Manual Interferon: The Dawn of Recombinant Protein Drugs (Ernst Schering Foundation Symposium Proceedings)

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Important Links. Follow Us. App Download. On October 1, , the FDA announced accelerated approval of a combination of immunotherapy drugs for the frontline treatment of advanced melanoma. The FDA based its approval on results from a clinical trial showing that patients who received the combination had better responses than those who received ipilimumab alone. The Cancer Research Institute launches the first-of-its-kind website devoted to cancer immunotherapy designed specifically for cancer patients and their caregivers.

Through TheAnswerToCancer. The site provides a robust but accessible overview of the science behind cancer immunotherapy, detailed information about cancer immunotherapy clinical trials, and voices from the cancer immunotherapy community. Coley to Cure shows that the story of the Cancer Research Institute is the story of cancer immunotherapy. This page retrospective helps readers understand the central role that CRI has played in bringing the field of cancer immunology to its current era of fruition, and what it is doing to set the pace for the future.

The drug, manufactured by Amgen, is the first of a novel class of agents known as bispecific T cell engagers BiTE , which consist of two monoclonal antibodies joined together. One end of the BiTE binds to a molecule on T cells, and the other end binds to a molecule on cancer cells; by bringing the two together, the BiTE facilitates cancer cell killing. The FDA approval was based on a phase II clinical trial showing that, of the patients evaluated, Opdivo is FDA-approved for treating metastatic melanoma in patients who have failed prior treatment.

Ongoing studies suggest it may benefit patients with many different cancers, including lung, brain, head and neck, stomach, and kidney cancers. The FDA announced that Merck's Keytruda pembrolizumab was granted accelerated approval for advanced or unresectable melanoma, making it the first PD-1 inhibitor cleared in the US.

The promising immunotherapy drug nivolumab received its first regulatory approval in July for use in inoperable melanoma in Japan, under the name Opdivo. This makes it the first anti-PD-1 cancer therapy to clear this hurdle. As a new collaboration with Cancer Research Institute CRI , Cancer Immunity will publish its final issue and Cancer Immunology Research will continue to publish cutting-edge research in cancer immunology. All content of Cancer Immunity, founded in , will be posted on the Cancer Immunology Research website, allowing readers to access content for both journals in one location.

With enthusiasm for cancer immunotherapy mounting thanks to recent successes in the clinic with immune-based cancer treatments such as anti-CTLA-4 and anti-PD-1 antibodies, and the FDA approvals of sipuleucel-T prostate cancer vaccine and ipilimumab for the treatment of melanoma, and in light of the many promising immunotherapies now in clinical trials with potential for near-term FDA approval, the Cancer Research Institute launched the first annual Cancer Immunotherapy Awareness Month in June as a way to increase public awareness of the power of immunotherapy to revolutionize cancer treatment and of the need for continued public support for research to bring these treatments to more patients sooner.

The inauguaral month featured a series of five webinars from leading experts in the field, including Kunle Odunsi, M. June, M. Wolchok, M. Willem Overwijk, Patrick Hwu, and colleagues demonstrated that Montanide incomplete Freund's adjuvant , which is used in a number of cancer vaccines, can induce specific T cell sequestration, dysfunction, and deletion at vaccination sites. DOI: The new guidelines promise to help accelerate progress in cancer immunotherapy development by making data interpretation and comparison easier for investigators and regulatory agencies. CRI relaunches the online, open access journal Cancer Immunity and adopts it as its official journal.

An anti-PD-1 antibody developed by Bristol-Myers Squibb generates excitement with results from a phase I trial showing that, among 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. 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.

Since the review was first published in , Hallmarks has served as the defining model of cancer. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell Mar 14; PMID: 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 gp peptide vaccine had significant improvement in overall clinical response, providing further validation for vaccine approaches to cancer treatment. N Engl J Med Jun 2; Yervoy is the first drug of any kind ever shown to extend survival in metastatic melanoma.

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 vivo expansion and long-term functional persistence of gene-modified cells.

T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med Aug 10; 3: 95ra Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med Aug 25; Epub Aug Steven A. Photo courtesy of rockcellarmagazine.

J Clin Oncol Jun 1; Ofatumumab Arzerra , a human anti-human CD20 monoclonal antibody to treat chronic lymphocytic leukemia, is approved by the FDA. Phase I study of KW, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol Mar 20; Cancer Research Institute and the Ludwig Institute for Cancer Research announce the launch of the Cancer Vaccine Acceleration Fund CVAF , a new model of venture philanthropy to drive academic-industry partnership and speed the development of promising multi-component therapeutic cancer vaccines.

