THE CURE WITHIN®
VACCINATING AGAINST CANCER
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A pioneering cancer vaccine being developed by a researcher at the University of Pennsylvania boosts natural immune defences against deadly disease. With help from Pennies in Action®, it could one day be the preventive cure needed to fight off breast cancer and other tissue-related cancers.
THERE ARE BROAD approaches to treating cancer – surgery, chemotherapy and radiotherapy – and while refinements in each continue to improve survival rates, cancer remains a serious condition. Some scientists believe certain cancers arise spontaneously and can be removed by a healthy immune system, and that the failure of this immune response is what leads to the development of malignant tumours – an idea which in recent years has impelled research toward a vaccine.
Vaccines teach the immune system how to respond rapidly to various threats, such as bacteria, viruses and other microorganisms, but because the system is primarily geared toward dealing with these microbial infections, it often struggles to respond effectively against cancer, due to the latter’s dissimilarity with common germs. Vaccines have a number of advantages over traditional therapies: they do not have the harsh side-effects associated with chemotherapy; can be administered repeatedly, unlike radiation therapy; and while surgery, chemo- and radiotherapy only deal with disease present at the time of treatment, vaccines provide long- term protection. They can also be preventative;
if high risk individuals can be identified for a specific cancer, they can be vaccinated prior to the onset of clinically-apparent disease or at its very early stages, preventing the formation of malignant tumours.
KICKSTARTING THE IMMUNE RESPONSE
Dr Brian Czerniecki is Rhodes-Harrington Professor in Surgical Oncology at the University of Pennsylvania. His research focuses on dendritic cell biology and T-cell interactions, and having developed vaccines for the treatment of cancer, is involved in several clinical trials treating patients with early stage breast cancer and working on identifying molecular targets which can be exploited to prevent metastasis. Czerniecki and his colleague Dr Gary Koski, Associate Professor at Kent State University’s Department of Biological Sciences whose research, funded with the help of the American Cancer Society, includes immunology, cancer and infectious diseases, have developed an ingenious vaccine designed to coax the immune system into reacting to certain proteins on the cancer cells as if they are bacterial proteins. The result is that the patient’s own immune system will attack the cancer with a quality and intensity usually reserved for microbial infections.
This ‘vaccine-induced immuno-editing’ is something of a revolution; not only does it help the immune system to locate and destroy the cancer, avoiding the unpleasant side-effects of traditional therapies, but the immune response lasts for years after vaccination, protecting the patient from recurrence. One of Czerniecki’s past patients is former Olympic coach and competitor Uschi Keszler who, having survived breast cancer, went on to found the non-profit organisation Pennies in Action®. Keszler chose not to undergo chemo- or radiotherapy so as not to compromise her immune system, opting solely for surgery – an ideal which aligned well with Czerniecki’s work. Keszler was so impressed with Czerniecki that she set up Pennies in Action® in order to raise awareness of, and fund his research into, a cancer vaccine. The foundation has raised money to provide new computers, microscopes and incubators, in addition to vaccine production, a new peptide library and funds for the first clinical trials. There is also money for an open trial for invasive breast cancer for human epidermal growth factor receptor two positive (HER2+). “Czerniecki’s work goes from lab to bedside, bringing huge benefits to patients who would otherwise be
unable to receive the vaccine,” Keszler explains. “We make sure we target money in order to maximise patient benefit.”
SEEING THE FINISH LINE
One of the continuing goals of this research has been to help patients overcome this fear by empowering them in decision making about their treatment, emphasising their role as
stakeholders in their own care. “Most people are much more afraid of the treatment than of cancer itself, but Czerniecki’s protocol is non-toxic, humane and biodegradable,” enthuses Keszler. Thus, this emphasis on patient choice and control is likely to become more commonplace in the coming years as patients are made more aware of their options and given greater say in how they wish to be treated. It is an idea which resonates with Keszler: “I accompany patients through their treatments and some doctors seem not to understand the psyche of a cancer patient, or what you should and should not say to them; the importance of preserving hope. They could learn so much from Czerniecki and how he handles patients”.
