LEARNING OUTCOMES

Molecular Oncology Cancer represents a special type of pathology that can be potentially dangerous even when affecting only an individual cell. At a molecular (biochemical-interactions) level, fundamental cellular functions (proliferation, apoptosis, differentiation, tissue architecture) are controlled by networks of signaling-proteins. Signaling-proteins networks decide when and in which way a cell will activate the above mentioned basic cellular functions. Special discrete sets of mutations / alterations, inheritable at the somatic level, from a parental to a daughter cell, can give origin to new progressively transformed cells, endowed with more permissive controls of these same functions. We want the student to learn the basic features of this pre-neoplastic and subsequently neoplastic transformation process. By about ten years, medicinal chemistry has started to discover selective inhibitors of altered signaling-proteins affected by excess of function (especially kinase inhibitors). We want the student to enter the world of possible selective corrections of altered pathways and altered signaling-network sub-regions. Molecular Immunology This course is aimed to provide a broad view of the current knowledge of the molecular mechanisms involved in the antigen-specific immune response and in innate immunity. Examples of translational applications of this basic knowledge to biotechnology approaches of therapy and diagnosis in neoplastic and immune-mediated diseases will be discussed.

AIMS AND LEARNING OUTCOMES

Knowledge of the molecular mechanisms responsible for the generation of neoplasia, complexity of the tumor microenvironment, clinical manifestations and features of the main neoplasia, ability to integrate the basic knowledge with the use of specific drugs that can interfere with the tumor cell growth and influence on the immune system. Knowledge of basic principle of the immune response in neoplastic, infectious, allergic and autoimmune diseases and of the up-to-date drugs used to modulate the immune response. 

TEACHING METHODS

Frontal classes

SYLLABUS/CONTENT

MOLECULAR ONCOLOGY

General concepts

Tumor cells, tumor microenvironment (TME), immune and non-immune components of TME.

The cancer genome

Molecular methods in cancer

Hallmarks of Cancer, multiple hits

Signal transduction in cancer cells (Ras-Pi3k-receptor mediated signalling)

Microbiome and Cancer

Oncogenic viruses “Cancer critical genes”: Oncogenes and tumor suppressor genes 

DNA repair in Normal and Cancer Cells

Cancer epigenetics: methylation, acetylation, bromodomain proteins, IDH1 and IDH2

Precision Medicine in Oncology

Molecular biology of lymphoma and immune reaction to lymphoma cells.

Molecular biology of cutaneous melanoma (mutations, signal transduction, feedback mechanisms, resistance and adaptation, Target therapy. Immune reaction to melanoma cells

Molecular biology of colorectal cancer: FAP, Lynch syndrome, sporadic tumours. Molecular mechanisms in CRC. Immune reaction to CRC cells.

Molecular Biology of lung cancer

IMMUNOLOGY

Introduction to cytokines and their receptors
Pro-inflammatory cytokines 
Role of DAMPS and PAMPS  and PPR and danger signals
TLR ligands and signaling
TNF: regulation of secretion, role of ADA17/TACE, TNFRI and II and signalling, biological effects, role in inflammation and host defense and in disease. 
RA as a prototype of autoimmune/inflammatory disorder, role of protein citrullination and autoantibodies.Role of RANK/RANKL in bone erosions.Etanercept and infliximab as prototypic TNF blocking agents and their biosimilars.
Use of TNF and its derivatives in cancer therapy (ILP,TNF immunocytokines)

CD40/CD40L as a member of TNF family. Role in T cell responses,  cross-priming and B cell responses (class switch). Genetic deficiency of CD40L and hyper-IgM syndrome.

IL-1/IL-1R. Processing of Il-1 by caspase 1: role of PAMPS and inflammasomes.IL-1 signaling and biological activities.Regulation of IL-1 activity by IL-1 antagonist and decoy receptor.
IL-1 blockers (Ankinra, rinolacept and canakinimab) in disease.
IL-1 superfamily and IL-18.

IL-6 as pro-inflammatory cytokine.Soluble IL-6R and its role in trans-signaling.Anti-IL-6 and IL-6R antibodies (tocilizumab).
Inflammatory bowel disease (CD and UC) pathogenesis and biologicals used for treatment (anti-alpha4beta7 integrinVedolizumab to block lymphocyte homing).