A PDspecific monocolonal antibody induces frequent tumor regressions in patients with advanced melanoma, renal cancer, lung cancer, and colon cancer with very low rates of toxicity. Response correlates with tumor membrane expression of B7-H Phase I study of single-agent anti-programmed death-1 MDX in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.

J Clin Oncol Jul 1; 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. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med Jul 29; Improved survival with ipilimumab in patients with metastatic melanoma.

small molecule protein interactions ernst schering foundation symposium proceedings Manual

N Engl J Med Aug 19; Alvaro Morales reports the results of a multicenter study on the efficacy of a mycobacterial cell wall-DNA complex in patients with non-muscle invasive bladder cancer refractory to standard intravesical therapies. Intravesical mycobacterial cell wall-DNA complex in the treatment of carcinoma in situ of the bladder after standard intravesical therapy has failed. J Urol Mar; J Exp Med ; This finding is instrumental for the immunologic monitoring of vaccination trials targeting the NY-ESO-1 tumor antigen.

Clin Cancer Res Jul 1; Oncophage, the therapeutic vaccine for kidney cancer developed by Pramod Srivastava, is approved in Russia, making it the first therapeutic vaccine worldwide to be approved for patients. A randomized Phase 3 trial comparing adjuvant therapy with autologous tumor-derived heat shock protein gp96 vitespen vs. Lancet Jul 12; CTLAspecific antibodies are shown to induce tumor responses in renal and prostate cancers. Granulocyte macrophage colony-stimulating factor--secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer. Ipilimumab anti-CTLA4 antibody causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis.

J Immunother Nov-Dec; CRI Investigator Gabriel Rabinovich and his team identify a novel mechanism of T cell homeostasis based on differential glycosylation of T helper cell subsets. Nature Immunol Aug; 8: A therapeutic vaccine to treat dogs with late-stage melanoma, created by Jedd D. Wolchok, receives conditional approval from the United States Department of Agriculture.

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Ravetch for his work on Fc receptors, leading to fundamental discoveries critical to improving the design of therapeutic antibodies. FDA approves trastuzumab Herceptin for use with other drugs in the adjuvant treatment of women with early-stage node-positive HER2-overexpressing breast cancer. J Clin Invest Mar; Rosenberg and colleagues show that bulk T cells transduced with T cell receptor genes are used to treat patients with melanoma, bypassing the need to expand tumor-specific T cells from patients with cancer.

Cancer regression in patients after transfer of genetically engineered lymphocytes. Science Oct 6; 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, that recognize antigens different than those of the vaccine.

It suggests that immunosuppression prevails in tumors prior to vaccination. High frequency of anti-tumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens.

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J Exp Med Jan 17; Contrasting frequencies of anti-tumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen. Daniel E. Speiser and coworkers demonstrate that human cancer-specific cytotoxic CD8 T cells are strongly activated after vaccination with peptides and CpG oligonucleotides, representing the currently most powerful synthetic cancer vaccine formulation.

Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. Int J Cancer Jul Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J Exp Med Oct 17; T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity Jul; Rong-Fu Wang and colleagues are the first to describe a mechanism that can reverse immune suppression by regulatory T cells, mediated through Toll-like receptor 8.

Science Aug 26; Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med Dec 22; Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science Sep 29; Letrozole is approved by the FDA for the adjuvant treatment of early-stage breast cancer in postmenopausal women who have already been treated with 5 years of tamoxifen therapy. The first tumor antigenic peptides produced by peptide splicing are reported by Ken-Ichi Hanada and James C.

Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature Jan 15; An antigenic peptide produced by peptide splicing in the proteasome. Science Apr 23; An antigen produced by splicing of noncontiguous peptides in the reverse order. Science Sep 8; CRI Investigator Gabriel Rabinovich and his team identify a novel strategy mediated by secretion of the sugar-binding protein galectin-1 that is used by tumors to escape the immune response.

Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege. Cancer Cell Mar; 5: J Immunol Mar 1; The monoclonal antibody bevacizumab Avastin is approved by the FDA for use with other drugs in the treatment of metastatic colorectal cancer. Bevacizumab blocks the activity of vascular endothelial growth factor VEGF , which stimulates angiogenesis.

The monoclonal antibody cetuximab Erbitux is approved by the FDA for the treatment of metastatic colorectal cancer. Cetuximab inhibits the activity of a protein called epidermal growth factor receptor EGFR , which is overexpressed in some cancers. Shevach for their contributions to the understanding of regulatory T cells. Vincenzo Cerundolo and colleagues demonstrate that co-injection of invariant natural killer T iNKT cell agonists together with antigenic proteins enhances antigen-specific CD4 and CD8 T cell responses. This concept has been tested in the clinic to jump-start antigen-specific T and B cell responses.