It is hoped that in the near future, Czerniecki’s vaccine will be approved and become a standard treatment available for all. It has taken a lot of hard graft but the end is in sight. At the end of 2013 Czerniecki’s groundbreaking paper on ‘Inhibition of CD4+CD25+ regulatory T cell function and conversion into Th1-like effectors by a Toll-like receptor-activated dendritic cell vaccine’ was published in PLOS ONE, a highly acclaimed scientific journal. This recognition is the culmination of years of work and brings confidence that the efforts have been worth every penny.
THE VACCINE: EXPLAINED
The T lymphocyte (T cell) is a very important white blood cell; found in the immune system it is capable of directly attacking infections or cancer and controlling other cells. Czerniecki’s work has shown that T cell subtype Th1 is critical for successful immunity against cancer in particular and is unique in its ability to produce a factor called interferon gamma (IFN-γ).
A regulatory T cell (Treg) can switch off strong immune responses during repair or keep the immune system in check to prevent autoimmune disease, however cancer cells have evolved to subvert such regulatory powers. In fact, tumours recruit Tregs to protect its own defenses from the immune system.
Czerniecki’s vaccine strategy is centered on a white blood cell called a dendritic cell (DC). DCs collect information on potential dangers to the body and present these to T cells. The T cells then decide how best to deal with the threat. By extracting DCs from cancer patients, Czerniecki was able to infect them with the cancer so when inserted back into the body Th1-type T cells embarked on a search and destroy mission against any cell bearing the cancer proteins presented by the DC. It had been a concern that despite the tumor’s line of Treg bodyguards might effectively blunt the attack. However, Czerniecki and his team have shown that this might not be the case. When Treg cells and normal T cells were incubated together in the test tube, as expected, Treg cells prevented regular T cell activity. Interestingly, when DCs were added, regular T cells regained their function and the cease and desist orders typical of Tregs appeared to be annulled. Looking more closely, the team was surprised to find that Tregs were no longer looking or behaving like Treg. Instead, they were taking on the character of the cancer-fighting Th1 cells, and were even making IFN-γ. The vaccine DCs turned the pacifists into fighters!
VITAL PRIVATE FUNDING
As with most healthcare research, funding remains a challenge, with constant friction between the desires for novel therapy versus the need to build on an existing programme to bring therapy to completion. This is particularly apparent when those therapies are not being developed by commercial corporations. Clinical trials are expensive and many agencies do not have the money available to fund them. “In the US, the largest supporter of biomedical research is the National Institutes of Health (NIH),” reveals Koski. “When I applied for my first major NIH grant in 2002, the proportion of grant applications that received funding was close to 20 per cent; that has now dropped to between 5 and 8 per cent.”
It is partly a problem of plurality; there are now so many different cancer-related organisations, all of which are looking to raise money, that it has become something of a competition of who can raise the most. “People have forgotten that we are all in this for the same reason – we should be working together for the same cause,” Czerniecki admits. “Everyone is fighting the bad guy, trying to be the hero that defeats him, but if we stopped competing with one another and formulated a plan together we could defeat cancer.”
With public funding spread ever-more thinly, the importance of alternative funding through private donors and research foundations has significantly increased, and Czerniecki and Koski believe private funding now represents the best chance of achieving their goals, enabling researchers and clinicians to conduct cutting-edge clinical research with near-term impact. In Koski’s view, the reason for this change is the cap placed on traditional NIH awards of US $2.5 million over the course of five years. “This is enough money to perform relatively small phase I or phase II clinical trials to establish the safety of new treatments and hint at possible effectiveness,” says Koski. “However, in order for a new treatment to gain Food and Drug Administration (FDA) approval, it must undergo phase III trials.”
These trials involve a larger number of subjects (100+) whom are randomly assigned either the experimental treatment or the current standard, such as chemo- or radiotherapy. The study is also performed at multiple centers to ensure reproducibility. This makes them too expensive to complete on the existing funding allowance, making it essential researchers explore other sources of capital. The team is also attempting to forge global relationships in an effort to coordinate an international response to this worldwide problem and it is hoped the vaccine may have significant benefits in terms of cancer prevention in poorer countries where screening is not routine.
