Meeting Summary
The awesome power of the human immune system is well documented. Harnessing this power against cancer has been the dream of cancer immunologists worldwide, and has been the sole mission of the Cancer Research Institute (CRI) since its founding in 1953.
Substantial progress in cancer vaccine and antibody-based therapy research—much of it funded or guided by CRI—is providing new hope for many cancer patients, especially those that have exhausted standard forms of cancer therapy. A new generation of sophisticated, targeted immunotherapies is advancing steadily through the early stages of clinical research, and it is only a matter of time—and not much time, at that—before immune-based therapies move to the fore of the oncologist’s arsenal.
Recent advances in our understanding of the body’s immune system and its relationship to cancer have given renewed vigor to the field of cancer immunology. The CRI International Symposia Series is recognized as the premier forum among the world’s foremost immunologists and cancer immunologists for sharing and learning about these advances.
This year, 350 scientists gathered together at the Manhattan Conference Center in New York City’s Millennium Broadway Hotel to share and discuss the latest findings in the pursuit of effective cancer vaccines.
Day One: Innate immunity, imaging technology, cancer stem cells
Day Two: Anti-tumor immunity, CT antigens, immune regulation
Day Three: Immune regulation, lymphocyte maturation, clonal expansion
DAY ONE
This year’s meeting, Cancer Vaccines 2005, began with lectures on key discoveries in basic immunology research—the stuff that provides the foundation for the entire field of cancer immunology. We first explored the innate immune system—the body’s oldest, most primal system for immediate defense against infectious agents—and how the application of classical genetics to the study of the innate response, particularly the roles Toll-like Receptor (TLR) signaling and Natural Killer (NK) cells play in this response, is yielding some important discoveries about how we can learn to mediate this first-line defense system against tumor growth.
In the meeting’s next session, imaging immune responses, we discussed developing technologies that are enabling cancer researchers to see how the immune system is working at the molecular and cellular levels, in real time and in living tissue. New analyses of the application of altered peptide ligand (APL) in the study of the immunological synapse—the cluster of membrane proteins and cytosolic molecules that forms at the junction between a T cell and an antigen presenting cell (APC)—are bringing coherency to some apparently conflicting observations regarding signaling within the synapse.
Recent advances in real-time in vivo imaging technology—in particular the new imaging process called multiphoton intravital microscopy (MP-IVM)—have allowed prolonged, three-dimensional observations of highly dynamic events that occur hundreds of micrometers below the surface of solid tissues in living animals. Specifically, researchers discussed how MP-IVM has allowed them to map the kinetics of CD8+ T-cell activation by antigen-presenting dendritic cells both in and outside the presence of the immune-inhibiting regulatory T cells. We also heard about recent, real-time observations of dendritic cell (DC) migration into lymph nodes and the consequences of DC interaction with T cells within the lymph nodes. These studies are contributing to a more accurate picture of the molecular, cellular, spatial, and temporal aspects of cell interaction in signaling events in host immune responses.
Also on day one, the latest data was presented on stem cells and what they have in common with cancer cells—particularly their ability to self-renew perpetually. We learned how researchers are finding a genetic link between these shared abilities that suggests that cancers derive their immortal characteristics from stem cells. Targeting these “cancer stem cells” is not just possible, say some researchers, but essential for successful immunotherapy.
Day one concluded with an introduction to the conference’s third session, which focused on laboratory observations of anti-tumor immune responses in animals and in humans. The final lecture of the day presented data from a cancer vaccine study that employs an improved bacteria-based antigen delivery mechanism. This vaccine takes advantage of the Salmonella bacterium’s ability to introduce antigen—in this case, the cancer-testis antigen NY-ESO-1—into the immune environment in a way that stimulates both an innate and adaptive immune response. Observations of significant tumor regression in mice suggest a promising novel mechanism for cancer vaccination in humans.
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DAY TWO
The conference was in full-swing as we continued the third session and its focus on anti-tumor immune responses. In the previous lecture, we were introduced to the NY-ESO-1 cancer-testis (CT) antigen. Today’s first lecture delved deeper into the role of CT antigens in the development of cancer vaccine therapy. Particular attention was drawn to the association of germ-cell development with cancer genesis and how CT antigen results from aberrant expression of germ-cell genes in cancer. Similarities in germ cell and cancer cell behaviors reinforce the importance of the study of germ-cell gene-associated CT-antigens as therapeutic targets.
It is now evident that long-chain, full-protein-based cancer vaccines seem to yield stronger, more effective immune responses against cancer. However, monitoring the specific immune response when using such complex proteins has proven quite difficult. Nevertheless, as we learned in this day’s second lecture, it is imperative that we develop a simple, standardized technique for observing the cancer-specific immune response to these vaccines. We heard about the latest advances toward this end and the implications of these findings on vaccine design.
NY-ESO-1 entered the stream of discussion again, this time within the context of two clinical trials testing ovarian cancer vaccines. This CT antigen is known for its ability to instigate strong, spontaneous immune responses in some patients, and remains one of most immunogenic antigens known so far, making it quite suitable for vaccine studies. In these trials, researchers attempt to stimulate a robust response from both CD4+ and CD8+ T cells, two potent immune players that are known to work better when operating together.