J Immunol Nov 15; Shimon Sakaguchi and colleagues report that the transcription factor Foxp3 is a key regulatory gene for the development of regulatory T cells. Control of regulatory T cell development by the transcription factor Foxp3. Science Feb 14; Nature Immunol Apr; 4: Benoit Van den Eynde shows that tumors frequently express tryptophan-degrading enzyme indoleamine 2,3-dioxygenase IDO and thereby resist immune rejection.

This work opens the way to the search for IDO inhibitors to boost the efficacy of cancer vaccines. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med Oct; 9: George Coukos and colleagues provide the first data indicating a relationship between tumor immunity and ovarian patient outcomes, reporting that the presence of tumor-infiltrating lymphocytes in the primary tumor strongly correlated with patient survival. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.

N Engl J Med Jan 16; A CTLAspecific antibody, inhibiting the CTLAmediated immune checkpoint, induces clinical regressions in patients with advanced melanoma but also causes immune-related toxicity. The first clinical trials using monoclonal antibodies to induce CTLA-4 blockade in patients with malignant melanoma are published. Fong L, Small EJ.

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Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol Nov 10; Two studies show for the first time that adoptive T cell therapy for patients with advanced melanoma using in vitro-expanded T cells can cause tumor regressions. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science Oct 25; Larry Samelson and colleagues report the description of signaling microclusters containing the TCR with critical signaling enzymes and adapter molecules.

T cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J Cell Biol Sep 30; Vincenzo Cerundolo and colleagues report on studies of the structural, kinetic, and functional analysis of lipid binding to CD1 molecules. To gain insights 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[i] and CD1d molecules loaded with the NKT cell agonist alphaGalactosylCeramide.

Structure of human CD1b with bound ligands at 2. Nat Immunol Aug; 3: The crystal structure of human CD1d with and without alpha-galactosylceramide. Nat Immunol Aug; 6: Pramod Srivastava, Giorgio Parmiani, and colleagues report that immunization with autologous tumor-derived gppeptide complexes elicits tumor regression in stage IV melanoma patients, without any immunization-related adverse events.

Vaccination of metastatic melanoma patients with autologous Tumor-derived heat shock protein gppeptide complexes. J Clin Oncol Oct 15 ; Researchers, including Mark J. Smyth, provide the first demonstration that TRAIL tumor necrosis factor-related apoptosis-inducing ligand is critical in immune surveillance of cancer.

Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver NK cells. Nature Medicine Jan 7; 7: David Raulet and Lewis Lanier, separately, show that tumor cells 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.

Nature Sep 13; Ectopic expression of retinoic acid early inducible-1 gene RAE-1 permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. John M. Kirkwood and ECOG report the second independent adjuvant interferon trial to improve both relapse-free and overall survival compared to a vaccine control.

Salvage intravesical therapy with interferon-alpha 2b plus low dose bacillus Calmette-Guerin is effective in patients with superficial bladder cancer in whom bacillus Calmette-Guerin alone previously failed. J Urol Oct; Reporting in the journal Nature, Stanley G. Nathenson and his colleague Steven C.

This revealing structure demonstrates that CTLA-4 occurrs as a dimer with bivalent properties allowing it to bind 2 B-7 dimers and form an alternating array likely important for its negative signaling capabilities. CTLA-4 has since been shown to have important therapeutic uses. Nature Mar 29; In our laboratory we had the idea of localizing on tumor cells, with specific monoclonal antibodies, molecules, such as Major Histocompatibility Complexe MHC , loaded with viral peptides, which can activate the T lymphocytes to attack the target tumor cells.

Thank to a 3 years support provided by CRI, we were able to make the first demonstration of this therapeutic strategy in experimental animals. Furthermore, [we] demonstrated that an MHC like molecule, called CD1d, loaded with a glycolipid ligand, called alphaGalCer, also targeted to the tumor cells by monoclonal antibodies, was capable to specifically inhibit tumor growth in vivo and to give a sustained activation of the Natural Killer Cells known to be important in the innate immunity.

Later this project was sponsored by industry, and may become a clinically useful form of cancer therapy; but the role of CRI in the initiation of this project was essential. B7-Dc, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med Apr 2; Dietmar J.