An explanation of the PLOS ONE Inhibition of CD4+CD25+ Regulatory T Cell Function and Conversion into Th1-Like Effectors by a Toll-Like Receptor-Activated Dendritic Cell Vaccine article in layman's language by Dr. Gary Koski.
The immune system is made up of a number of different types of white blood cells, and each type has its own unique functional responsibilities. One of the most important kinds of white blood cell is the T lymphocyte. They act as the fighting generals of the immune system. This means that they are capable of directly attacking threats to the body, like infections or cancer. It also means that they give orders to other cell types and direct their activities. Even among these T cells, there are several distinct types. Dr. Brian Czerniecki’s work has shown that a T cell subtype called “Th1” is critical for successful immunity against cancer. Th1 cells are distinguished from other T cell types by their ability to produce a factor called Interferon gamma (IFN-γ).
Amazingly, not all T cell types are fighters. Some are actually pacifists! There are times when strong immune responses need to be shut off. For example, after a damaging infection has been successfully defeated by the body, the immune system must be eased back into a state of quiet alertness so that healing can begin. In other instances, the immune system must be held in check so that it does not accidently attack normal, healthy tissues and trigger so-called “autoimmune” diseases like rheumatoid arthritis or lupus. This necessary capacity to lull the immune system into a state of quiescence is the province of the “regulatory” subtype of T cell (Treg). Treg cells provide “cease and desist” orders to other cells of the immune system at times when strong responses are either unneeded or potentially damaging.
Unfortunately, cancer cells have learned a number of tricks to subvert the Treg cells. The Tregs can be recruited to the site of the tumors and produce biochemical signals that turn off immunity around the cancer, preventing an attack. So the cancer actually gets the Treg cells to serve as a kind of bodyguard to protect it from the immune system!
Dr. Czerniecki’s cancer vaccine strategy is centered on another type of white blood cell called a dendritic cell (DC). If T cells are the General Officers of the immune system, DCs are the reconnaissance scouts. DCs collect information on potential dangers to the body and present these to T cells. The T cells then decide how best to deal with the threat. Dr. Czerniecki’s approach is to remove DCs from the bodies of cancer patients, expose them in the test tube to synthetic cancer proteins, and then activate the DCs using biochemical signals of bacterial infection. These signals of infection make the DCs behave as though the cancer proteins come from a microbe, insuring a powerful immune response dominated by Th1-type T cells. When placed back in the body, the DCs present the cancer protein to the T cells, and the T cells respond by embarking on a search-and-destroy mission against any cell bearing the cancer proteins presented by the DC.
It had been a concern that despite the strong anti-tumor activity generated by this vaccination approach, the tumor’s line of Treg bodyguards might be able to effectively blunt the attack. However, in a series of elegant experiments just published in the online journal PlosOne, Dr. Czerniecki and his team showed that this might not be the case. When Treg cells and normal T cells were incubated together in the test tube, as expected, the Treg cells prevented the activity of the regular T cells. Interestingly, when the vaccine DCs were added to the mix, the regular T cells regained their function. The vaccine DCs thus appeared to countermand the cease and desist orders that typically emanate from Tregs. But when Dr. Czerniecki’s team looked more closely at the Treg cells, they were surprised to find that they were no longer looking or behaving like Treg. Instead, they were taking on the character of the cancer-fighting Th1 cells, and were even making IFN-γ. The vaccine DCs even turned the pacifists into fighters!
To my knowledge, no vaccine procedure has ever before shown the potential to shut down Treg function, let alone actually convert them into cells with the characteristics of cancer-fighting Th1-type T cells. This may be part of the explanation of why Dr. Czerniecki’s laboratory is observing such remarkable clinical responses in their ongoing clinical trials to vaccinate against early breast cancer. Congratulation to Dr. Czerniecki and his team!
FAQs ABOUT VACCINE DR. GARY KOSKI
I have been asked by Uschi Keszler, founder of Pennies in Action, to field some often-asked questions regarding the exciting breast cancer vaccine initiative that she and her organization are supporting. As an experienced Immunologist, and one who has had some involvement in the development of this approach, I feel that I am in an excellent position to offer my personal thoughts and opinions on why this matter should be worthy of your attention and support.
What is this all about?
