Cancer Immunology & Application Tumor Immunity MRC Seoul National Univ. College of Medicine 서울의대 의학박사. 박 윤

Edward Jenner developed the first vaccine against smallpox in 1796 Nature Medicine 9, (2003) Edward Jenner, ~

Coley’s toxins Using a bacterial vaccine to treat primarily inoperable sarcoma, Coley accomplished a cure rate of better than 10%. New York surgeon, William B. Coley, active career

His cancer immune surveillance theory published in 1967, which refines similar views held by Lewis Thomas, underpins the current belief that tumors can be recognized and eliminated by the immune system. Frank Macfarlane Burnet (1899−1985) Immunity 21:2, (2004) The Nobel Prize in Physiology or Medicine 1960 Cancer immunoediting: from immune surveillance to tumor escape (acquired immunological tolerance and the clonal selection theory of antibody production)

(LAK, lymphokine-activated killer) LAK Therapy

Administration of monoclonal antibodies which target either tumour- specific or over-expressed antigens. Eliminate the tumor cells in a variety of ways: Apoptosis induction Complement- mediated cytotoxicity ADCC NK MØMØ Conjugated to toxin / isotope Antibody-based immunotherapy

Definition - Active specific immunotherapy - Induce an immune response to specified cancer-associated antigens and stimulate the cancer patients’ own immune system to attack the cancer and to prevent them from recur NormalOften decreasedImmune surveillance SimpleComplicatedInoculated immunogen LimitedLimitlessAntigens Before the pathogen encounter In tumor bearing stateTime of vaccination Viral vaccineCancer vaccine Cancer Vaccines and Immunotherapy Cancer Vaccine vs Viral Vaccine

Activation of tumor- specific immune response Nature Immunology 2, (2001)

J. Clin. Invest. 113: (2004) Approaches to anti-tumor vaccination (eg. GM-CSF)

Relative merits of cancer vaccine design strategies Desirable feature Non-purified (tumor cell, DC) Semi-pure (cell lysate, exosome) Pure (peptides, DNA) Effectiveness Relevant antigens Multiple antigens Multiple response Elegance Purity Reprod, manufacture Quality control

The four major subtypes of immunoregulatory cells and their proposed mechanisms of action Clinical Cancer Research Vol. 12, , August 15, 2006

Treg cell populations in lymphoid organ and tumor tissue

I. Prospective Therapeutic Cancer Vaccine Strategies - Modified tumor cell vaccine - Dendritic cell vaccine -Adoptive T cell transfer with lymphodepetion

Genetic modification of tumor cells GM-CSF-secreting tumor-cell vaccines and CTLA-4 antibody blockade show synergistic anti-tumor effects.

J. Clin. Invest. 113: (2004) Generation of anti-tumor DC vaccines from peripheral blood monocytes Dendritic cell cancer vaccine

Dendreon's Therapeutic Cancer Vaccine Approach The target antigen is incorporated into Dendreon's Antigen Delivery Cassette ™.antigenAntigen Delivery Cassette Dendritic cell precursors are co-cultured with Dendreon's Antigen Delivery Cassette, binding to receptors. The dendritic cells actively internalize the Antigen Delivery Cassette. The antigen-loaded dendritic cells - after a simple infusion -- educate T-cellsT-cells to recognize the target antigen. The activated T-cells proliferate and recognize the target antigen on the surface of tumor cells. The T-cells then destroy the cancer cells. ▶ Application

Ready within 48 hours... ▶ Application

Nat Rev Immunol Apr;5(4): Dendritic cells as therapeutic vaccines against cancer

Steven A. Rosenberg MD, PhD Chief, Surgery Branch National Cancer Institute Bethesda, MD, USA Adoptive cell therapy (ACT) requires the generation of highly avid tumor-antigen-reactive T cells Current clinical protocols for adoptive cell therapy. Nature Reviews Cancer 3, (September 2003)

Tumor regression can be triggered by transgenic pmel-1 T cells. A, a mouse bearing a large, established, vascularized B16 mouse melanoma tumor shown after the start of treatment (19 d after tumor implantation). B, the same mouse (day 67) Clin Cancer Res Sep 15;13(18): Adoptive cell therapy in a lymphoreplete host

Computed tomography (CT) scans of the liver in a patient with metastatic melanoma show dramatic tumour regression of liver metastases after the administration of tumour-reactive tumour-infiltrating lymphocytes (TILs) following lymphodepletion. The patient is still disease-free after 27 months. Anti-tumor response induced by lymphodepletion and adoptive cell therapy Nature Reviews Immunology 6, (May 2006)

‘Anti-tumor vaccination in the setting of lymphodepletion and adoptive cell transfer’ A 50% objective response rate was reported after a lymphodepleting conditioning regimen prior to adoptive cell transfer for patients with metastatic melanoma, and robust long-term persistence of the adoptively transferred cells was observed Lymphopenia creates selective advantage for some populations of T cells, eliminating regulatory T cells and inhibit endogenous ‘cytokine sinks’ TLR 4-mediated systemic immune response, by reactivation of entero-microbes after lymphodepletion may be an additive effect

Mechanisms underlying the impact of lymphodepletion on adoptively transferred T cells. A | Adoptive cell therapy (ACT) in a lymphoreplete host B | Systemic chemotherapy or radiation before ACT might modify the tumour-bearing host. Improvement of cancer vaccine

Nat Rev Immunol. 6(4): (2006) Enhancement of vaccine-mediated anti-tumor immunity in cancer patients after depletion of regulatory T cells

II. Adjunctive & Preventive Cancer Vaccine Strategies -Protein, peptide, DNA vaccines -After surgery, chemotherapy and radiotherapy -Aim to inhibit tumor recur and metastasis

Innate immune response through Toll-like receptors

ANTIMETABOLITES 5-FU Ara-C 6-MP Thioguanine Fludarabine Methotrexate Gemcitabine TOPOISOMERASEI INHIBITORS Irinotecan Topetecan Adriamycin Danunorubicin Etoposide ALKYLATING AGENTS / PLATINUM Cisplatin Carboplatin Oxaliplatin Cyclophosphamide Melphalan Chlorambucil MICROTUBULE INHIBITORS Vincristine Vinblastine Vinorelbine Paclitaxel Docetaxel Cytotoxic Chemotherapeutics Low dose : Treg Myeloid derived suppressor cell