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Kappes discovers a mouse with a mutation in a master regulator gene controlling T cell fate. Six years later, he identifies the gene as Th-POK, and later shows that its disregulation causes lymphoid transformation. This finding is significant in linking how cells develop with how cancers develop. Regulation of lineage commitment distinct from positive selection. Science Nov 5; Eiichi Nakayama and colleagues first report involvement of regulatory T cells Tregs in the human tumor immune response. Tumor rejection by in vivo administration of anti-CD25 interleukin-2 receptor alpha monoclonal antibody.

Cancer Res Jul 1; Int J Cancer Oct 22; James N. Ihle and colleagues demonstrate that the Stat5 proteins, redundantly, are essential mediators of IL-2 signaling in T cells. Stat5 Is required for ILinduced cell cycle progression of peripheral T cells. Immunity Eric S. Lander and colleagues provide the first evidence that gene-expression profiling can distinguish between cancer types. In addition to distinguishing between two types of leukaemia on the basis of expression profile differences, the method could also predict their responsiveness to chemotherapy.

Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science Greenberg, Alan N. Nathan, Herbert F. Oettgen, Lloyd J. Old, Drew M. Pardoll, Michael Pfreundschuh, Steven A. Rosenberg, Stuart F. Schlossman, Hans Schreiber, Robert D. Schreiber, Hiroshi Shiku, Pramod K. Cancer Res Aug 15; Bruce A. Beutler establishes the genetic basis linking toll-like receptor 4 TLR4 to the identification of microbes. Science Dec 11; Science Jun 12; Direct isolation, phenotyping and cloning of low-frequency antigen-specific cytotoxic T lymphocytes from peripheral blood.

Curr Biol Mar 26; 8: Cutting edge: rapid cloning of tumor-specific CTL suitable for adoptive immunotherapy of melanoma. J Immunol Jun 15; In collaboration with Pedro Romero, Vincenzo Cerundolo and colleagues demonstrate that, unlike virus-specific CTLs, the highest frequency of tumor-specific CTLs can be found in tumor-infiltrated lymph nodes.

Ex vivo staining of metastatic lymph nodes by class I major histocompatibility complex tetramers reveals high numbers of antigen-experienced tumor-specific cytolytic T lymphocytes. J Exp Med Nov 2; High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med Sep 21; Abraham Kupfer describes the three-dimensional structure of supramolecular activation clusters SMACs , the interface between an antigen presenting cell and a lymphocyte including key molecules the T cell receptor and the major histocompatibility complex , [i] later coined the immunological synapse and further elucidated by Arash Grakoui, Michael Dustin, Paul Allen, and Andrey Shaw.

Three-dimensional segregation of supramolecular activation clusters in T cells. Nature Sep 3; A novel adapter protein orchestrates receptor patterning and cytoskeletal polarity in T cell contacts. Cell Sep 4; The immunological synapse: A molecular machine controlling T cell activation. Charles A. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature Jul 24; Yao-Tseng Chen, collaborating with researchers in the laboratory of Lloyd J.

Zheng W, Flavell RA. Cell May 16; Yongwon Choi, with Ralph Steinman and others, identifies a new tumor necrosis factor family member TRANCE later called RANKL ,[i] and subsequently demonstrates its role in the immune and bone system, and also in bone-residing cancers such as multiple myelomas. J Biol Chem Oct 3; J Exp Med Dec 15; TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med Sep 7; The first monoclonal antibody for cancer rituximab, Rituxan, directed to CD20 on B lymphocytes is approved for the treatment of non-Hodgkin lymphoma by the FDA.

Dominique Bonnet and John E. Dick report the first conclusive evidence for cancer stem cells, identified in acute myelogenous leukemia AML. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine Jul; 3: Yasuaki Tamura, working with colleagues in the laboratory of Pramod Srivastava, demonstrates that tumor-derived heat shock protein-peptide vaccines can be used to treat a wide array of pre-existing tumors in mice.

Immunotherapy of metastatic lung cancer by heat shock protein preparations. Science Oct 3; Science Oct 31; 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. Nature Aug 21; Nature Aug 1; Coffman, Tim R. Mosmann, and Stuart F. Yasushi Itoh and Ronald N. Germain report studies emphasizing the hierarchical organization of T cell receptor TCR signaling thresholds for induction of distinct cytokine responses, and demonstrate that this threshold phenomenon applies to individual cells.

The existence of such thresholds suggests that antigen dose may dictate not only the extent, but also the quality of an immune response, by altering the ratios of the cytokines produced by activated T cells. Itoh Y, Germain RN.