Dr. Brian Czerniecki and his team of investigators have developed a vaccine strategy for secondary prevention of breast cancer. Secondary prevention is the capacity to prevent the recurrence of cancer once the primary tumor has been identified and surgically eliminated. This vaccine strategy temporarily removes some of the breast cancer patient’s own white blood cells prior to surgery. During a 2-day period outside the body the cells are exposed to breast cancer proteins as well as biochemical signals that mimic infection. The cells are then re-administered back to the patient each week for 4-6 weeks prior to the scheduled surgery. The re-introduced white blood cells then signal the body’s immune system to attack the cancer. Whatever remains of the tumor is then surgically removed and the patient is closely followed to monitor for recurrence of disease. When non-vaccinated patients receive the best current standards of care after surgery (including local radiation and chemotherapy), tumors still recur in up to 20-25% of the patients within 5 years. Reducing this number with a vaccine would be the most cost-effective and humane way to prevent all of the morbidity and mortality that occurs as a result of breast cancer recurrence after surgery. This includes local recurrence, metastatic disease, death due to advanced cancer, and all of the financial cost and side-effects of chemo- and radiation therapy.
Why focus on preventing recurrence?
Why not develop a vaccine to prevent breast cancer in the first place? It is very difficult to predict who, among those who have never had breast cancer, will develop it within a 3-5 year window. Testing an experimental vaccine for primary prevention would therefore require the immunization of thousands of individuals in order to catch the handful that would otherwise develop it. Such a large trial would be financially prohibitive. On the other hand, individuals who have already developed a high-grade early breast cancer, and had it surgically removed, are at considerable risk for experiencing a recurrence in 3-5 years. By focusing on this high-risk group, it will require fewer vaccinated patients to prove that immunization suppresses recurrence rates. Such a smaller trial is of course more financially manageable. However, it should be noted that a vaccine that is proven to prevent recurrence would almost certainly also prevent cancer from ever developing in the first place. Therefore the development of a vaccine that prevents recurrence shortens the path to achieving true cancer prevention.
Does Dr. Czerniecki’s vaccine show any sign of providing secondary protection?
In two “phase 1-2” clinical trials conducted at the University of Pennsylvania, over 50 women were vaccinated. Some of these women have been followed out beyond 88 months (over 7 years). In the subset of women whose breast cancers did not express the estrogen receptor (about half), absolutely no recurrences have been observed. Blood samples taken from women up to 5 years after vaccination demonstrate white blood cells that still respond against breast cancer proteins, indicating a very long-lived immune response, which is necessary to provide extended protection from recurrence.
In what way are these results exciting and different from other breast cancer vaccines I have heard of?
First, Dr. Czerniecki has over a seven-year track record of immunizing real people with breast cancer using this vaccine. This is not a pie-in-the-sky idea that has been tried only “in the test tube” or in mouse models. The vaccinated patients have had real, tangible results. Seven of the patients, when sent to surgery after receiving the course of vaccinations, had no detectable cancer left in their breasts. Several of the patients showed such a large degree of tumor shrinkage that the remaining disease could be safely removed using a lumpectomy procedure, rather than having to remove the whole breast. Past attempts by others to produce anti-cancer vaccines show that immunity wanes a few weeks after vaccination. The responses from Dr. Czerniecki’s vaccine have been shown to last for years, potentially offering patients long-term protection from recurrent tumors. Finally, there have been no recurrences in a large subset of our patients. No current therapy, established or experimental, has ever shown this level of prevention. The results of these trials have been published in peer-reviewed journals including Cancer Reserarch (2007), Cancer (2012) and the Journal of Immunotherapy (2012).
Why are these results so good?
The body’s immune system is primarily designed to attack microbes (bacteria and viruses). Dr. Czerniecki’s vaccine strategy is unique in that it, by design, “tricks” the immune system into responding against cancer as though it was a dangerous infection. In addition, we are attacking the breast cancer at a very early stage. Remember, the common vaccines against infections that you are familiar with are all preventative. They don’t work once you are already sick. The medical establishment has become very good at detecting breast cancer at earlier and earlier stages. Unfortunately, women with one bout of breast cancer are at high risk for recurrence. The challenge therefore is to develop treatments that will preserve the health of the patient in the long-run without the debilitating and dangerous side-effects of radiation therapy and chemotherapy.