Chemokines and their receptors: role in inflammation, lymphoid organ architecture, angiogenesis, cancer, and HIV entry (chemokine R inhibitors maravirpq and plerixafor) 

IL-12 cytokine family.
IL-12 R and their biological functions. IL-12 in cancer immunotherapy and gene therapy and  NHS-IL12 immunocytokine.
The Th1/Th2 paradigm of Th differentiation reciprocal role of IL-12 and IL-4, involvement of transcriptions factors, role of Th1 and Th2 responses in host defense from pathogens.
Other Th differentiation pathways.

Interferons, biological activities and their role in viral infections and activation of phagocyte oxidative killing.
Role of IFNgamma in immune regulation through induction of PDL1, IDO and IL-18BP.
Cytokines that mediate and regulate adaptive immunity: IL-2 and its receptors in the regulation of T cell responses. SCID due to genetic defect in IL-2Rgamma chain, IL-7R or JAK3.IL-2 in cancer immunotherapy.Use of IL-2/toxin chimera for treatment of CD25+ CTC lymphomas (Ontac).

TH2 and ILC2 cells and their pathogenic role in allergy.The Th2 cytokines IL-4, Il-13 and Il-5.
Pathogenesis of the allergic reactions.Common allergens and drugs.Role of mast cells, eosinophils and their Fcepsilon R1. Allergy therapeutics and role of  Specific Allergen immunotherapy.
MAbs for refractory asthma therapy which target: the Fc portion of IgE, IL-5 or the IL-4/IL-13 and their receptor systems. 
Bradikinin-mediated angioedema.Role of the complement system in angioedema and defects of C1 inhibitor.

Tumor immunology: Animal models of cancer immunotherapy, Abscopal effect 
Autoimmune paraneoplastic syndromes, the immunoscore, tumor antigens (differentiation antigens vsneoantigens), the three “e” theory (immunoediting).
Cancer Immunotherapy: passive (mAbs) vs. “adoptive” and “active”.
Passive” Immunotherapy: monoclonal antibodies targeting tumor-associated  molecules. 
From murine to chimeric, humanized and human mAbs.scFv.
Examples: Anti-Her2 mAbs (trastuzumab and pertuzumab). Anti-CD20 mAbs (rituximab). Effector mechanisms activated by mAb Fc portion (C, ADCC and ADCP)
MAbs inhibiting tumor angiogenesis (bevacizumab)
Antibody-drug conjugates: targeting of CD30 by brentuximabvedotin.
Use of “BITE” (bi-specific T cell engager) that re-direct T cells to tumor cells (e.g. anti-CD3/anti-TAA): Blinatumomab.
Adoptive transfer of effector cells of the immune system:
TILs, T cells expressing transgenic TCR or chimeric receptors (CAR) that  confer tumor-specificity to transduced T cells. From 1st to 4th generation CAR-T cells.

Therapies that activate the host immune system 

Immune-enhancing  cytokines and their fusion proteins
Oncolytic viruses as carriers of cytokine genes (T-vec)
Cancer vaccines. Prophylactic (e-g. Hepatitis B) vs therapeutic vaccines- Problems and pitfalls.

Trgeting tumor-realted immune regulation for reactivating anti-tumor T cell esponses:
IDO-Blockers
Targeting of Tregs
Blockade of Immunesuppressive cytokines
Immune checkpoints blockers
Mechanisms of CTLA4-mediated and PD-1-mediated T cell inhibitions.

Immune checkpoint blockers (anti-CTLA4, -PD1-anti-PDL-1), their main indications in cancer therapy and side effects.

RECOMMENDED READING/BIBLIOGRAPHY

 Cancer Principles and Practice of Oncology, Primer of the Molecular Biology of Cancer, Third edition, Vincent T. DeVita, Jr, Theodore S. Lawrence, and Steven A. Rosemberg, Editor; Wolters Kluver.

Cellular and Molecular Immunology 10th Edition - February 19, 2021,Editor: Elsevier; Authors: Abul Abbas, Andrew Lichtman, Shiv Pillai 

eBook ISBN: 9780323757508, Paperback ISBN: 9780323757485

Review and original articles on the specific topics of molecular oncology and immunology.