophages - killing via ADDC - killing via production of cytokines such as TNF - killing via production of toxic oxygen or nitrogen intermediates

Spontaneous tumors in wild-type and immunodeficient mice:

Spontaneous tumors in wild-type and immunodeficient mice

Tumors arising in immunodeficient mice are more immunogeneic than tumors arising in wild-type mice:

Tumors arising in immunodeficient mice are more immunogeneic than tumors arising in wild-type mice Assayed by transplanting tumors into wild-type or immunodeficient mice

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Schreiber et al. Immunity 2004 Tumor Elimination - Equilibrium - Escape

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Tumor-infiltrating lymphocytes Correlation with survival in ovarian cancer patients Zhang et al. NEJM 348:203, 2003

Tumor Antigens Discovery & Definition:

Tumor Antigens Discovery & Definition

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Experimental Demonstration of Antigen-specific Tumor Immunity

Tumor Antigens:

Tumor Antigens Tumor-specific antigens Expressed by tumors ONLY Tumor-associated antigens Preferentially expressed by tumors Oncofetal antigen Expressed by tumors in adult, but also expressed by fetal (not adult) tissues

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Types of Tumor Antigens Recognized by T cells

Serological identification of tumor antigens - Serex:

Serological identification of tumor antigens - Serex Some cancer patients have antibodies reactive with their own tumor Use patients’ sera to expression clone the tumor antigens Surprizingly, many of the antisera recognized the same tumor-associated antigens that detected by CTL

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Immunotherapy Strategies 1) Cytokine infusions 2) Induction of local inflammation Innate System 3) Tumor-targeted antibodies (e.g.,Herceptin) 4) Adoptive transfer of tumor-specific T cells 5) Donor lymphocyte infusions after BMT/HSCT (allogeneic bone marrow or hematopoietic stem cell transplant) “Passive” Adaptive System 6) Vaccination “Active” Adaptive System

Passive Immunotherapy Anti-tumor monoclonal antibodies :

Passive Immunotherapy Anti-tumor monoclonal antibodies

Antibody-dependent cellular cytotoxicity:

Antibody-dependent cellular cytotoxicity

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FDA-approved therapeutic monoclonal antibodies CD20 Her2 EGF-R VEGF CD33 CD52 CD20 CD20

Rituxan Pivotal Trial: Treatment of Patients With Relapsed B Lymphoma:

Rituxan Pivotal Trial: Treatment of Patients With Relapsed B Lymphoma McLaughlin et al. J Clin Oncol. (1998) 16:2825 Rituxan ® 375 mg/m 2 (IV) Monitoring every 3 months x2 years Weeks 1 2 3 4 8 16 E v a l u a b l e P a t i e n t s 1 6 6 O v e r a l l R e s p on s e 8 0 ( 48% ) C o mp l e t e R e s p on s e 1 0 ( 6 % ) P a r ti a l Re s po n s e 7 0 ( 42% )

Passive Immunotherapy Inhibitory Receptor Blockade with Monoclonal Antibodies (e.g. CTLA-4, PD-1):

Passive Immunotherapy Inhibitory Receptor Blockade with Monoclonal Antibodies (e.g. CTLA-4, PD-1)

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Peptide/MHC CTLA-4 CD28 TCR B7 B7 APC Unrestrained Proliferation Attenuated Proliferation APC Tumor CTLA-4 Blockade Enhances Tumor-Specific Immune Responses GM-CSF Vaccine Peptide-pulsed DCs Chemotherapy Irradiation Anti-angiogenesis Hormone therapy Surgical reduction

Passive Immunotherapy Adoptive transfer of Antigen-specific CTL:

Passive Immunotherapy Adoptive transfer of Antigen-specific CTL

Adoptive T cell therapy:

Adoptive T cell therapy Labor intensive – patient specific CD8+ CTL need CD4+ helper T cells to persist

Active Immunotherapy Vaccination:

Active Immunotherapy Vaccination

First vaccine to prevent human cancer! vaccine for papilloma virus for cervical cancer! :

First vaccine to prevent human cancer! vaccine for papilloma virus for cervical cancer!

Successful Active Vaccination against Virus-induced Cancers:

Successful Active Vaccination against Virus-induced Cancers Vaccine to feline leukemia virus for cats Vaccine to herpes virus (Marek’s virus) in chickens Vaccine to hepatitis B in humans to prevent liver carcinoma Vaccination to HPV prevents cervical cancer

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Active Immunization - Tumor cells or antigens Tumor cells or extracts (Melacin) Tumor peptide + adjuvant vaccine Tumor peptide loaded on dendritic cell Tumor antigen cDNA vaccination Tumor antigen in recombinant virus Feeding dendritic cells dead tumors Feeding dendritic cells tumor RNA

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Disease-free survival in melanoma patients by Melacine vaccination [p=0.04] SWOG-9035

Mechanisms of Tumor Escape from Immune Responses:

Mechanisms of Tumor Escape from Immune Responses Loss of MHC or TAP Loss of co-stimulatory molecules Antigenic variation Secretion of immunosuppressive factors E.g. TGF- b , IL-10 T cells don’t penetrate solid tumors Exhaustion of T cells T regulatory cells suppress anti-tumor responses

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Loss of Class I MHC Expression in a Prostate Carcinoma

Therapeutic strategies to overcome tumor evasion:

Therapeutic strategies to overcome tumor evasion Loss of MHC -Type I interferon Secretion of immunosuppressive factors Neutralizing TGF- b , IL-10 Exhaustion of T cells -Treat with IL-15 or block PD-1 T regulatory cells suppress anti-tumor responses -Deplete Treg

In Vivo Depletion of CD25+ T cells Facilitates Tumor Rejection:

In Vivo Depletion of CD25 + T cells Facilitates Tumor Rejection Shimizu et al. J. Immunol . 1999,163:5211-18

TGF-b blockade allows tumor rejection:

TGF- b blockade allows tumor rejection Gorelik & Flavell Nat Med 7:1118, 2001

Full Discosure Inflammation promotes cancer!:

Full Discosure Inflammation promotes cancer!

Stuff to Remember:

Stuff to Remember Tumor express antigens that can be recognized by the immune system T cells recognizing tumors can be detected in cancer patients…but they are inefficient Tumors attempt to evade the immune system by loss of antigens and secretion of suppressive factors Vaccination against tumor antigens is possible..but is difficult because many of these antigens are perceived as ‘self’ mAbs against tumor-associated Ags can be effective

Thank you..:

Thank you..

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