Day One: Experimental Cancer Immunology
Day Two: Human Cancer Immunology and Cancer Vaccine Development
Day Three: Human Cancer Immunology and Cancer Vaccine Development 

Day One: Experimental Cancer Immunology 

Albert Bendelac, M.D., Ph.D.
The University of Chicago, Chicago, IL
Natural and synthetic antigenic ligands of NKT cells and their role in anti-tumor rejection

CD1d-restricted NKT cells have been reported to regulate primary as well as transplanted tumors, but the ligand that activates NKT cells in these conditions has remained elusive. An agonist ligand of their TCR, aGalactosylCeramide, was serendipitously identified based on the anti-tumor properties of marine sponge extracts. However, a-glycosylated ceramides have not been identified in vertebrates suggesting that they are not the natural ligands. Dr. Bendelac’s group has used genetic mutations of enzymes controlling key steps of lipid metabolic pathways to zoom in on candidate classes of lipids, and synthetic chemistry to evaluate their ability to stimulate NKT cells. Dr. Bendelac will present his group’s results suggesting that a single self-glycosphingolipid can function as an agonist ligand of mouse and human NKT cells. Furthermore, his group has identified microbial ligands that function as agonist NKT cell ligands. Together, his results suggest that NKT cell dual recognition of self and foreign glycolipids may explain their function in cancer as well as infection.

Vincenzo Cerundolo, M.D., Ph.D., MRCPath.
University of Oxford, Oxford, U.K.
Role of NKT cells to assist priming of antigen specific T-cell responses

Most cancer vaccines fail to stimulate the kind of T-cell response that occurs during natural infection by pathogens. Dr. Cerundolo is seeking to optimize tumor vaccination techniques by studying and then mimicking the intracellular signals that stimulate strong T-cell responses. His aim is to produce adjuvants that will boost the abilities of dendritic cells (DC) to stimulate antigen-specific T-cell responses. One successful method that has produced exciting results has been to induce modification of DC function in vivo by stimulating invariant CD1d-dependent Natural Killer-like T cells (iNKT cells) with a soluble protein antigen and alpha-glactosylceramide (alpha-GalCer), a ligand for iNKT. This has been shown to provide mature DC cells with enhanced immunostimulatory capacity. Dr. Cerundolo will show how this enhances the priming and boosting of cytotoxic T lymphocyte (CTL) responses to a number of peptide and protein antigens, including a clinically relevant, HLA-A2-restricted epitope derived from the human tumor antigen NY-ESO-1. CTL responses induced in the presence of iNKT cell stimulation eradicated established tumors while responses without the adjuvant were ineffective. These strong results demonstrate the therapeutic potential for iNKT cell activation as an effective vaccine adjuvant.

Shimon Sakaguchi, M.D., Ph.D.
Kyoto University, Kyoto, Japan
Natural CD4+ regulatory T cells in tumor immunity

Regulatory T cells (TR) are essential players in the control of our own immune systems, ensuring that our powerful self-defenses do not mistakenly attack our own healthy tissues. It has been shown, however, that these cells may also impede immune responses against tumors. Dr. Sakaguchi’s group is attempting to determine the beneficial impact, if any, of attenuating or suppressing TR activity in cancer therapy. In studies with mice, Dr. Sakaguchi has shown an improved immune response when monoclonal antibodies (mAb) specific for natural TR are introduced and bind to the inhibiting regulatory T cells, allowing other immune cells to function unimpeded. Dr. Sakaguchi will discuss the successes of mAb specific for different TR molecules, and will also discuss the identification of a TR molecular marker, Foxp3, which can be instrumental in the monitoring of T-cell infiltration against tumors.