Interferon: The Dawn of Recombinant Protein Drugs

J Exp Med Aug 29; The complete papers of Dr. William B. Coley are archived at Yale University. Topotecan is approved by the FDA for the treatment of metastatic ovarian cancer. The FDA approves another topoisomerase I inhibitor—irinotecan—for the treatment of metastatic colorectal cancer. Mark M. Steve Gerondakis and colleagues establish that Rel from the c-rel gene in mice is a positive or negative regulator of transcription in macrophages and that Rel has distinct roles in different macrophage populations. The Rel subunit of NF-kappaB-like transcription factors is a positive and negative regulator of macrophage gene expression: distinct roles for Rel in different macrophage populations.

Leslie J. Berg, Mark M. Davis, and colleauges demonstrate that a T cell receptot TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists. A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists. Immunity Jul; 5: Ellen V. Rothenberg and Susan B. Ward report that the interleukin-2 IL-2 transcriptional apparatus integrates multiple types of biochemical information in determining whether or not the gene will be expressed, using multiple diverse transcription factors that are each optimally activated or inhibited by different signaling pathways.

A dynamic assembly of diverse transcription factors integrates activation and cell-type information for interleukin 2 gene regulation. Diana L. Sylvestre and Jeffrey V. Ravetch demonstrate by differential reconstitution in vivo that FcgRIII on mast cells is necessary for the inflammatory response to experimental immune complexes. A dominant role for mast cell Fc receptors in the Arthus reaction. Immunity ; 5: Anjano Rao and colleagues find evidence in mice that transcription factor NFAT1 exerts a negative regulatory influence on the immune response.

An enhanced immune response in mice lacking the transcription factor NFAT1. Science ; Allison and Matthew Krummel demonstrate that a monoclonal antibody directed against the CTLA-4 molecule in a mouse model of melanoma could result in the rejection of tumors and that this rejection also resulted in immunity to a second exposure to tumor cells. Enhancement of antitumor immunity by CTLA-4 blockade. Science Mar 22; Bruno Lemaitre and Jules A.

Hoffmann demonstrate that Toll receptors in Drosophila mediate immune defense against fungal infection. Cell Sep 20; Andy Peters and Ursula Storb show that the initiation of Ig gene transcription targets Ig gene somatic hypermutation SHM , by duplicating the variable V region promoter upstream of the constant C region and showing that a second wave of mutations occurs over the C region.

This finding led them to propose a novel hypothesis of SHM, namely that a mutator factor now known to be AID loads on the transcription complex near the promoter, travels with the elongating RNA polymerase, and stochastically dissociates, thus limiting SHM to the VJ region.

Peters A, Storb U. Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity Jan; 4: Progress in understanding the mechanism of somatic hypermutation. Immunol Rev Apr; Granulocyte-macrophage-colony-stimulating factor enhances immune responses to melanoma-associated peptides in vivo. Int J Cancer Jul 3; Bogen B. Eur J Immunol Nov; Kirkwood reports the first significant improvement of both survival and relapse-free interval for melanoma patients treated with high-dose Interferon alfa-2b E Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains CD Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

J Immunol Aug 1; Human neoplasms elicit multiple specific immune responses in the autologous host. Gary Koretsky and colleagues report the discovery of SLP J Biol Chem Mar 31; Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE Int J Cancer Dec 11; Int J Cancer Jan 18; A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Science Sep 1; Arthur M. Krieg and coworkers characterize CpG oligonucleotides and discover that they are robust stimulators of immune cells.

CpG oligonucleotides are TLR9 agonists and have broad therapeutic application in humans. Nature Apr 6; Jak-STAT signaling induced by the v-abl oncogene. The FDA approves tretinoin, a differentiating agent related to vitamin A, for use in the treatment of acute promyelocytic leukemia. Tretinoin is also known as all-trans retinoic acid ATRA. Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells.

Science Mar 25; Science May 12; These genes are expressed in many tumors and are silent in normal tissues except male germline cells. Many of them encode tumor-specific antigens recognized by T lymphocytes. Structure, chromosomal localization, and expression of 12 genes of the MAGE family. Immunogenetics ; BAGE, a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity Feb; 2: A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma.

J Exp Med Sep 1; James Darnell, George Stark, and Ian Kerr report studies demonstrating the importance of interferon to elucidate signal trafficking from the cell surface to the nucleus. Science Jun 3; Akiko Uenaka and Eiichi Nakayama identify a murine leukemia antigen recognized by cytotoxic T cells. J Exp Med Nov 1; Matzinger P. Tolerance, danger, and the extended family. Ann Rev Immunol ; Being both tumor-specific and widely expressed in human tumors, MAGE-A3 is an ideal cancer vaccine target and will be the focus of many clinical trials, including the largest clinical trial ever conducted in lung cancer, MAGRIT, launched by GlaxoSmithKline in Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes.