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The history of Immuno-Oncology

After decades of research, we are entering a whole new era of cancer care that is based on immune system activation and involves the development of new tools.

The history of Cancer Immunotherapy started a long time ago: let us go through its main steps and key figures, from its very beginnings to the present day.





Edward Jenner, a British doctor known for the invention of the smallpox vaccine, is considered the father of immunology

Edward Jenner, the father of immunology

Edward Jenner, an English physician and naturalist known for the introduction of smallpox vaccine, is regarded as “the father of immunology”.



First serum therapy

Emil von Behring (who was to be awarded the first Nobel Prize in Physiology or Medicine in 1901) and Shibasaburo Kitasato find that injecting diphtheria toxin into animals produces a serum containing an anti-toxin that provides passive anti-diphtheria immunity; this was the first time serum was used as therapy and demonstrated that immunity did not need to arise internally but could be transferred.



William B. Coley, Memorial Hospital of New York, is considered the father of cancer immunotherapy

William B. Coley inaugurates the idea of immuno-oncology

William B. Coley from the Memorial Hospital in New York first attempts immune-modulating therapy for cancer by inoculating a patient with cultures of erysipelas, today known as Streptococcus pyogenes. For this reason, Coley is regarded as the father of cancer immunotherapy.



First use of bacterial toxins

William B. Coley creates a mixture of two bacteria - Streptococcus pyogenes and Serratia marcescens – later known as Coley’s toxin. His first patient is a young man with an inoperable malignant sarcoma. After treatment with the bacterial toxins, the patient reports complete remission, lasting until his death 26 years later of a heart attack.



Richard Pfeiffer author of many fundamental discoveries in immunology and bacteriology

Pfeiffer phenomenon: further evidence of humoral immunity

Richard Pfeiffer is remembered for his many relevant discoveries in immunology and bacteriology, most notably the phenomenon of bacteriolysis. Pfeiffer demonstrates the rapid killing of cholera bacteria in the cell-free serum of previously immunized guinea pigs. This discovery was later known as bacteriolysis or “Pfeiffer phenomenon”.

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The German pathologist Paul Ehrlich

The role of molecules in immuno-oncology

In his side-chain theory, German pathologist Paul Ehrlich introduces several important ideas which are later developed in the mid-1950s, including the hypothesis that antibodies are pre-existing receptors located at the cell surface.



Discovery of blood types

Karl Landsteiner discovers blood groups A, B, and O, and lays the foundation for the medical practice of blood transfusion. This Austrian (naturalized American) biologist and physiologist also made major contributions to understanding how antibody molecules combine with antigen, and the specificity of antibodies at the chemical level. For these studies, he was awarded the Nobel prize for Physiology or Medicine in 1930.

Successful transplantation of tumors in animals

In 1901-1903, Leo Loeb, in Canada and the United States, and Carl Jensen, at the Institute for Agriculture and Veterinary in Copenhagen, successfully performed tumor transplantations in rats and mice.




Swedish chemist and physicist Svante Arrhenius coins the term “immunochemistry” and hypothesizes that antigen-antibody complexes are reversible.



Lloyd J. Old, supporter of the theory of immunosurveillance, according to which the immune system can play a decisive role in the suppression of the tumor

Paul Ehrlich introduces the hypothesis of immune surveillance

Paul Ehrlich suggests that certain molecules inside the body are able to fight tumors. The idea of “immune surveillance”, i.e. that the immune system may play a key role in tumor suppression, would undergo several periods of acceptance and skepticism until 2001, when Robert Schreiber, Lloyd Old and others provided firm experimental evidence of the phenomenon.

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Albert Coons develops immunofluorescence

Albert Coons was the pioneer of immunofluorescence, a technique that allows physicians and biologists to identify specific antigens or unknown antibodies, whose known counterpart is variously linked to a marker.



First adjuvant developed

Jules Freund and Katherine McDermott develop the first adjuvant, a pharmacological or immunological agent that can modify the effect of other agents. Adjuvants can be added to a vaccine to modify the immune response by stimulating a higher number of antibodies and increased protection, thus reducing the amount of injected foreign material. Adjuvants can also be used to improve the efficacy of a vaccine, contributing to change the immune response to specific types of immune system cells. Today, adjuvants are a fundamental component of cancer vaccination strategies.



Discovery of the major histocompatibility complex (MHC)

George Snell develops congenic mouse lines – animal strains that are isogenic except for one particular narrow and easily observable genetic expression – which were key in determining the Major Histocompatibility Complex (MHC).



Discovery of antibody production by plasma cells

Astrid Fagraeus demonstrates antibody production by plasma cells or plasmocytes, later to be identified as the product of B lymphocytes.

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A new natural selection theory of antibody formation

Niels K. Jerne publishes his natural selection theory of antibody formation, marking the beginning of a series of other discoveries and advancements including the development of the clonal selection theory of antibody production by David Talmage and MacFarlane Burnet.



Pillar of tumor immunology

Richmond T. Prehn and Joan Main develop strains of inbred mice to demonstrate specific cancer antigens.



Interferon discovered

Alick Isaacs and Jean Lindenmann discover interferon, a virus-fighting protein produced by animal cells. They identified three main types of interferon (I, II and III). In addition to fighting virus infections, interferons can also fight tumors.



BCG Vaccine Shows Promise Against Cancer

Lloyd J. Old and Baruj Benacerraf demonstrate that bacillus Calmette-Guérin (BCG), an attenuated microorganism used as a vaccine against tuberculosis, inhibits tumor growth in mice. Today, BCG vaccine is widely used as first-line treatment for superficial bladder cancer.

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More evidence of antitumor immunity

Building on the work of Richmond Prehn, scientists George Klein, Hans-Olof Sjogren, Eva Klein and Karl Erik Hellstrom from Karolinska Institute in Stockholm conduct experiments in mice and provide more evidence that tumors can be recognized by the immune system and that immune responses are tumor-specific and protective. Also at the Karolinska Institute, L. Révész reports on additional experiments providing evidence of tumor-specific antigens.



White blood cells make interferon

Ion Gresser reports that white blood cells, called leukocytes, make interferon.



Interferon can arrest cell growth

Kari Cantell and colleagues in the laboratory of Werner Henle demonstrate, for the first time, a cytotoxic, non-antiviral activity of interferon, thus suggesting that interferon can suppress cells that have not been virally infected, such as cancer cells.



New assay lays groundwork for future

Niels K. Jerne and Albert Nordin develop an in vitro technology for the enumeration of antibody-forming cells. This technique continues to form the basis for current immunological assays, such as ELISPOT (acronym for Enzyme-linked ImmunoSPOT ). ELISPOT measures antigen-specific T cell responses and is an essential tool for immunological monitoring in clinical trials of cancer vaccines and immunotherapies.

First cancer-specific antigen identified

Garry Abelev and his colleagues report the discovery of alpha-fetoprotein (AFP, or oncofetal protein, OFA) as a serum marker for liver cancer and germ-cell tumors.



Epstein Barr virus, belonging to the family of herpesviruses, is the virus responsible for infectious mononucleosis and is involved in the genesis of some epithelial tumors and some types of lymphoma

First virus linked to human cancer

Sir Anthony Epstein, Bert Achong and Yvonne M. Barr identify a new herpesvirus, later known as Epstein-Barr Virus (EBV), in cultured Burkitt’s lymphoma cells. Later, with Gertrude and Werner Henle, Sir Anthony Epstein also isolates the agent of Burkitt’s lymphoma cells and reports that it is a new member of the human herpesvirus family, representing the first time a virus is linked to human cancer.



 Interferon gamma, virus inhibitor, which is produced by leukocytes in response to phytohemagglutinin

New interferon identified

E. Federick Wheelock discovers a new virus inhibitor, today known as interferon gamma, that is produced by leukocytes in response to phytohemoagglutinin (PHA).



Nobel Prize for the discovery of tumor viruses and for the hormone treatment of prostate cancer

Peyton Rous and Charles Huggins share the Nobel prize for discoveries of tumor viruses and hormonal control of prostate cancer, respectively.



New treatment for acute lymphoblastic leukemia

Herbert Oettgen reports the first treatment with L-asparaginase in patients with acute lymphoblastic leukemia.



First cell-surface differentiation antigens identified

Ted Boyse and Lloyd J. Old identify Ly antigens (originally named LY-A and LY-B, and later called Ly-1, Ly-2, and Ly-3), the first cell-surface antigens distinguishing normal cells of different lineages, thus introducing the concept of cell-surface antigens (differentiation antigens). This discovery led directly to the CD (cluster of differentiation) classification and the use of cell-surface markers to distinguish and classify normal and malignant cells.

CD8 cells, known as killer T cells, are capable of killing foreign and dangerous cells, including cancer cells

Lloyd J. Old and Eiichi Nakayama discovered antigen LY-B / Ly-2, later renamed CD8. CD8 cells, known as killer T cells, are one of the major cells of the adaptive immune response and are capable of directly killing foreign or dangerous cells, including cancer cells.



Interferon cures cancer in mice

Ion Gresser reports that interferon can be used to cure cancer in mice.

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BCG vaccine causes melanoma regression

Donald Morton reports significant tumor regression in melanoma patients after administration of Bacillus Calmette-Guerin (BCG).

T cells described

Richard K. Gershon and Kazunari Kondo demonstrate a role of T cells, suppressor T cells, in the induction of immunological tolerance.

Immuno-oncology as the new frontier of medicine

In these years, the scientific community becomes fully aware of the role and potential of immuno-oncology, and regards it as a new therapeutic tool that can be used in synergy with surgery, chemotherapy, radiation therapy and biological terapie for cancer treatment.



Nobel Prize for discoveries on the chemical structure on antibodies

Rodney Porter and Gerard Edelman share the Nobel Prize in Physiology or Medicine for their discoveries about the chemical structure of antibody molecules. They deduce that all antibodies have a common main structure containing a constant region and a variable region, the latter conferring high specificity to these proteins.



Dendritic cells discovered

Zanvil Cohn and Ralph Steinman discover the dendritic cell, a new immune cell specialized in antigen capture that plays a crucial role in adaptive immunity. For this seminal work, Dr. Steinman is later awarded the 2011 Nobel Prize in Physiology or Medicine.



The cancer immunosurveillance controversy

Osias Stutman reports that immunosuppressed mice, i.e. mice with inhibited immune system, are no more likely to develop cancer than normal mice, implying that the immune system does not confer protection. Stutman’s work discredits the theory of cancer immunosurveillance and, with it, the fundamental premise of tumor immunology.

NK cells identified

Swedish scientists Rolf Kiessling, Eva Klein and Hans Wigzell identify natural killer cells (NK cells or NK lymphocytes) in the mouse; these cells are particularly relevant because they recognize and destroy tumor cells and virus-infected cells. Two months later, Mikael Jondal reports the identification of the human NK cell.

Technique makes possible monoclonal antibody production

Georges Kohler and César Milstein developed a technique to produce hybrid cells, called hybridomas, that are capable of generate monoclonal antibodies.



T cell growth factor (TCGF) discovered

During their studies in mice, Francis W. Ruscetti, Doris Morgan and Robert C. Gallo discover the T cell growth factor (TCGF), later renamed interleukin-2 (IL-2), making it possible to grow and expand normal lymphocytes long term. This breakthrough also allows researchers to isolate T cells and study the viruses that affect them.



First clinical trial of interferon for cancer

First clinical trial of interferon alpha in 14 cancer patients. This is the first human testing of a biological treatment for cancer, conducted by Jordan U. Gutterman at the MD Anderson Hospital and Tumor Institute (now called MD Anderson Cancer Center) at Houston, Texas.

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First biochemical description of the αβ-T cell receptor

James P. Allison, Bradley W. McIntyre and David Bloch report the first biochemical description of the αβ-T cell receptor.



First description of LAK cells (Lymphokine Activated Killer cells)

Steven A. Rosenberg first describe LAK cells, i.e. lymphocytes that belong to the immune system and basically represent the activated form of NK (Natural Killer) cells. Activation makes these cells highly efficient in their destructive activity; for example, tumor cells that are not sensible to normal natural killer cells can be suppressed by LAK cells.

First treatment with rituximab

Ronald Levy reports the first successful treatment of a patient with a monoclonal antibody against the idiotype of a B-cell lymphoma. This led to the development of rituximab as an anticancer agent.

Identification of new antigens from cytotoxic t cells

Thierry Boon and colleagues from the Ludwig Institute for Cancer Research, Brussels, develop a new method to identify two main categories of tumor antigens that induce T-cell response in melanoma patients.



Identification of t cell antigen receptor (TCR)

A team of researchers including Philippa Marrack, John Kappler and James P. Allison provides conclusive evidence for the identification of T- cell antigen receptor (TCR).

Gershon awarded for the discovery of T cell suppressors

The New York Cancer Research Institute gives Richard K. Gershon the “Coley Award” for his studies on the role of thymus-derived T cells in inducing immune tolerance. His research led to the identification of T cell subpopulations, such as helper T cells, whose function is to activate B cells (lymphocytes produced in the bone marrow), suppressor T cells (that inhibit immune response), and cytotoxic T cells (that directly attack cancer cells and transplanted organs).

Identification of a relationship between human papilloma virus (HPV) and cervical cancer

Harald Zur Hausen identifies the human papillomavirus as the causative agent of cervical cancer, leading to the development of vaccines for the prevention of cervical cancer.



Identification of interleukin 2 as B-cell growth factor

Some researchers demonstrate that interleukin 2 (IL-2) is also a growth factor for B cells and thus stimulates the immune system to fight against infections and tumor cells.

Cloning of TNF-alpha and TGF-beta

Human genes for the tumor necrosis factor (TNF-alpha) and the transforming growth factor (TGF- beta), first identified in 1975 by Lloyd J. Old and Elisabeth A. Carswell, are successfully cloned.

First trials with interferon for the treatment of melanoma

Edward Creagan and John M. Kirkwood start the first trials of recombinant interferons for the treatment of melanoma.

Clinical experiments show T cell ability to attack tumors

Lloyd J.Old, Herbert F. Oettgen and Alexander Knuth conduct the first clinical experiments demonstrating that T cells can be “trained” to recognize and attack an established tumor.



Cloning of T-cell surface proteins

Researchers in the laboratory of Richard A. Axel, including Leonard Chess and Dan Littman, clone the genes for the CD4 [i] and CD8 [ii] T-cell surface proteins.

Identification and cloning of TGF-beta

Rik Derynck and his colleagues identify and clone the transforming growth factor beta (TGF-beta)

Tumor necrosis factor first demonstrated in cancer pathogenesis

Bruce Beutler and Anthony Cerami provide the first demonstration of the role of tumor necrosis factor in cancer pathogenesis.

Organization of immunoglobulin gene reported

Susumu Tonegawa, Leroy Hood and colleagues report on the organization of immunoglobulin genes, showing how so many antibody patterns can be produced by such a limited number of genes. These ideas were also very important in understanding the structure and formation of T-cell receptor.

LAK cells and IL-2 cells induce regression of metastases in melanoma and renal cancer

Steven A. Rosenberg and colleagues report that treatment with high doses of IL-2 (interleukin 2) cells and LAK (Lymphokine Activated Killer) cells caused regression of metastases in patients with melanoma and renal cell carcinoma, representing the first to describe cancer regression in humans following immunotherapy treatment.