Hiroshi Shiku, M.D.
Mie University School of Medicine, Mie, Japan
Regulatory T cells recognizing SEREX-defined self-antigens in anti-tumor immune response

It is known that regulatory T cells play a key role in maintaining immunological homeostasis. There are a number of self-antigens considered natural ligands for the maintenance of regulatory T cells. Dr. Shiku has identified via SEREX several broadly expressed selfantigens that, when administered via vaccination to mice, contributed to immunosuppression and a resulting increase in tumor growth. CD4+CD25+ T cells drawn from these mice showed a strongly suppressive activity on antigen-specific CD4+CD25- T cells and CD8+ T cells. Dr. Shiku will explain his group’s proposal that the SEREX-identified selfantigens used in his study represent selfantigens that elicit naturally occurring CD4+CD25+ regulatory T cells, providing possible targets for the control of regulatory T-cell activity. He’ll also share results from another study involving chemically-induced carcinogensis in mice that links these regulatory T cells with the control of Natural Killer (NK) cell reactivity, providing good argument for the existence of immuno-surveillance in this study.

Lewis L. Lanier, Ph.D.
University of California San Francisco, San Francisco, CA
NKG2D-mediated immune responses

NKG2D is a receptor found on NK cells, CD8+ T cells, and gamma delta-TcR+ T cells that activates the function of those cells when it binds to its ligands. NKG2D signals are associated with both innate and adaptive immune responses and have also been linked to autoimmune disorders, including type I diabetes and rheumatoid arthritis. In humans and mice, at least six genes have been identified that encode high-affinity ligands for NKG2D. Dr Lanier will discuss several of these genes and their ligand products, and will share the results of his group’s investigations into the process of NKG2D regulation. Specifically, he has learned that chronic exposure of NK cells to NKG2D ligands can result in an inactivation of NKG2D-mediated tumor immunity. Dr. Lanier will demonstrate how these findings can be linked to recent observations documenting a potential tumor escape mechanism involving the secretion of soluble forms of NKG2D ligands in cancer patients. Understanding how some tumors can evade immune detection will be of significant importance to the design of immune-based cancer therapy strategies.

Hans Schreiber, M.D., Ph.D.
The University of Chicago, Chicago, IL
Targeting tumor stroma to destroy cancer variants

Cancer cells are typically unstable, and subpopulations of cancer cells may “look” quite different to the immune system from their parent cells. These younger cells, called antigen-loss variants (ALV) because they no longer express the same antigens on their surfaces as their parent cells, often escape immune recognition. Dr. Schreiber’s group is studying why some ALV cells are detected and destroyed despite their difference surface appearances, and has linked this phenomenon to higher levels of antigen presentation in the parent cells. The destruction of ALV, he found, occurred as a result of attack from tumor-specific cytolytic T cells on tumor stroma cells that cross-presented the parent antigen. Dr. Schreiber will discuss the importance of targeting tumor stroma as a means to track down and destroy variant cancer cells.

Zheng Cui, M.D., Ph.D.
Wake Forest University School of Medicine, Winston-Salem, NC
“Magic bullets” against cancer cells in cancer-resistant SR/CR mice

Dr. Cui’s “amazing mice,” which recently garnered significant media attention because of their surprising super-immunity to cancer, once again take the spotlight as Dr. Cui shares the latest data on his group’s studies into how the mice are able to resist cancer so effectively. Cui will report significant insights into the mechanical process of the mice’s rapid immune response, which has the unique ability of mobilizing all types of effector cells, including NK cells, neutrophils, macrophages and T-lymphocytes, which work in concert to deploy their individual cancer-killing capabilities. Dr. Cui found that tumor-infiltrating leukocytes play a critical role in the destruction of the tumor, as mice without these cells were unable to mount a response while mice lacking any of the other effector cells still showed robust resistance to the cancer. Dr. Cui also will also demonstrate how immunity against cancer can be transferred from his SR/CR mice to wild-type mice. It is hoped that the study of these unique, naturally cancer-immune mice will shed light on ways to induce the same kind of immunity in humans.

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Day Two: Human Cancer Immunology and Cancer Vaccine Development

James P. Allison, Ph.D.
Memorial Sloan-Kettering Cancer Center, New York, NY
Blockade of T-cell inhibitory signals: A new paradigm in tumor immunotherapy?