Generating robust, effective T-cell responses in tumor immunotherapy has proven challenging, despite the identification of many target antigens. As we began the conference’s fourth session on immunotherapy, we found that researchers are looking for ways to overcome the obstacles that can prevent strong immune responses in some patients. Since many candidate tumor antigens are self-proteins that are over-expressed by the cancer, many immune systems learn to ignore the dangerous cancers because they often “appear” to immune sentinels as normal cells. Researchers are working to dissect and define the components of these antigens that are required for stimulating an immune response; they are also working to expand colonies of immune cells that do react and to manipulate the T-cell receptors so that they will recognize the cancer cells as dangerous.
Encouraging data on how some vaccination methods have been significantly improved was given, including data from studies that show that vaccines administered with anti-CTLA-4 (a monoclonal antibody that interferes with normal suppression of the immune system) showed an overall objective tumor regression rate of 13% (compared to 3.8% shown in an analysis of previous studies). Furthermore, a strong link between autoimmunity and cancer regression is seen. We also heard of a study where more than half of the participating melanoma patients treated with a cell transfer approach using expanded colonies of tumor infiltrating lymphocyte (TIL) and interleukin-2 showed objective clinical responses.
As we moved into the late afternoon of day two, we learned about other immunotherapeutic approaches that seek to circumvent the immune system’s inherent resistance to manipulation. One approach is to vaccinate with irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF), which is known to enhance tumor immunity by improving tumor antigen presentation by mature dendritic cells and macrophages. Data from several phase I clinical trials testing vaccination techniques based on this approach show increased tumor immunity in a majority of individuals.
Improved immunity, however, is often not enough to prevent recurrence of progressive disease. Antigen-loss variants—cancer cells that no longer exhibit the antigen targeted by the immune system—present a major challenge to effecting prolonged immunity, as does negative immune regulation. Blockades to negative immune regulation, such as anti-CTLA-4 monoclonal antibody, are known to strengthen immune responses; however, taking the foot off this brake of the immune system can result in autoimmunity.
Researchers are working now to discover whether tumor destruction can be facilitated using this antibody adjuvant approach without also causing serious autoimmunity. A pivotal phase III clinical trial testing a fully human antibody to CTLA-4 in melanoma patients is now underway and was also discussed. Also shared was data on a new co-signaling pathway that is known to play a role in T-cell differentiation, and T-cell effector and memory phase response, and how this knowledge can assist in the development of other, more effective vaccination techniques.
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DAY THREE
On this, the final day of the symposium, we delved more deeply into the ongoing studies of the regulatory mechanisms of the immune system and how they affect tumor immunity.
Specific evidence of how suppression of the immune response via the effect of regulatory T cells was given, including data showing the impact these regulatory cells have on Natural Killer T-cells (NKT) and Natural Killer (NK) cells, and how this broad immune suppression correlates to increased cancer proliferation and metastasis. We saw how vaccination with SEREX-defined self-antigens can lead simultaneously to both positive and negative immune responses. We also saw how treatment with anti-GITR antibody has been shown to help minimize the negative response and increase overall tumor suppression.
Other researchers are looking at the genetic mechanisms that lead to regulatory T cell proliferation in hopes of learning to block or diminish their growth during cancer vaccination therapy. An analysis of genes differentially expressed in regulatory T cells and helper T cells revealed the expression in certain regulatory T cells of the transcription factor Foxp3. Fox3p-expressing regulatory T cells are known to arise within the thymus in response to the generation of self-reactive T cells. In this way, their presence helps maintain immune homeostasis. We saw how deficiencies in Fox3p lead to fatal autoimmune disorders in mice and humans. Researchers hope to learn how to modulate this regulatory checkpoint in order to more fully unleash the power of the immune system during cancer vaccination.
Data was presented from several phase I and II clinical trials that are testing means of modulating these regulatory checkpoints, including the administration of agents such as Ontak—interleukin-2 that is genetically fused with diphtheria toxin—and Toll-like receptor 8 (TLR8) ligands, both of which were shown to reduce immune regulation. These data demonstrate that positive clinical benefit can result from careful control of the inhibiting regulatory mechanisms.
The meeting’s sixth and final session addressed how the mechanisms of cell maturation, and antigen uptake and presentation by Dendritic Cells (DC) are being studied in order to learn how better to stimulate increased immune responses from CD8 and CD4 T cells. We heard about studies in mice that show that manipulation of these mechanisms is resulting in prolonged immunity, which can also be conferred via adoptive transfer (injecting the cancer-specific lymphocytes from one mouse into another).
Finally, we looked more closely at the relationship of CD4+ “helper” T cells to CD8+ T lymphocytes (CTL) and the mechanisms through which helper Ts boost CTL activity and endow them with the capacity for further antigen repertoire expansion upon re-stimulation. The relevance of these findings to cancer immunotherapy was made evident.
A PDF copy of the meeting program, which includes speaker and poster abstracts, is available here. Click here to read the meeting summary published in the December 2005 issue of Nature Immunology. HTML and PDF copies of individual speaker abstracts and a copy of the meeting's closing remarks from Dr. Kunle Odunsi of the Roswell Park Cancer Institute can be found on Cancer Immunity's site here.
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