Anti-tumor response with high-dose interleukin 2

Steven Rosenberg and colleagues observe anti-tumor responses in 3 of 10 patients treated with high dose interleukin 2 (IL-2).

New discovery on immunoreceptors

Larry Samelson provides the first demonstration that the T-cell receptor (TCR) is coupled to tyrosine kinase pathways, now known to be true for all immunoreceptors.

Description of the TH1-TH2 model

Timothy Mosmann and Robert Coffman propose the Th1-Th2 model of T helper cell function. Th1 cells produce interferon-gamma, which plays a major role in anti-tumor immunity and in defending against intracellular pathogens, while Th2 cells produce IL-4, IL-5 and IL-13, which protect against infections and help mediate antibody responses.



First humanized antibodies created

Greg Winter produces the first humanized antibody by replacing the complementarity regions in a human antibody with those from a mouse. Winter also developed techniques to obtain fully humanized antibodies for therapeutic purposes.

Evidence that CD8 co-receptor is involved in antigen recognition by killer T cells

Harald von Boehmer, Rose Zamoyska and Michael Steinmetz demonstrate that CD8 co-receptor is actively involved in the process of antigen recognition by killer T cells.

CTLA-4 identified

CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), a transmembrane protein receptor expressed in cytotoxic T cells, is identified.

First description of an antigen-specific form of T-cell anergy

Marc Jenkins and Ron Schwartz first describe an antigen-specific form of T-cell anergy.

First patient treated with autologous tumor-infiltrating lymphocytes in combination with IL-2 in melanoma

Steven A. Rosenberg and colleagues administer the first treatment with autologous tumor-infiltrating lymphocytes in combination with interleukin 2 (IL-2), reporting tumor regression in 9 of 15 melanoma patients.

Progress on the treatment of advanced cancer

Steven A. Rosenberg administers LAK cells and interleukin 2 cells to 157 patients with advanced cancer, obtaining complete regression in 9 patients and significant tumor reduction (50% or more) in 20 patients.



Nobel Prize for the discovery of antibody diversity

The Nobel Prize in Physiology or Medicine is awarded to Susumu Tonegawa for his discovery of the genetic principle for generation of antibody diversity.

New discoveries on cell survival and death

David Vaux, Suzanne Cory and Jerry Adams provide evidence that cell survival is regulated independently of cell proliferation, and that impaired cells death, similar to enhanced proliferation, is a key step in cancer development.



Cloning of CTLA-4

CTLA-4 (Cytotoxic T-lymphocyte associated Antigen-4), a co-stimulatory molecule involved in T cell-APC cell interaction, is cloned for the first time.

Discovery of the key role of P53 gene mutations in cancer development

Bert Vogelstein and colleagues discover that P53 gene mutations play a key role in the development of the most common types of cancer.

Interleukin -12 (IL-12) identified

Giorgio Trinchieri and his team at the Wistar Institute in Philadelphia identify interleukin-12 (IL-12), a cytokine that helps regulate the body’s resistance to infections and cancer.

First use of the T-body approach

Zelig Eshhar and colleagues first use the T-body approach to redirect T cells to recognize and attack tumor cells.

First evidence for the importance of the immune system in genome conservation

Thierry Boon and Etienne De Plaen clone the gene encoding the antigen recognized by the CTL and demostrate that the tum- antigen is generated by a point mutation. In collaboration with Christophe Lurquin, they further show that CTL recognize a peptide bearing the mutated residue. This is the first work demonstrating the key role of the immune system in preserving genome integrity, and led to the concept that cells bearing mutations are immunogenic. The research conducted by these scientists also established the technology that was later used to clone human tumor antigens recognized by CTL.

The role of CD28 in T-cell costimulation discovered

Carl June, Craig B. Thompson and colleagues demonstrate the role of CD28 protein in T-cell costimulation.



Biochemical initiators of t-cell activation discovered

Christopher E. Rudd and Stuart F. SIhlossman discover the biochemical initiators of T-cell activation, CD4- and CD8-p56lck complexes.

Mutations in the P53 gene found to play a role in human cancer development

Bert Vogelstein and colleagues report that mutations in the p53 gene play a role in the development of many common human cancers.

PRR: the chemical receptors of innate immunity

Charles Janeway introduces the hypothesis that components of the immune system, especially antigen-presenting dendritic cells, require the microbial stimuli contained in adjuvants to become activated and acquire the capacity to induce productive responses from antigen-specific lymphocytes. Without such activation by recognition of infection, the immune system ignores or even becomes tolerant to the antigens. He also suggests that the evolutionarily conserved features of pathogen-associated molecular patterns are detected by the immune system through a set of specialized receptors called PRRs (Pattern Recognition Receptors).

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First characterization of peptides by spectrometry

Don Hunt and Victor Engelhard report the first characterization of peptides from an MHC Class I molecule by mass spectrometry.

ZAP-70 discovered

Arthur Weiss and colleagues report the discovery of ZAP-70, a protein usually expressed in T cells (and of fundamental importance for initiation of T-cell signaling) and in NK cells.

First locoregional perfusion in patients with melanoma and sarcoma

Ferdy Lejeune and colleagues report the first study of locoregional perfusion with tumor necrosis factor in patients with melanoma and sarcoma.

From the development of a murine model to a tnf release assay through tumor antigen cloning

Lloyd Old, Thierry Boon and colleagues develop the TNF release assay for mouse systems in which release of tumor necrosis factor by T cells could be used to assess specific T-cell recognition, facilitating the cloning of human tumor antigens.

Identification of the stat signaling pathway

Xin Yuan Fu and James E. Darnell Jr. report the discovery of the STAT gene family and the cloning of the first two STAT family members, STAT1 and STAT2. The discovery of the STAT signaling pathway is a major scientific breakthrough, because it is involved in immunity control, development, and cancer pathogenesis.

Elucidation of CD28/CTLA4 signaling mechanisms

James Allison contributes to elucidate CD28/CTLA-4 signaling mechanisms and identifies a molecule that can inhibit T-cell activation when associated to certain types of cancer cells.

Demonstration of tolerance induction by costimulation blockade

Jeffrey Bluestone and colleagues provide the first demonstration of tolerance induction by costimulation blockade. These studies show the functional effects of CTLA-4 Ig as a potential tolerogen, and led to the discovery of CD86 and the development of selective immunosuppressive drug abatacept.



Discovery of major histocompatibility complex class II

Theodore S. Jardetzky and others describe the three-dimensional crystal structure of the major histocompatibility complex (MHC) class II molecules in the presence of superantigen.

GVAX vaccine found to stimulate the immune system

Drew Pardoll, Glenn Dranoff, Elizabeth Jaffee, Hyam Levitsky and others demonstrate that a vaccine composed of tumor cells irradiated and genetically modified to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) could induce tumor anti-immunity in mouse models. This vaccine was later known as GVAX.

Discovery of melanoma antigens

Giorgio Parmiani is the first who unequivocally demonstrates that human melanoma antigens recognized by T cells include molecules belonging to the normal melanocyte family. The molecular properties of these antigens were described one year later by both Steve A. Rosenberg (MART-1) at the National Cancer Institute and Thierry Boon (Melan-A) at the Ludwig Institute for Cancer Research in Brussels. These important discoveries were later used to develop an immunotherapy treatment for melanoma.

New discoveries on CD4+ T-cell activation

Kenneth M. Murphy and Anne O'Garra discover that dendritic cells and macrophages are required for T-helper 1 (Th1) activation of CD4 + T cells.

Discovery of first tyrosinase-derived tumor antigen

Vincent Brichard, Thomas Wölfel and Thierry Boon identify the first CTL-defined tumor antigen derived from the tyrosinase protein, an enzyme found in circulating melanoma cells.

Identification of the first inhibitory receptors

Lorenzo Moretta and colleagues report on the identification of inhibitory receptors expressed on the surface of natural killer (NK) cells.



First demonstration on treatment with monoclonal antibodies

Alan Houghton, Carl F. Nathan and colleagues first demonstrate that treatment with monoclonal antibodies can lead to reproducible tumor responses in cancer patients with solid tumors.

Discoveries on soluble antigen presentation

Antonio Lanzavecchia finds that efficient presentation of soluble antigen by cultured human dendritic cells is maintained by Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) plus interleukin 4 (IL-4) and downregulated by tumor necrosis factor alpha.

Discovery of a new member of the tyrosine kinase family: JAK-3

John J. O'Shea and colleagues find that JAK-3 (a new member of the non-receptor tyrosine kinase family involved in signal transduction mediated by several cytockines that are variously involved in hematopoietic cell maturation and differentiation and in immune system regulation) is coupled to the interleukin-2 receptor (IL-2R) in human peripheral blood T cells and in natural killer cells. Interaction with interleukin 2 (IL-2) leads to the phosphorylation and activation of JAK-3.

PDC subset in circulating blood discovered

Ralph Steinman and Nina Bhardwaj discover the plasmacytoid dendritic cell (pDC) subset in circulating blood.

Discoveries on gene MAGE-A3

Benoit Van den Eynde, Pierre van der Bruggen, Béatrice Gaugler and Thierry Boon test a vaccine in patients with metastatic melanoma patients using an antigenic peptide encoded by MAGE-3 and presented by HLA-A1. Vaccination with the MAGE-A3 protein showed a high therapeutic potential and was used in many clinical trials in later years.

New discovery on interferon

James Darnell, George Stark and Ian Kerr report studies demonstrating the relevance of interferon to elucidate signal trafficking from the cell surface to the nucleus.

Identification of new gene families: MAGE, BAGE AND GAGE

A team of scientists led by Thierry Boon identify new families of cancer-germline genes: MAGE, BAGE and GAGE. These genes are expressed in many tumors and remain silent in normal tissues except male germline cells. Many of these genes encode tumor-specific antigens that can be recognized by T lymphocytes.

NKT cell discovered

Albert Bendelac discovers NKT cells, which share the features of both T-cell and NK-cell populations. In fact, NKT cells express αβ-type antigen receptors like T lymphocytes, although (unlike in T lymphocytes) the receptor is not generated by somatic recombination but are germline-encoded, just like NK lymphocyte receptors.



The role of the JAK-STAT signaling pathway discovered

Paul Rothman demonstrates the role of the JAK-STAT signaling pathway in malignant tumors.

First ceses of regressions of melanoma metastases reported

Marie Marchand and Thierry Boon report the first cases of clinical regression of melanoma metastases after vaccination with a MAGE-A3 peptide. Other cases of regression will be reported a few years later, confirming these promising clinical results.

Adapter protein SLP-76 discovered

Gary Koretsky and colleagues discovered cytosolic adapter protein SLP-76.

New discovery on CD4+ AND CD25+ Treg cells

Shimon Sakaguchi describes natural Treg cells CD4+ and CD25+ and their role in immunosuppression.

Tretinoin approved by the us food and drug administration

Tretinoin, retinoic acid derived from Vitamin A, is approved by the US Food and Drug Administration for the treatment of acute promyelocytic leukemia.



The first significant improvement for melanoma patients reported

John M. Kirkwood reports the significant improvement for both survival and relapse rates in patients with melanoma treated with high-dose interferon alpha-2b.

Enhanced immune response with GM-CSF

German scientists Elke Jaeger, Dirk Jaeger, Julia Karbach and Alex Knuth report enhanced immune response with granulocyte-macrophage colony-stimulating factor (GM-CSF).

Tumor rejection

James P. Allison and Matthew Krummel show that a monoclonal antibody directed against the CTLA-4 molecule may result in the rejection of tumor, and that this rejection also occurs after a second exposure to tumor cells.

New discoveries on the transcription factor of activated T-cells

Anjano Rao and colleagues find evidence in mice that NFAT1 (Nuclear Factor of Activated T cells) transcription factor negatively affects the immune response.

New drugs approved

The US Food and Drug Administration approves topotecan for the treatment of metastatic ovarian cancer and irinotecan for metastatic colorectal cancer.



Discovery of the missing link between the innate and adaptive immune responses

Ira Mellman, Ralph Steinman, Shannon Turley and Antonio Lanzavecchia provide the first clear demonstration that dendritic cell maturation occurs in response to microbial products or pro-inflammatory mediators, activating their antigen presentation and processing capacities. By showing that ligands associated with innate immunity enable dendritic cells to initiate T-cell responses, this work provided the key missing link between the innate and adaptive immune responses.

Cloning of the IΚB kinases IKK-1 and IKK-2 reported

Frank Mercurio and Anjana Rao report the cloning of IκB kinases IKK-1 and IKK-2, two key regulators of the transcription factor NFκB.

Discovery on autologous heat shock protein peptide vaccines

Yasuaki Tamura demonstrate that a protein-peptide complex consisting of a 96 kDa heat shock protein (Hsp) can be used as a vaccine to treat a wide range of tumors in mice.

Two new monoclonal antibodies approved by the US FDA

The US Food and Drug Administration approves two new monoclonal antibodies: rituximab, that targets the CD20 protein for the treatment of B-cell non-Hodgkin’s lymphoma, and daclizumab, the first humanized monoclonal antibody.

First demonstration of immunoselection in the presence of antigen-specific cytotoxic t lymphocytes

Some researchers in Frankfurt, including Elke Jaeger, Dirk Jaeger, Julia Karbach, and Alex Knuth, provide the first demonstration of immunoselection in vivo in the presence of antigen-specific CTLs.

Discovery of a new family of tumor necrosis factor receptors

Yongwon Choi, Ralph Steinman e altri identificano un nuova famiglia di recettori del fattore di necrosi tumorale, inizialmente chiamata TRANCE e successivamente rinominata RANKL , dimostrandone il ruolo nel sistema immunitario e nell’osso, come pure nel tumore osseo e nel mieloma multiplo.

Role of transcription factor GATA3/STAT6 discovered

Richard Flavell shows that transcription factor GATA3/STAT6 induces differentiation of naïve CD4+ T cells into Th2 cells and further amplifies Th2 response by stimulating Il-4 production.

The role of TLR4 in immune response discovered

Charles A. Janeway and Ruslan Medzhitov demonstrate that toll-like receptor 4 (TLR 4) can mediate the immune response.



Discoveries of c-Rel protein

Hsiou-Chi Liou and colleagues find that c-Rel protein is essential for B lymphocyte survival and cell cycle progression, and that it plays a key role in T-cell activation and proliferation.

Immunological synapse created

Abraham Kupfer describes the three-dimensional structure of the SupraMolecular Activation Cluster (SMAC), the interface between the antigen-presenting cell and a lymphocyte; the SMAC will be later coined immunological synapse and further elucidated by Arash Grakoui, Michael Dustin, Paul Allen and Andrey Shaw.

New discoveries on tumor-specific cytotoxic lymphocytes

Vincenzo Cerundolo, Pedro Romero and colleagues demonstrate that, unlike virus-specific CTLs, the highest frequency of tumor-specific lymphocytes can be found in tumor-infiltrated lymph nodes. Extending these studies to vitiligo patients and using MHC Class I tetramers, they also show that peripheral blood lymphocytes have a higher frequency of cytotoxic T cells expressing melanocyte-specific skin-homing molecules. These results illustrate the interphase between tumor immunity and autoimmunity, since many tumor antigenic proteins are co-expressed by normal and tumor cells.

A landmark study published on CD8+ T cells

Haruo Ohtani and his team at the Kitasato University School of Medicine publish a study demonstrating A relationship between the presence of tumor-infiltrating CD8+ T cells and colon cancer prognosis. In particular, the Japanese team report that the accumulation of CD8+ T cells within the tumor predicted improved survival, whereas accumulation of the same cells in the tumor periphery did not correlate with survival.



Crystal structure of T-cell receptor determined

Ellis L. Reinherz and colleagues describ the crystal structure of T-cell receptor in complex with peptide and MHC Class II.

Demonstration of the role of stat 5 proteins in T-cell signaling

James N. Ihle and colleagues demonstrate that Stat5 proteins play a key role in mediating IL-2 signaling in lymphocytes.

Tregs cells and immune response

Eiichi Nakayama and colleagues reporte that regulatory T cells (Tregs) are involved in the tumor immune response.

Evidence that PD-1 receptor is an immune checkpoint

Tasuku Honjo and colleagues show that PD-1 knockout mice develop an autoimmune syndrome, suggesting that the receptor PD-1 is an immune checkpoint.

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Identification of two new ligands for PD-1

Researchers identify two ligands for PD-1: the B7-H1 protein, also called PD-L1 B7, discovered by Lieping Chen and Tasuko Honjo, and the B7-DC protein, or PD-L2, discovered by Drew Pardoll and Tasuko Honjo.

Imatinib mesylate against chronic myeloid leukemia

Imatinib mesylate demonstrates to be effective for the treatment of chronic myeloid leukemia (CML). It is the first anti-cancer drug developed specifically to target the molecule defect that causes a specific type of human cancer (LMC in this case). The example of imatinib mesylate shows that the understanding of the genetic lesions underlying tumors is a prerequisite for the development of effective therapies.

Alemtuzumab approved for chronic lymphatic leukemia

The US Food and Drug Administration approves alemtuzumab, a humanized monoclonal antibody for the treatment of chronic lymphatic leukemia.

Combination of interferon alpha 2B and BCG vaccine effective in the treatment of bladder carcinoma

Michael O’Donell reports on the efficacy of the combination of interferon alpha 2b plus BCG (bacillus Calmette-Guérin) vaccine in patients with refractory bladder carcinoma.

NK cells: identification of a new mechanism of tumor cell recognition

After separate research, David Raulet and Lewis Lanier show that cell tumors expressing ligands for the natural killer cell activating receptor NKG2D are destroyed by natural killer cells in vivo, establishing a new mechanism for how natural killer cells recognize tumor cells.

The critical role of trail in immune surveillance of cancer

Mark J. Smyth and other researchers provide the first evidence on the key role of TRAIL (Tumor necrosis factor-Related Apoptosis-Inducing Ligand) in immune surveillance of cancer.

New findings on the theory of cancer immunosurveillance

The theory of cancer immunosurveillance is revived with the publications of Robert D. Schreiber, Lloyd J. Old and Mark J. Smyth who show that mice lacking interferon-gamma, IFN-gamma receptor, or IFG-gamma-producing cell types or perforin, have increased susceptibility to B-cell lymphoma. These studies help underpin the relevance of the immune system in cancer development and revive the theory of cancer immunosurveillance.



Discoveries on Fc receptor polymorphism

Patients with Fc receptor polymorphism show better clinical responses to CD20-specific and EGFR-specific monoclonal antibodies, suggesting that Fc-receptor mediated immune responses are crucial to their anti-tumor activity.

Peptide vaccines for patients with stage IV melanoma

Pramod Srivastava, Giorgio Parmiani, Michele Maio and colleagues report that immunization with heat shock protein gp96 induces regression in patients with stage IV melanoma, without any immunization-related adverse events.

Discoveries on lipid binding to CD1 molecules

Vincenzo Cerundolo and colleagues report on the study on the structural, kinetic and functional analysis of lipid binding to CD1 molecules. In order to gain insight into the structure and function of CD1 molecules, the researchers applied two novel refolding protocols and were able to solve the crystal structure of CD1b molecules with distinct lipid antigens and CD21d molecules loaded with the natural killer T cell agonist alpha-galactosylceramide. These structures elucidate, for the first time, the ligand-binding mechanisms of CD1b via a network of four interlinked hydrophobic channels, which provide a unique adaptable required to present a broad range of ligands and the ability of CD1d molecules to undergo conformational changes.

Description of TCR signaling

Larry Samelson and colleagues describe the signaling pathway of T cell receptor (TCR) microclusters, which also contain enzymes and adapter molecules.

Further evidence that IL-2 is a potent regulatory T-cell stimulator

A team of researchers demonstrates that interleukin-2 (IL-2) is a potent regulatory T-cell stimulator. IL-2 is a cytokine necessary signal for the development, survival, and expansion of Tregs that downregulate self-reactive lymphocyte responses, thus preventing anemia, enteritis, and other autoimmune sequelae.

First demonstration of tumor regression induced by adoptive T-cell therapy

Two distinct studies show, for the first time, that adoptive T-cell therapy can cause tumor regression in patients with advanced melanoma. The therapy was performed by taking T cells from patients, making the cells able to recognize specific antigens in order to destroy them, and re-injecting them into the body.

The first trials using monoclonal antibodies published

The Journal of Clinical Oncology published reports of the first trials using monoclonal antibodies to induce CTLA-4 blockade in melanoma patients.

The first radionuclide-linked monoclonal antibody approved to treat non-Hodgkin’s lymphoma

The first radionuclide-linked monoclonal antibody (ibritumomab tiuxetan) is approved by the US Food and Drug Administration to treat some forms of B-cell non-Hodgkin’s lymphona. The antibody binds to CD20 antigen that is present on the surface of both healthy and malignant B cells, but not on their precursors. The radionuclide-linked antibody kills such cells and the surrounding ones. Moreover, the same antibody can trigger antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and apoptosis. These actions cause the suppression of B cells from the body of a non-Hodgkin’s lymphoma patient and allows a new population of healthy B cells to develop.



Association between tumor immunity and outcomes

George Coukos and colleagues provide the first data showing an association between tumor immunity and outcomes in patients with ovarian carcinoma, demonstrating that the presence of tumor-infiltrating lymphocytes in the primary tumor is strictly related to patient survival.

Discoveries on a CTLA-4 specific antibody

A CTLA-4 specific antibody induces clinical regression in patients with advanced melanoma, but also causes immune-related toxicity.

Discoveries on antigen-specific CD4 and CD8 T cells

Vincenzo Cerundolo and colleagues demonstrate that co-injection of invariant natural killer T (NKT) cells agonists together with antigenic proteins enhances antigen-specific CD4 and CD8 T cell responses. This mechanism has been tested in clinical research to start antigen-specific T and B cell responses.

Discoveries on IDO boost vaccine efficacy

Benoit Van den Eynde demonstrates that tumors often express tryptophan-degrading enzyme indoleamine 2 3-dioxygenase (IDO), which allows tumor cells to resist immune rejection. This work will be followed by further research on IDO inhibitors to improve vaccine efficacy against cancer.

New cancer immunotherapy division directed by Michele Maio in Siena

Michele Maio is the first director of the newborn Cancer Immunotherapy Division at the University Hospital of Siena (Azienda Ospedaliera Universitaria Senese, AOUS), a center of reference for immune-oncology at the national and international level.

Discoveries on Foxp3

Shimon Sakaguchi and colleagues report that the transcription factor Foxp3 (Forkhead box P3) has a major physiological function in controlling the immune response, as it ensures immunological tolerance and prevents autoimmunity. Soon after, Alexander Rudensky, Roli Khattri and Fred Ramsdell publish a work in “Nature Immunology“ reporting that Foxp3 is expressed by regulatory cells CD4+CD25+ and programs their development and function.