The human immune system is magnificent in its multipronged complexity, a deadly force, capable of destroying the most harmful invading bacteria, viruses, or cancer cells. Such a powerful force must be carefully regulated lest these "cellular assassins" turn against our own healthy tissues, causing debilitating and even fatal diseases. Evolution has provided our bodies with a host of control mechanisms that keep our immune systems in check and prevent autoimmunity. In the early stages of the T cell immune response, for instance, the costimulatory molecule CD28 plays a role in the proliferation of T cells while, conversely, the CTLA-4 molecule inhibits production of T cells. Interestingly, both CD28 and CTLA-4 bind to the same location on the T cell surface. While CTLA-4 is beneficial when protecting against autoimmunity, its inhibitory capabilities can get in the way of stimulating a T-cell immune response against a tumor. Dr. Allison's group has been studying the effects of blocking the activity of CTLA-4. When CTLA-4's inhibitory influence is blocked, Dr. Allison's group observed the rejection and long-lived immunity to highly immunogenic tumors, and when vaccines against less-immunogenic tumors were administered in conjunction with CTLA-4 blockers, similar positive results were observed. Medarex of New Jersey has developed a fully human monoclonal antibody against CTLA-4, and early phase clinical trials testing the new mAb have shown significantly improved immune responses in cancer patients. Dr. Allison will discuss the results of trials in patients who previously received vaccines for melanoma and ovarian cancer, and will discuss research into a newly discovered inhibitory molecule that, interestingly, is presented on some tumor cell surfaces and can be linked to tumor evasion of the immune system.

Thomas Spies, Ph.D.
Fred Hutchinson Cancer Research Center, Seattle, WA
Relevance of NKG2D and its ligands in tumor immunity

Natural killer (NK) cells are so-called because they are “born to kill” a specific target, even before that target has been introduced to the body. Typically, they attack virally infected and cancerous cells, having receptors that allow them to detect the lack of expression of MHC class I molecules, which tend to become downregulated in these kinds of damaged cells. NKG2D is the name of one of these receptor sites found on NK cells, which when encountering one of its many ligands produced by the damaged cell activates NK cells and costimulates effector CD8 T cells. The NKG2D ligands MICA and MICB are expressed abundantly in lung, breast, kidney, ovarian, prostate, gastric and colon carcinomas and in melanomas. While experiments have shown that NKG2D can effectively promote NK cell and T-cell mediated tumor rejection in mice, human tumors expressing the MIC ligands are able to effectively evade immune detection by shedding substantial amounts of soluble MIC into the bloodstream. This “smokescreen” of decoys causes a systematic downregulation of NKG2D and thus impairs the responsiveness of NK cells and tumor antigen-specific T cells. Furthermore, preliminary studies indicate that tumors somehow can cause dendritic cells (DC) that come in contact with them to irregularly express MIC, impairing their ability to stimulate other parts of the immune system. Dr. Spies’ group has loaded DC with anti-MIC antibody opsonized melanoma, breast and ovarian tumor cells to prime anti-tumor T-cell responses. He’ll share the results of his studies, which suggest this could be an effective immunization technique against a large variety of histologically distinct tumors that may also be applicable to adoptive T-cell therapy.

Pramod Srivastava, Ph.D.
University of Connecticut School of Medicine, Farmington, CT
Specific immunogenicity of heat shock proteom-peptide complexes: New developments

Dr. Srivastava has helped to pioneer the study of heat shock proteins (HSP), proteins that play important “chaperoning” roles in normal cells and which appear when cells undergo environmental stresses caused by heat, cold, and oxygen deprivation, for instance. Dr. Srivastava will present evidence that HSPs chaperone cancer-related peptides to the cell surface, making it possible for potential recognition and destruction by the immune system. He’ll share new information on the isolation and sequencing of a large number of peptides associated with HSPs, as well as new data on the characterization of peptide-binding domains for these HSPs. Dr. Srivastava will contest claims that the immunogenicity of one of the HSPs, gp96, is non-specific, and will reassert that HSP uptake is mediated through CD91 on antigen-presenting cells, again contesting recently published data to the contrary. Dr. Srivastava will also discuss some newly HSP-related cellular mechanisms that will have practical applications to HSP-based immunotherapies for cancer.

Elke Jäger, M.D.
Krankenhaus Nordwest, Frankfurt, Germany
Vaccine strategies against NY-ESO-1 in cancer patients

One of the most immunogenic antigens known to date, NY-ESO-1 is capable of generating spontaneous immune responses in approximately 50 percent of patients with advanced cancers expressing it, often with more favorable prognoses for these patients that those with no NY-ESO-1 expression. Dr. Jäger’s group has been testing various vaccination strategies in their phase I clinical studies, including intensity variations and the use of vaccinia- and fowlpox vectors encoding the full-length NY-ESO-1 protein. Vaccination produced strong CD4+ and CD8+ T-cell responses in many of the patients, including those who had not produced antibody prior to vaccination. Dr. Jäger will report cases of observed partial remissions and prolonged stabilization of disease during vaccination, evidence of the efficacy of recombinant NY-ESO-1 viral constructs as vaccines designed to induce potent T-cell responses.

Ian D. Davis, MB BS, Ph.D.
Ludwig Institute for Cancer Research, Melbourne, Australia
NY-ESO-1 protein-based cancer vaccines: The Melbourne experience

Dr. Davis will report his group’s exciting research into a cancer vaccine based on the highly immunogenic NY-ESO-1 antigen administered with ISCOMATRIX™, a saponin-based adjuvant produced by CSL Limited that has been shown to promote cellular and humoral immune responses in NY-ESO-1 preclinical and clinical models. Antigen uptake and presentation by dendritic cells was found to be improved with ISCOMATRIX™, resulting in a long-lived T-cell stimulatory capacity which was maintained for several days longer than when patients were given only dendritic cells pulsed with peptide. This prolongation may provide DCs more opportunity to stimulate tumor-specific T-cell responses against a broad array of NY-ESO-1 epitopes. In an unplanned analysis, Dr. Davis’s group discovered that patients who received the vaccine in a phase I clinical trial appeared to have superior clinical outcomes to those treated with placebo or protein alone. These results have prompted the initiation of further clinical trials specifically studying relapse-free survival rates in patients and also testing different ways of administering the vaccine with adjuvant.

Weisan Chen, Ph.D.
Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia
Comprehensive analysis of T-cell responses after vaccination with NY-ESO-1 protein

Even when vaccination produces strong results, it is often difficult to know exactly which immune mechanisms are at work and why. Standardized monitoring of immune responses in patients who have received vaccine therapies is, therefore, an essential component in the process of effective cancer vaccine development. Dr. Chen’s group is studying pre- and post-vaccination T-cell responses in patients whose cancers express the CT antigen NY-ESO-1. In those patients who received the NY-ESO-1/IMX vaccine (which includes the potent adjuvant, ISCOMATRIX™) and who showed a robust T-cell response against the target antigen, Dr. Chen discovered that the majority of the CD4+ and CD8+ T cell responses were induced by the vaccine. Dr. Chen’s group also detected several naturally occurring polyclonal T-cell responses specific for multiple epitopes found on an epitope-rich region of NY-ESO-1, and believes that analysis of the T-cell response to this region might serve as a quick screening strategy for both naturally- and vaccine-induced immunity. Dr. Chen’s method of detailed T-cell analysis can help to further our understanding of the scope and efficacy of both natural and vaccinated anti-tumor cellular immune responses, and can also shed light on which epitopes induce the strongest immune response by these cells.

Pierre G. Coulie, M.D.
Catholic University of Louvain, Brussels, Belgium
Possible mechanisms of tumor regression after vaccination with MAGE antigens

Dr. Coulie’s group has observed tumor regression in about 20 percent of the metastatic melanoma patients who received their MAGE antigen-based vaccines. Curiously, though, the mechanisms of tumor regression do not appear to be those the group expected. Rather than stimulating a new immune response against the tumor composed primarily of anti-vaccine cytolytic T cells (CTL), the vaccine seemed to fail to stimulate the CTL levels required for such a strong response. Nevertheless, the tumors regressed, far out of proportion to the level of anti-vaccine CTLs found post-vaccination. Something else was causing the regression. Examination of the tumor environment showed that high levels of anti-tumor CTLs, formed naturally by the body prior to vaccination, were largely responsible for the regression. Somehow, Dr. Coulie’s MAGE vaccine altered the tumor environment in a way that the previously ineffective naturally occurring anti-tumor CTLs were now unexpectedly able to regress the tumor with vigor. The vaccine, then, is as a welcome side effect able to reinvigorate a standing army of tumor-specific immune cells, and also seems to spawn new anti-tumor CTL. Dr. Coulie is now working to understand how the vaccine triggers the immune intervention of the previously powerless lymphocytes.

Vincent Brichard, M.D., Ph.D.
GlaxoSmithKline Biologicals, Rixensart, Belgium
Development of cancer vaccines with the MAGE-3 protein

Dr. Brichard will discuss GSK Biologicals’ results of early phase trials testing cancer vaccines composed of recombinant MAGE-3-derived protein with and without adjuvant in patients with various cancers but with a focus on patients with metastatic melanoma and non-small cell lung cancer. Adjuvants administered include the GSK proprietary adjuvant AS02B, CpG 7909, and a new adjuvant, AS15, which contains CpG 7909. Dr. Brichard will report evidence for improved immune responses in patients with early-stage cancers and who did not have cancerous lesions in the viscera. He’ll also discuss how AS15 stimulated a mostly type 1 T-cell response, resulting in strong CD8 T-cell activity. His group’s work shows promise for an effective vaccination approach against metastatic melanoma and non-small cell lung cancer.

Djordje Atanackovic, M.D.
University of Hamburg, Hamburg, Germany
Danger signals and the development of new cancer vaccine strategies

Inflammation results when the immune system detects danger to the body, usually in the form of bacterial and viral infection, but also when tissue is damaged or becomes cancerous. Immune cells recognizing the threat emit chemicals, or inflammatory danger signals, that trigger an array of physiological responses, including the stimulation and attraction of other immune cells to the problem site. Cancer vaccines today are often accompanied by adjuvants composed of substances that first simulate and then often create in actuality an acute inflammatory response that helps to help draw immune attention to the target tumor. Dr. Atanackovic’s group has shown that adding such substances to MAGE3 protein-based cancer vaccines is required for effective immunization in cancer patients. Specifically, he has found that an absence of these inflammatory danger signals can critically impair the ability of tumor-specific T cells to locate and attack their target cancer cells. He has found, for instance, lower levels of these substances in patients with head and neck cancers. His group is currently developing clinical trials aimed at improving the power of inflammatory signal-based adjuvants.

Danila Valmori, Ph.D.
Columbia University, New York, NY
SSX antigens as cancer vaccines

The SSX family of gene-products is one of the most exciting new discoveries in cancer antigen research. Antigens produced by these genes are expressed normally in the testes and also in many different kinds of tumors, making them excellent candidates for vaccine targets, as are other antigens of this nature, called CT (cancer-testes) antigens. Little is known about the biological function of the SSX genes, however Dr. Valmori will discuss their likely role in gene transcription and how their expression can occur as a result of chromosomal translocation. Dr. Valmori is one of the first researchers to look at the viability of SSX-antigen based vaccine therapies in melanoma patients. She will share the results of her studies into spontaneous CD4+ and CD8+ T-cell responses to these antigens and the implications of her findings on the development of SSX-based vaccines.

Francine Jotereau, Ph.D.
INSERM Unité 601, Nantes, France
Cross-presentation: A mechanism used by melanoma cells for the generation of a tumor-specific antigen derived from the matrix metalloproteinase 2

Despite the large array of known melanoma antigens that are recognized by T cells, vaccination attempts targeting these antigens have been limited in their efficacy. One possible reason is the choice of target. Dr. Jotereau’s group is looking at melanoma antigens that are known to trigger natural immune responses. Observing a better clinical prognosis for patients whose tumors were infiltrated by lymphocytes (TIL) either naturally or via adoptive transfer of TIL obtained ex vivo, Dr. Jotereau it attempting to identify the antigens targeted by these TILs. Her group has successfully identified one such antigen, the self matrix metalloproteinase-2 (MMP-2), which is secreted normally by many cells but whose epitope is only presented on melanoma cell surfaces via cross-presentation, a mechanism of antigen-presentation previously thought to occur only in immune cells. Dr. Jotereau will discuss the role of MMP-2 in melanoma growth and metastasis as well as the potential for its use as a vaccine target.

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Day Three: Human Cancer Immunology and Cancer Vaccine Development

Prof. Wei-Feng Chen
Peking University Health Science Center, Beijing, P.R. China
Identification and characterization of human hepatocellular carcinoma-associated antigens

Hepatocellular carcinoma (HCC) is the second-deadliest cancer in China. As it is resistant to chemo- and radiotherapy, the need for immune-based therapies against HCC is of utmost importance. HCC cells express a number of cancer-testes (CT) antigens, a family of cancer-associated antigens that is believed to be the best repository of viable antigen targets against cancer. Most HCC cells express at least 2 or 3 of these antigens, laying the basis for the design of a multivalent antigen-specific cancer vaccine that can target multiple antigens. Dr. Chen’s group has identified several novel HCC antigens, as well, and will discuss the frequency of these in HCC patients as well as their viability as possible vaccine targets based on their ability to elicit T-cell responses. Dr. Chen’s team has also designed prognostic screening based on these HCC antigens that can help predict the clinical course of a patient. The methods for this screening, as well as Dr. Chen’s plans for future testing of these antigens toward the development of effective vaccines will be shared.

Ali Osmay Gure, M.D., Ph.D.
Ludwig Institute for Cancer Research, NY Branch, New York, NY
Immunity to SOX Group B and ZIC2 antigens: Novel neuro-ectodermal targets and clinical indicators in small cell lung cancer

Lung cancer is the most deadly tumor type in the US and Europe, with small cell lung cancer (SCLC) accounting for 15 to 18 percent of these cases. SCLC is a highly aggressive cancer, with up to 70 percent of patients displaying distant metastases at the time of diagnosis. Survival rate for these patients is between 9 and 18 months. Antigenic targets that could be used for vaccine therapy for these patients are urgently needed. Dr. Gure’s group has identified SOX Group B and ZIC2 proteins as highly immunogenic neuro-ectodermal antigens presented in 47 percent of SCLC patients screened. Better overall survival, a larger proportion of limited-stage disease, and longer times to progression were observed for all patients whose cancer expressed with the SOX Group B or ZIC2 antigens. Despite the infrequence of autoimmune paraneoplastic neurological disease (PND), a disease that sometimes occurs in association with SCLC, antibodies to neuro-ectodermal antigens associated with PND are found in up to 25 percent of patients. The presence of these antibodies has been linked to less aggressive SCLC, and suggests the possibility of effective immunization utilizing multiple neuro-ectodermal tumor antigens. Dr. Gure will discuss his group’s initial investigations into this new array of potential vaccine targets.

Kunle Odunsi, M.D., Ph.D.
Roswell Park Cancer Institute, Buffalo, NY
Lessons from a pilot clinical trial of vaccine therapy with an NY-ESO-1 peptide of dual MHC class I and II specificities in ovarian cancer

Dr. Odunsi has been spearheading the Cancer Vaccine Collaborative’s clinical investigations into the efficacy of cancer vaccine therapies for ovarian cancer patients. His studies target epithelial ovarian cancer (EOC), which initially responds well to frontline therapies such as surgery, radiation, and chemotherapy but recurs within two years in approximately 85 percent of patients. Once relapse occurs, there is no known curative therapy. Immunotherapies that can establish a sustained immune system response against recurring cancer cells are a promising strategy toward prolonged health maintenance in these cancer patients. Dr. Odunsi has been working to isolate the cellular markers, called antigens, on these cancer cells that will serve as potential targets for immune-based therapies. Two essential characteristics of these antigenic targets are 1) that their expression be restricted primarily to cancer cells (tissue specificity) and 2) that the immune system can easily recognize them as a threat and mount an immune response against any cells bearing those antigens (immunogenicity). In his lecture, Dr. Odunsi will discuss the repertoire of more than 17 “cancer-testis” (CT) antigens (antigens found only in cancerous and immune-proof male germ cells, making them excellent therapeutic targets) he has identified in EOC. Dr. Odunsi has determined the relationship between the expression of these antigens to the infiltration of immune cells into tumors and the resulting clinical outcome. Furthermore, his work is helping to shed light on the role of the CD8+ tumor infiltrating lymphocyte in EOC. Armed with this new understanding, Dr. Odunsi is developing a new prognostic method that will better determine a patient’s predicted clinical course. More significant, however, is the contribution of Dr. Odunsi’s work to improving our abilities to accurately monitor immune responses in patients undergoing investigational cancer vaccine therapy. The more accurately researchers can monitor immune responses, the better they can hone their cancer vaccines in order to yield an immune response of maximum benefit. He will report on the preliminary results from a phase I clinical trial testing an immune target with the characteristic of possibly being able to simultaneously trigger immune responses in both CD4+ and CD8+ T cells (rather than only one), two kinds of immune cells whose combined response is believed necessary for a significant, sustainable immune response.

Daniel Speiser, M.D.
Ludwig Institute for Cancer Research, Lausanne, Switzerland
Tumor specific T cells induced in melanoma patients either naturally or by vaccination with peptides, IFA ± CpG oligodeoxynucleotides

Most cancer vaccines today are able to elicit T-cell responses in only a fraction of patients. Dr. Speiser’s team, however, has created a cancer vaccine that reproducibly induces T cell responses in all patients. This allows for the first time for the study of vaccine-only induced T-cell responses (versus natural or spontaneous T-cell responses not caused by the vaccine). His team has developed a new technology that accurately and efficiently identifies the repertoire of tumor-reactive T-cells and is applying this technique to their studies, allowing them to identify which vaccine components result in what type of immune response, and to better understand their relation with disease regression, recurrence, and progression. Describing this technology in action, Dr. Speiser will discuss a remarkable case of one patient who displayed a strong monoclonal response by Melan-A specific CD8+ T cells. This line of T cells was largely responsible for controlling the patient’s tumor prior to vaccination. After vaccination with Melan-A peptide in Incomplete Freund’s Adjuvant and with the same vaccine plus Cpg 7909, the number of these T cells increased. These same cells were found to be the dominant aggressors in tumor infiltration. Dr. Speiser’s group was able to clone these T cells and they, too, reacted specifically to the patient’s tumor. This patient is now without detectible disease, and is under continued monitoring to help further elucidate his strong CD8 T-cell response. In another study, Dr. Speiser’s group tested whether the CpG oligodeoxynucleotide (CpG ODN), 7909, with its ability to trigger dendritic cell maturation, would lead to a strong activation of antigen specific CD8+ T cells when accompanied with a peptide vaccine. Remarkably, all the patients who received the vaccine showed increased frequency of antigen-specific T cells. These results support the use of CpG ODN as adjuvants, contradicting previous convention that held CpG ODN as ineffective. Dr. Speiser’s findings, unexpected as they are, are nonetheless highly encouraging and underscore the importance of clinical investigation of vaccines in humans.

Phil Greenberg, M.D.
University of Washington, Seattle, Washington
Isolating tumor-reactive T cells and making them work in tumor therapy

Dr. Greenberg’s lab is working to overcome the difficulties associated with T-cell therapies against cancer, and has now resolved several major impediments to pursuing T-cell therapy as a modality for treating patients with established malignancies. Foremost is the difficultly in generating and expanding tumor-reactive CD8+ T cells to numbers sufficient for tumor therapy. Successes in vitro with generating such responses have not been duplicated in vivo. By studying the differences between the in vitro and in vivo environments, Dr. Greenberg has discerned and will discuss ways to improve a CD8+ T-cell response that spawns greater numbers of these cells and an increases our ability to clone and expand them. Adoptive T-cell immunotherapy, an immunization technique that frequently involves removing autologous T cells from a patient, altering and growing them ex vivo, and then re-injecting them into the patient, has been attempted with limited success for reasons Dr. Greenberg will describe. His team is working out approaches to genetically alter the T-cells to make them more robust in “hostile environments” where their activity is normally hindered.

Glenn Dranoff, M.D.
Dana-Farber Cancer Institute, Boston, MA
GM-CSF based cancer vaccines

Dr. Dranoff’s team has been exploring the immune-stimulating effects of vaccination with irradiated tumor cells expressing granulocyte-macrophage colony stimulating factor (GM-CSF), a cytokine that causes stem cells to grow into white blood cells of the immune system. GM-CSF based cancer vaccines have been shown to produce long-lasting ant-tumor immunity in mice through improved antigen presentation by dendritic cells and macrophages, which in turn improves the activities of CD4 and CD8 T cells, iNKT cells, and antibodies. In patients with metastatic melanoma, vaccination produced strong T and B cell infiltration at tumor sites resulting in substantial tumor reduction. Dr. Dranoff has studied these infiltrating cells to determine to which antigens they are binding, including ATP6S1, OGFr and ML-IAP, a protein that inhibits melanoma apoptosis and is associated with tumor evasion of immune attack. Dr. Dranoff will report on the specifics of his clinical trials and will share some of his insights into the mechanisms and targets of immune-mediated tumor destruction observed in patients who received the GM-CSF based vaccines.

Dennis Panicali, Ph.D.
Therion Biologics Corporation, Cambridge, MA
The evolution of poxvirus based cancer vaccines

The potential of using poxvirus vectors as a means to deliver therapeutic recombinant vaccines for a number of diseases has been known to science since the early 80s. By the late 80s, researchers had begun to use poxvirus vectors to express tumor-associated antigens (TAA), hoping to trigger an immune response in mice against tumors. While several of these vectors were successful in preventing tumor growth, they did little to treat pre-existing tumors. Despite more than two decades of research, the few recombinant poxvirus vectored vaccines on the market today are for veterinary use only, most notably rabies.

In the last several years, however, poxvirus-based cancer vaccines have evolved significantly. Researchers have at their disposal a more varied pallet of poxvirus strains that, while not highly virulent in humans, are nevertheless able to elicit a strong immune response. Vectors created from these viruses have a large capacity for carrying within their genetic structures multiple complex molecules including TAAs, cytokines, and co-stimulatory molecules, which, when combined on a single vector, are found to have a greater capacity for triggering a multifaceted immune responses against tumors. Thus we have a highly efficient means of delivering multiple payloads on a single warhead, so to speak. Coupling these powerful poxvirus vectors with improved cancer immunization techniques is resulting in significant advances in vaccination. Most notably, researchers have seen a more robust immune response with improved clinical endpoints in animals that have been treated with the vaccines. In early-phase clinical trials, vaccines deploying these poxvirus vectors have been shown to induce tumor-specific T cell responses in humans, a strong indicator of their potential to produce long-lasting immune regulation of tumor growth. Dr. Panicali’s group is beginning the first randomized phase III clinical trial of a poxvirus-based cancer vaccine, and will report the preclinical and clinical data leading up to this trial.

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