What is the next step?
In order to gain approval from the FDA for using this vaccine as a standard therapy, a successful “Phase 3” trial must be completed. Such a trial will be conducted at multiple institutes (so that other groups of physicians can replicate the University of Pennsylvania results), and must involve a larger number of patients (around 200, so that statistics can prove conclusively that we are really preventing recurrence). We can begin such a trial almost as soon as we secure the necessary funds.
If these results are really so good, why hasn’t money already been obtained for the phase 3 trial?
The first two phase 1-2 trials were generously supported by prestigious “R01” awards from the National Institutes of Health, which funds the bulk of health-related research conducted at Universities and Biomedical Research Institutes across the United States. Unfortunately, NIH “caps” their awards at $500,000 per year for 4-5 years (2-2.5 million per grant, maximum). Such funds can support early trials involving 30-40 subjects, but we calculate that a multicenter phase-3 trial will cost around 15 million dollars. The NIH simply does not have a common funding mechanism that covers something this large. Likewise, private funding organizations such as the American Cancer Society and the Susan G. Komen Foundation place most of their emphasis on awards of similar, smaller scale.
Another avenue would be the formation of a startup company and the attraction of venture capital. Unfortunately, the cancer therapy options that are most profitable are not necessarily the ones that are best and most desirable from the standpoint of the patient. Outside investors may not be able to resist selling out to a generous offer from a large pharmaceutical company. The pharmaceutical company may in turn decide that there is more money to be made selling standard chemotherapy than preventative vaccines and “shelve” their newly-acquired technology. Dr. Czerniecki and his colleagues strongly believe in the entrepreneurial spirit that drives innovation in the United States, but we must acknowledge that we should first strive for a transparent, fully independent demonstration of the vaccine’s effectiveness. Only after the vaccine’s value is common knowledge, and there is considerable demand from the public for this new preventative, should the technology be transferred to business interests. This approach will ensure that the vaccine eventually gets to the people who need it.
Will this vaccine have a large impact on health?
Our “proof-of-principal” vaccine is directed at a single protein called HER-2 that is produced by about 30% of all individuals with breast cancer. We are already planning a strategy to expand and improve the vaccine therapy to increase the number of individuals who would benefit from immunization. First, we are pairing vaccination with a short course of the anti-estrogen drug Tamoxifen. Early studies suggest that this combination may improve overall effectiveness for individuals with cancers expressing the estrogen receptor. Second, we are laying the scientific groundwork for including additional cancer-related proteins such as HER-1 and HER-3. A vaccine formulation including HER-1, 2 and 3 could potentially allow protection of up to 90% of breast cancer patients. Perhaps even more important, these cancer-related proteins are also found on other common cancers including cancer of the lung, pancreas, ovary, colon and prostate. This means that when fully developed, this vaccine technology has the potential to impact some of the most common tumor types.
I hope that I have answered most of your questions, and that you find this cause worthy of your support.
An Explanation of the Vaccine Process from Dr. Gary K. Koski, PhD
Dr. Koski is a long-time associate of Dr. Czerniecki, and a collaborator in his vaccine research. He sent this to Uschi when she asked for a non-scientific explanation of the research:
Unfortunately, there is not really a simple way to explain what we do in a very concise way that is both accurate and can be easily understood by non-scientists. However, I shall do my best.
If T lymphocytes are the fighting generals of the immune system, dendritic cells act as the reconnaissance scouts. DCs like to take up station at sites of anatomical barriers, i.e. where the "inside" meets the "outside", (the skin, mucous membranes, alimentary canal). Here they wait for two things, signs of infection and/or inflammatory tissue damage. The surface of a DC is studded with specialized receptors, which act as sensors for infection or inflammation. When they contact such signals, a specialized maturation/activation/migration program is initiated. DCs collect a "snapshot" of the proteins present in the environment of the activation signals (such as proteins from an infectious agent), gain access to draining lymphatic vessels, and travel to the lymph nodes. The lymph nodes are populated by many T lymphocytes. The DCs seek out T cells and "present" the proteins acquired at the peripheral sites. The T cells then become activated by the DCs and then go out on a "search and destroy" mission to eliminate anything that resembles the proteins presented by the DC (such as a bacterium infecting the body). Now here are the reasons why we think our approach is giving us superior results. Please note in many cases, we were not the first to try some of these things (though in certain instances we were), but mostly it is the fact that we assembled a number of innovations into an integrated strategy.