Tositumomab approved for the treatment of non-Hodgkin’s lymphoma

The US Food and Drug Administration approves tositumomab, an anti-CD20 IgG 2a monoclonal antibody derived from immortal murine cells, for the treatment of follicular lymphoma (non-Hodgkin’s lymphoma).



Two new molecules approved for the treatment of metastatic colorectal cancer

The Food and Drug Administration approves two new molecules for the treatment of metastatic colorectal cancer: the monoclonal antibodies cetuximab – that inhibits the activity of a protein called epidermal growth factor receptor (EGFR), overexpressed in certain types of cancer – and bevacizumab, that inhibits the activity of the vascular endothelial growth factor (VEGF), an angiogenesis-stimulating factor.

Demonstration of immune response induced by vaccination

A Phase 1 clinical study conducted at Weill Medical College of Cornell University, USA, demonstrates that vaccination with a cancer-specific recombinant protein antigen can induce a full immune response mediated by antibodies, CD4+ T cells and CD8+ T cells. In this study, patients with non-small cell lung cancer were treated with a vaccine containing MAGE-3 antigen plus the immunological adjuvant AS02B, reporting T-cell response and a MAGE-3-specific antibody response.

NIBIT, Italian Network for Tumor Biotherapy

Creation of the NIBIT

Michele Maio and Giorgio Parmiani create the Italian Network for Tumor Biotherapy (Network Italiano per la Bioterapia dei Tumori, NIBIT) in Siena. The NIBIT includes the main Italian groups working in the field of clinical and preclinical research on the biotherapy of human tumors. Michele Maio is currently the President of both the NIBIT and the NIBIT Foundation, which was established in 2012.

Discovery of a new strategy used by tumors to escape the immune response

Gabriel Rabinovich and his team at the Cancer Research Institute identify a new strategy mediated by secretion of protein galectin-1 that is used by tumors to escape the immune response.



Discovery of better survival indicators in colorectal cancer

In an article published in the New England Journal of Medicine and Science, Wolf Hervé Fridman and Jérôme Galon provide quantitative insights into the immune system variables involved in the clinical course and prognosis of colorectal cancer, demonstrating that the type, density and location of immune cells within tumor samples were found to be a better predictors of patient survival than previous pathological criteria for tumor staging.

Mechanism reversing immune response first described

Rong-Fu Wang and colleagues are the first to describe a mechanism, mediated through Toll-like receptors, that can reverse immune suppression by regulatory T cells.

New important discoveries on cancer vaccine

Daniel E. Speiser and colleagues demonstrate that cancer-specific cytotoxic lymphocytes are strongly activated following vaccination with peptides and CpG oligonucleotides, representing the currently most powerful synthetic cancer vaccine formulation. Circulating cancer-specific T cells become highly functional in vivo, which correlates with the survival of melanoma patients.

Immunotherapy study by Ian Frazer leading to development of a vaccine against cervical cancer

The Cancer Research Institute provides funding to a research group led by Austrialian scientist Ian Frazer for a Phase Ib study on HPV infection. The research would lead to the development of preventive vaccines for cervical cancer.

Discoveries on post-vaccination melanoma regression

Christophe Lurquin, Thierry Boon and Pierre Coulie show that post-vaccination melanoma regression involves tumor-specific T cells, some of which being already present before vaccination. It suggests that immunosuppression prevails in tumors prior to vaccination.

Discoveries about DNA damage response

David Raulet and colleagues show that the DNA damage response, a kinase cascade induced in early stage cancer cells, induces tumor cells to display ligands that activate natural killer cells against tumor cells.

New T-cell subtype identified

Chen Dong and Casey Weaver identify a new T cell lineage, which was termed as T helper 17 (Th17), capable of expressing a specific cytokine pattern and playing a key role in the body’s immune response. Th17 cells have since been shown to be critical in inflammatory diseases and cancer.

New breast cancer vaccine developed

Reshma Singh, in the laboratory of Yvonne Paterson, reports success with a novel breast cancer vaccine tested in mice utilizing Listeria monocytogenes bacteria that have been genetically engineered to produce HER-2/neu, an oncogene which is overexpressed in breast, ovarian, lung, pancreatic, and gastrointestinal cancers. Their vaccine is shown to stimulate immune responses specific to a broader number of HER-2/neu antigen epitopes than previously achieved.



T-cells transduced with t cell receptor genes used to treat patients with melanoma

Steven A. Rosenberg and colleagues show that T cells transduced with T cell receptor genes can be used to treat patients with melanoma.

New drugs approved to treat multiple myeloma

The US Food and Drug Administration approves the drugs thalidomide and lenalidomide for the treatment of patients with multiple myeloma.

The first demonstration to show the effects of a synthetic vaccine in humans

Daniel Speiser, Pedro Romero, and colleagues demonstrate that a synthetic vaccine can rapidly elicit strong specific CD8+ T cell responses in a majority of patients.

Vaccine for cervical cancer approved

The US Food and Drug Administration approves the cervical cancer vaccine, which protects against two types of HPV that cause approximately 70 percent of all cases of cervical cancer worldwide.

First fully human monoclonal antibody

Panitumumab, an anti-EGFR monoclonal antibody to treat metastatic colorectal cancer, is approved by the US Food and Drug Administration. Generated from transgenic mice with human immunoglobulin genes, panitumumab is also the first fully human monoclonal antibody approved for cancer therapy.



First clinicaltrial of adjuvant interferon

The first neoadjuvant trial of interferon (UPCI 00-008) reveals its effects are immunological, and mediated through modulation of STAT3 and dendritic cells, as well as T cell responses to melanoma.

Identification of a novel mechanism of t cell homeostasis

Gabriel Rabinovich and his team identify a novel mechanism of T cell homeostasis based on differential glycosylation of T helper cell subsets.

New findings on CTLA-4-specific antibodies

CTLA-4-specific antibodies are shown to induce tumor responses in renal and prostate cancers.

New parameters for cancer prognosis

Jérôme Galon and Wolf Hervé Fridman introduce the concept of “immune contexture”—associating the nature, the density, the functional orientation, and the location of immune cells within the tumor—to define the prognosis of cancer patients.

Cancer-immune equilibrium demonstrated

An international research led by Lloyd J. Old, Robert Schreiber, and Mark Smyth provides the first demonstration of cancer-immune equilibrium.



Genetically engineered T cells treat diffuse large B cell lymphoma

Stanley Riddell, Philip Greenberg, Michael Jensen and others report on a clinical trial showing that T cells engineered to express chimeric antigen receptors induce clinical responses in patients with B cell lymphomas.

New bispecific antibody developed

A recombinant antibody fragment that is bispecific is developed and designed to target the CD19 antigen on B cell lymphoma and the CD3 antigen on T cells, effectively using the T cells to kill tumor cells. The antibodies are named BiTE, for Bispecific T cell Engager.

First approval of therapeutic vaccine for kidneycancer

The therapeutic vaccine for kidney cancer developed by Pramod Srivastava is approved in Russia.



Identification of a new ny-ESO-1 epitope

Danila Valmori and Maha Ayyoub identify a new NY-ESO-1 epitope expressed by half of Caucasians, that is immunodominant. This finding is instrumental for the immunologic monitoring of vaccination trials targeting the NY-ESO-1 tumor antigen.

Protein BCL6 discovered

Chen Dong and others identify protein BCL6, a key transcription factor that regulates the differentiation and function of follicular helper T (TFH) cells. Protein BCL6 often mutates into diffuse large B-cell lymphoma, the most common type of lymphoma in adults, that accounts for 30% - 40% of new non-Hodgkin’s lymphoma diagnoses, and contributes to the pathogenesis of the disease.

TET proteins alter gene expression in stem cells and cancer

Anjana Rao, Mamta Tahiliani and L. Aravind discover the enzymatic activity of TET proteins that play an important role in maintaining genome stability. Loss of function and mutations in TET2 are shown to be frequent in myelodysplastic syndromes and myeloproliferative neoplasms including chronic myelomonocytic and acute myeloid lymphomas.

Therapeutic vaccine cures precancerous gynecological disease

A therapeutic vaccine, developed by Cornelis (Kees) Melief and Sjoerd Van Der Burg at Leiden University Medical Center, demonstrates durable complete responses in some women with HPV-16+ vulvar intraepithelial neoplasias, a disease that normally has a spontaneous regression rate of less than 2 percent.

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Ofatumumab approved to treat chronic lymphocytic leukemia

Ofatumumab, an anti-CD20 monoclonal antibody to treat chronic lymphocytic leukemia, is approved by the US Food and Drug Administration.

Elimination of leukemia cells reported

Ryuzo Ueda and colleagues report elimination of leukemia cells by CCR4 antibody in patients with adult T-cell leukemia (ATL).

PD-1 antibody shows promise in some types of cancer

A PD-1-specific monoclonal antibody induces frequent tumor regressions in patients with advanced melanoma, renal cancer, lung cancer, and colon cancer with very low rates of toxicity.

First therapeutic cancer vaccine approved

The US FDA (Food and Drug Administration) approves the use of sipuleucel-T for the treatment of prostate cancer. Sipuleucel-T is the first human cancer treatment vaccine to be approved in the United States. The cancer vaccine is the first to show a survival benefit in a phase III trial, conferring a four-month overall survival advantage in men with advanced castrate-resistant prostate cancer.

Checkpoint blockade with monoclonal antibodies targeting inhibitory receptors CTLA-4 extends survival

A CTLA-4-specific monoclonal antibody, ipilimumab, is the first agent in history to provide a survival advantage in patients with advanced melanoma in a large randomized phase III trial.



Gene profiling study of cancer-specific CD8+ T cells

Daniel E. Speiser and other CVC (Cancer Vaccine Collaborative) investigators perform the first gene profiling study of cancer-specific CD8+ T cells, and demonstrate that lymphocyte dysfunction in cancer tissue is due to multiple molecular alterations, similar as in “exhausted” T cells in patients with chronic infection. The data provide novel drug targets, and show that T cell exhaustion is reversible and limited to anatomical sites of disease.

Artificial antigen presenting cells can enhance adoptive therapy

Lee M. Nadler, Naoto Hirano, Marcus O. Butler and other CVC (Cancer Vaccine Collaborative) investigators report that a new technology using artificial antigen presenting cells (aAPC) could successfully enhance adoptive therapy of tumor antigen-specific CD8+ T cells. In a study involving nine patients with advanced melanoma, the aAPC technology could induce long-term increases in tumor-specific CD8+ T cells.

Hallmarks of cancer expanded

Douglas Hanahan and Robert Weinberg publish an update of their seminal review, Hallmarks of Cancer, adding to the list of cancer characteristics the ability of tumors to evade the immune system and emphasizing immune system-induced inflammation as an enabling characteristic in cancer development.

Peptide vaccine and interleukin-2 improve melanoma responses

Douglas J. Schwartzentruber and colleagues at The University of Texas MD Anderson Cancer Center demonstrate that patients with metastatic melanoma receiving high doses of interleukin-2 (IL-2) plus a peptide vaccine had significant improvement in overall clinical response, providing further validation for immunological approach to cancer treatment.

Adoptive immunotherapy artificially enhances immune system cells and programs them to destroy the tumor area

Investigators at the National Cancer Institute’s Center for Cancer Research di Bethesda, Maryland, led by Steven A. Rosenberg demonstrate that adoptive immunotherapy with CD8+ T cells genetically engineering to recognize the NY-ESO-1 antigen could induce significant tumor regressions in patients with metastatic synovial sarcoma and melanoma.

Immunotherapy drug ipilimumab approved for advanced melanoma

The US Food and Drug Administration approves the anti-CTLA-4 monoclonal antibody ipilimumab for the treatment of metastatic melanoma; it is the first immunotherapy drug shown to extend survival in metastatic melanoma.

Genetically modified T cells for the treatment of patients with chronic lymphocytic leukemia

Using a novel technique to genetically modify T cells for adoptive transfer, Carl June, Michael Kalos, David Porter, Bruce Levine, and colleagues at the University of Pennsylvania School of Medicine achieve clinical responses in patients with chronic lymphocytic leukemia, including two complete, durable (one year) clinical responses, accompanied by in vitro expansion and long-term functional persistence of gene-modified cells.

Antibody-drug conjugate approved for lymphoma

The US Food and Drug Administration approves a new chimeric mouse/human monoclonal antibody to treat Hodgkin’s lymphoma and anaplastic large cell lymphoma.

Nobel Prize for innate immunology for the role of dendritic cells in adaptive immunity

The 2011 Nobel Prize in Physiology or Medicine is awarded to Bruce Beutler and Jules Hoffmann for their discoveries on the mechanisms underlying the activation of innate immunity, and to Ralph Steinman for the discovery of dendritic cells and their role in adaptive immunity.



Regulatory T cells play role in immune response

Sebastian Amigorena and colleagues demonstrate that regulatory T cells play a critical role during the priming of immune responses. Regulatory T-cell depletion induces the activation and expansion of a population of low-avidity CD8+ T cells, which stabilized the interactions between antigen-presenting dendritic cells and low-avidity T cells. These results suggest that regulatory T cells play a critical role in the induction of high-avidity primary responses and effective memory.

Field-wide initiative on T cell assay reporting completed

Members of the Cancer Immunotherapy Consortium at the Cancer Research Institute, New York, and the Association for Cancer Immunotherapy at Mainz, Germany, announce the completion of the Minimal Information About T cell Assays (MIATA) Project. T-cell immune monitoring in clinical trials and the guidelines promise to help accelerate progress in cancer immunotherapy development by making data interpretation and comparison easier for investigators.

Study on anti-PD-1 R

The results of a Phase I study on an anti-PD-1 antibody generates excitement as they show that, among 236 patients with various types of cancer, the treatment shrank tumors in 28 percent of melanoma patients, 30 percent of patients with kidney cancer, and 18 percent of patients with advanced non-small cell lung cancer.



Therapy with t cells engineered with a chimeric antigen receptor achieves high response rate

Carl H. June, Michael Kalos, and colleagues achieve a high response rate (89%) in patients with acute lymphoblastic leukemia (ALL), using genetically modified T cells from a patient’s own body to attack cancer cells.

GUT microbiota help shape the anti-cancer immune response

In two publications, Laurence Zitvogel, Guido Kroemer and colleagues, and Giorgio Trinchieri, Yasmine Belkaid and colleagues demonstrate that gut microbiota help shape the anti-cancer immune response by mediating its effects on the tumor microenvironment.

Clinical trial on new immunotherapies started

Through the Cancer Research Institute’s Clinical Accelerator program, two new checkpoint inhibitor drugs, MEDI4736 (anti-PD-L1) and tremelimumab (anti-CTLA-4), are being tested in a phase I trial for patients with six different cancer types, including colorectal cancer, cervical cancer, head and neck cancer, kidney cancer, lung cancer, and ovarian cancer.

CAR T cell therapy attains complete responses in leukemia

Michel Sadelain, Renier Brentjens, Isabelle Riviere, and colleagues treat five adult patients with relapsed B cell acute lymphoblastic leukemia (B-ALL) with chimeric T cells and all patients had a complete response, forming a highly effective bridge to therapy with allogeneic hematopoietic stem cell transplantation.

Cancer immunotherapy "breakthrough of the year"

Science magazine - one of the world’s leading scientific journals - has deemed cancer immunotherapy the 2013 “breakthrough of the year”.



Nivolumab and ipilimumab: 90% response rate in melanoma

Mario Sznol announces one- and two-year survival rates of 94% and 88% from a phase Ib trial of nivolumab, a PD-1 checkpoint inhibitor, and ipilimumab in advanced melanoma.

CAR T cell therapy achieves high response rate

Steven A. Rosenberg announces successful data from its phase 1/2a clinical trial of patients with aggressive non-Hodgkin’s lymphoma treated with CAR T therapy. Eight of 13 patients with advanced B cell malignancies showed complete remissions, while four showed partial remissions. The total result was a 92% objective response rate. Furthermore, four of seven patients with chemotherapy-refractory diffuse large B-cell Lymphoma showed complete remissions. This is only the first report of successful treatment of diffuse large B-cell lymphoma with anti-CD19 CAR T cells.

The ontogeny of tumor-associated macrophages

Ming Li, Eric Pamer, and colleagues show that mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). Depletion of tumor-associated macrophages, but not mammary tissue macrophages, restores tumor-infiltrating cytotoxic T cell responses and suppresses tumor growth.

FDA approves ramucirumab for stomach cancer

The U.S. Food and Drug Administration (FDA) approved ramucirumab to treat advanced stomach cancer and gastroesophageal junction adenocarcinoma,

New treatment strategy induces immune response against ovarian cancer

Kunle Odunsi and colleagues show that a drug called decitabine increases the effectiveness of a vaccine designed to elicit an immune response against ovarian cancer.

News for pancreatic cancer

Elizabeth Jaffee and colleagues demonstrate a survival benefit in pancreatic cancer patients receiving the combination of GVAX Pancreas and CRS-207 cancer vaccines in a phase II trial. The mean overall survival of the patients receiving the combination (designed as “breakthrough therapy”) was 6.1 months compared to 3.9 months.

New cancer immunotherapy

The US Food and Drug Administration announced that pembrolizumab was granted accelerated approval for advanced or unresectable melanoma.

Blinatumomab approved by the Food and Drug Administration

The FDA approves blinatumomab for use in the treatment of B cell acute lymphoblastic leukemia (ALL). This monoclonal antibody is the first of a novel class of agents known as bispecific T cell engagers (BiTE), which selectively direct the human immune system against tumor cells.



The Food and Drug Administration approves immunotherapy combination for advanced melanoma

The FDA announced accelerated approval of a combination of immunotherapy drugs (ipilimumab e nivolumab) for the frontline treatment of advanced melanoma. The drugs are two immune checkpoint inhibitors that “release the brakes” on most T-cell-mediated immune responses, allowing them to mount a stronger and more effective attack against cancer.

FDA approves pembrolizumab for the treatment of lung cancer, and expands indications for nivolumab

Anti-PD-1 pembrolizumab receives approval by the FDA as second-line treatment for patients with lung cancer, for use in the treatment of both squamous and non-squamous non-small cell lung cancer that is no longer responding to chemotherapy. The FDA also expanded indications for nivolumab to include patients with non-squamous non-small cell lung cancer that has stopped responding to chemotherapy.

Ipilimumab in the adjuvant therapy of melanoma

The FDA approved ipilimumab for the adjuvant treatment of stage III melanoma.

FDA approves a new type of immunotherapy based on oncolytic viruses

The FDA approved a new type of immunotherapy for the treatment of advanced melanoma. It is an oncolytic virus therapy, i.e. genetically engineered viruses that have been tweaked to preferentially kill cancer cells. The virus used is a modified version of the herpes simplex virus I.

Monoclonal antibody for multiple myeloma

Daratumumab is the first monoclonal antibody approved by the Food and Drug Administration for multiple myeloma.

FDA approves nivolumab for kidney cancer

Nivolumab, a PD-1 immune checkpoint inhibitor, received FDA approval to treat metastatic renal cell carcinoma, the most common form of kidney cancer.

Elotuzumab approved for multiple myeloma

The FDA approved elotuzumab, the second monoclonal antibody for the treatment of patients with multiple myeloma. This humanized monoclonal antibody targets the antigen SLAM family member 7 (SLAMF7 gene) also known as CD319.



Nivolumab approved for Hodgkin’s lymphoma and for head and neck squamous cell cancer

The FDA granted approval to nivolumab, an anti-PD-1 checkpoint inhibitor, for the treatment of Hodgkin’s lymphoma and for head and neck squamous cell carcinoma (HNSCC).

Alliance AOU Siena/NIBIT foundation with Parker Institute for Cancer Immunotherapy and Cancer Research Institute

The NIBIT Foundation and the Cancer Immunotherapy Division of the University Hospital (AOU) of Siena, both directed by Dr. Michele Maio, enter the TESLA (Tumor neoantigEn SeLection Alliance) project in collaboration with the Parker Institute for Cancer Immunotherapy and the Cancer Research Institute to carry out research on cancer neo-antigens.

New anti-PD-1 drug approved for bladder cancer and lung cancer

The FDA granted approval for atezolizumab to treat the most common type of bladder cancer and non-small cell lung cancer. Atezolizumab acts an immunomodulator drug that blocks the programmed cell death ligand, known as PD-L1.

Pembrolizumab for head and neck squamous cell cancer

The FDA granted approval to pembrolizumab, an anti-PD-1 monoclonal antibody, for patients with head and neck squamous cell carcinoma and for metastatic non-small cell lung cancer.

Olaratumab for soft tissue sarcoma

The FDA granted approval to monoclonal antibody olaratumab for patients with soft tissue sarcoma for whom surgery and radiation therapy are not effective options.

New monoclonal antibody for multiple myeloma

The US Food and Drug Administration approves monoclonal antibody daratumumab for patients with multiple myeloma who had received at least three prior therapies.

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Nivolumab also approved for bladder cancer

Anti-PD-1 checkpoint inhibitor nivolumab received approval by the Food and Drug Administration also for the treatment of advanced urothelial cancer.

Nivolumab approved in italy for kidney cancer and lung cancer

AIFA, the Italian Drug Agency, approved nivolumab for the treatment of advanced renal cell carcinoma after prior therapy in adult subjects. Nivolumab was also approved (and authorized for NHS reimbursement) for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy in adult subjects.

Nivolumab montherapy for stomach cancer

The Journal of Clinical Oncology (JCO) published the results of the first Phase III randomized trial that demonstrated a significant improvement in patients with advanced gastric cancer.

Promising results for nivolumab in metastatic anal cancer

Lancet Oncology published the first promising results of a Phase II trial of nivolumab in patients with squamous-cell anal carcinoma who were refractory to chemotherapy or radiation therapy.

Pembrolizumab for CHL

Anti PD-1 drug pembrolizumab was approved by the FDA also for the treatment of classical Hodgkin’s lymphoma (CHL).

Combonation therapy with nivolumab and ipilimumab increases survival in patients with advanced melanoma

Treatment with anti-PD-1 monoclonal antibody nivolumab in combination with ipilimumab, another immune checkpoint inhibitor (CTLA-4), increases progression-free survival (PFS) in treatment-naïve patients with metastatic melanoma as compared to ipilimumab alone. These findings, that will carry many implications, come from Phase III study CheckMate 067, presented at the American Association for Cancer Research (AACR) conference in Washington.

Nivolumab increases long-term survival in lung cancer

Sixteen percent of patients with lung cancer treated with immunotherapy drug nivolumab are still alive at 5 years, which implies long-term survival for one of the most common types of cancer. These findings come from Phase I study CA209-003, presented at the American Association for Cancer Research (AACR) congress in Washington.

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