1) All vaccines used (like a standard tetanus shot) rely on the material provided by the immunization to be picked up by DCs for presentation to T cells. However, we believe that the sort of immune response needed to eliminate tumors is so intense, and of a particular type that the best way to achieve it is to actually culture large numbers of the DCs outside the body and then administer them already "loaded" with the vaccine proteins.
2) We activate the DCs in a special way that mimics infection. We use a special preparation of a compound that makes up the cell wall of bacteria called lipopolysaccharide (LPS). One of the sensors on the surface of DCs specifically recognizes LPS leading to their activation. We think that by "fooling" the DCs into believing they are under attack by a microbe, the response they generate will be particularly strong. We are the first to use LPS to activated DCs in a clinical trial. We believe that other methods to activate the DCs do not allow for maximal function.
3) We think that soluble products produced by the DCs supply special signals to T cells that allow them to be particularly effective against cancer. Brian showed that one of these soluble products, called Interleukin-12 (IL-12) endowed the T cells with the capacity to recognize and kill tumors in the test tube. T cells that were sensitized by DCs incapable of producing IL-12 could not recognize or kill tumor cells. Most other investigators trying to produce anti-cancer vaccines under appreciate the need for IL-12. By combining LPS with another cytokine called interferon gamma (IFN-g), the DCs can produce large quantities of IL-12. Most other methods of producing DCs for vaccination will not induce them to produce IL-12.
4) We inject the DC vaccines directly into the lymph nodes. Most others inject the DCs at distal locations with the expectation that the DCs will migrate to the nodes on their own. In fact, only a very small proportion of cultured DCs actually make their way to lymph nodes after injection. So people who do not inject directly into the nodes are cheating themselves of the best possible immune response.
5) We harvest the vaccine DCs at a time point where they are making maximal amounts of IL-12. The DCs follow a very precise program after activation and only make IL-12 for a very short window of time. Supplying the DCs too early or too late will squander the benefit of IL-12. Most other investigators give no thought to the kinetics of cytokine production and only supply DCs long after they stop making such products.
6) We specifically target cancer proteins that are associated with the tumor's ability to cause disease. HER-2/neu is a poor prognostic indicator. HER-2/neu over-producing tumors are more likely to recur after surgical resection, are more likely to be invasive and metastatic, and can be resistant to some front-line chemotherapy agents. We target such proteins so that if we are lucky, all of the tumor is killed. If we are slightly less than lucky, we can cull the tumor of the most dangerous cells leaving behind a residuum of disease that is less aggressive, more indolent, and more amenable to other therapies.
7) We target early disease. Most vaccines of the past have targeted later stage disease. This is because experimental therapies are usually supplied only when the conventional therapies have failed (hence the patient is further along in course of disease). This causes a number of problems. Late stage patients are sicker, often have little time to live, have large volumes of tumor needing to be destroyed, pre-treatment with radiation and chemo can negatively impact the bone marrow (and hence immune system), and advanced tumors are known to play tricks to turn off the immune response. For all of these reasons, we want to make vaccine therapy the first line of defense rather than the last line of defense. We hope to get to a point where vaccine therapy is used first, followed by surgery, and then, if necessary, radiation and or chemo (concentrating on techniques that do the least damage to immunity). It is also important to note that with advances in screening, we are likely in the future to catch tumors earlier and earlier. So our new therapies should be targeted here rather than late-stage disease. This does not mean that vaccines could not have benefit in later disease. But we should optimize them on early disease first before trying them out on later disease.
8) There are two types of T cells, so called "helper" T cells (Th) and the "Cytoxic" T cells (CTL). For a variety of historic reasons an excessive emphasis has been placed on CTL. Many vaccine attempts have focused exclusively on CTL, ignoring Th. We have formulated an approach that specifically recruits Th as well as CTL. We think this greatly enhances vaccine efficacy.
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