Immunotherapy And Advanced Prostate Cancer
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By William Cavanagh,
Bostwick Therapeutics,
a Division of Bostwick Laboratories

Edited from PCRI Insights February, 2008 v 11.1

(Image extracted from Figure 4)

Recent years have seen numerous studies undertaken where the immune system of a cancer patient has been manipulated in an attempt to cause it to “attack” cancers that have grown uncontrollable. Collectively, these manipulations are called “cancer vaccines” or “cancer immunotherapies”, and they differ radically from most current treatments for advanced prostate cancer.

Most all of us are familiar with the concept of “vaccination” or “immunization”, where material from infectious organisms such as bacteria and viruses is introduced into a person in order to protect that person from a disease in the future. This idea has its roots in the work of Dr. Edward Jenner, who realized in the late 1700s that by injecting patients with the cowpox virus (which is called “vaccinia”, and which results in a mild skin rash) he could prevent these same patients from developing smallpox, which was still an often fatal disease in Jenner’s time.

Although Jenner could not have possibly appreciated the science of virology and disease as we know it today, his work – along with the work of Pasteur and many others – ushered in the age of the vaccine. Many remember the work of Salk and Sabin in the 1950s, which all but eradicated poliomyelitis in the U.S. Through widespread public health initiatives and intensive research, vaccination against childhood diseases such as mumps, rubella, pertussis, etc. has become universal, and has essentially eliminated many diseases that have long sickened human populations.

So what do public health triumphs over infectious diseases via the vaccine have to do with human cancers?

The answer to this question hopefully lies in the vast efforts that have been made over the past 30 years to understand the human immune system, especially in the context of the cellular and molecular make-up of the immune system, and how it interacts with disease conditions.

Although what follows will be a vast over-simplification, it hopefully will assist in the comprehension of current study into cancer immunotherapy, or, the attempted motivation of the human immune system against cancer in much the same way that it deploys against infectious disease following successful vaccination.

Let’s start by exploring the human immune system and its components. Most of us are aware that our blood contains large numbers of white blood cells (WBC) in addition to the much more numerous red blood cells (RBC) that carry oxygen to our tissues and carbon dioxide away from them. In these white blood cells are found the cellular constituents of our immune systems. Now, importantly, we will divide these WBC into two families: the cells of myeloid origin and those of lymphoid origin (Figure 1).

Components of the Immune System

Innate (“Myeloid”) Immune System Adaptive (“Lymphoid”) Immune System
Response is non-specific Pathogen and Antigen specific response
Exposure leads to immediate maximum response Lag time between exposure and maximum response
No immunologic memory Exposure leads to immunologic memory
Found in nearly all forms of life Found only in jawed vertebrates

Figure 1. Simplified overview of the immune system.

These terms may seem a bit “Greek” (they are), but they represent two fundamentally different arms of the immune system, and deserve a bit of further explanation. “Myeloid” refers to bone marrow; much like red cells, myeloid cells (which include granulocytes and monocytes) are made in the bone marrow on a more or less constant basis. They continually find access to the circulation, where they travel throughout the body. Under certain circumstances, they will encounter scenarios that lead them to migrate toward sites of possible infections and contribute to a condition called “inflammation”.

The Role of Myeloid Cells

Very representative of this myeloid group is the neutrophil, a kind of granulocyte (Figure 2). Upon the cutting of the skin, for instance, the bacteria that normally cover us are able to enter the body, where certain types of them might cause disease. Neutrophils are able to detect the presence of bacteria through certain receptors on their surface, migrate to the site of the bacteria, and begin what is termed an “innate immune response”. If you have ever had such a cut in the skin become swollen and infected, you can thank and/or blame your neutrophils for creating this condition.

Figure 2. Neutrophils (among more numerous red blood cells)

Important in this example is the fact that the neutrophil (again, a myeloid cell) can directly detect the presence of bacteria that have entered the body, and can then stimulate a larger, killing type response. This includes the neutrophil engulfing, or “phagocytosing” the bacterial intruder. Neutrophils become activated in this fashion because they can sense the presence of molecules that did not come from you (the host).

So the neutrophil can distinguish certain kinds of protein made by the bacteria, and it can also determine that this protein was not produced by the host. Such antigenic discrimination is the hallmark of the immune response: “kill that which bears any antigen that does not look like you”.

Let’s back up a minute and discuss briefly the subject of antigen. The word itself is vague, based upon its origin as “something that stimulates the immune system to secrete an antibody“, an antibody being an immune molecule. However, the word is used much more broadly these days, and is more or less synonymous with “protein that provokes or is intended to provoke an immune response in a host”. (In case you’re wondering: prostate-specific antigen (PSA) is so named because it was found to provoke an antibody response in animals. It is in fact an enzyme manufactured by prostate cells, but because of the nature of its discovery it is has been stuck with that name).

Protein is without question the most fundamental molecule of all life. DNA, which we’re all familiar with, encodes protein; in other words, DNA is a code that tells cells how to make protein. If DNA provides the building blocks of life, then protein is the stuff of life itself. Protein creates the substrate for our growing bodies as we develop; it is the muscle that moves our skeleton, and that makes our blood vessels and nerves work. Protein also is present as the enzymes that allow us to digest food, to create energy and to detoxify poisons for our cells, and to break down other cellular components that are no longer needed by the cell. Protein that we make also provides the basis for intracellular communication, as proteins form receptors that occupy the surfaces of most cells and initiate critical cellular activities. These examples are among the myriad of functions performed by protein.

Getting back to our example above, one must consider that bacteria are also living; they have DNA, and they make protein specific to the machinations of their tiny lives. But the protein that bacteria make is so entirely different from the protein we humans make that our illustrative neutrophil can detect this protein and take lethal action against the invading organism.

Such is the “innate” immune system that is comprised, largely, of the myeloid cells from our bone marrow. These cells circulate the body, looking to detect unwanted presences on the basis of foreign – very foreign – protein.

Now we’re going to shift our admittedly simplified discussion to another circumstance that the immune system must contend with if our hypothetical host is to survive in a world where pathogenic microorganisms are a constant challenge to well-being and health. As an illustration, we’ll consider the case of the virus. Viruses are not cells, they are obligate cellular parasites – that is, viruses cannot live outside of the cells they infect. Viruses invade cells, where they are able to ‘hijack’ or take over important cellular functions to their own ends. Having invaded the cell, viruses can make many more copies of themselves using the cellular machinery of the hijacked cell – we will call this the host cell. (FYI, disease-causing bacteria, in the vast majority of cases, cannot invade the cell itself; they merely occupy the nutrient rich environment around the cells in our tissues.)

The problem for the virus is that, as a result of making the viral protein required for their replication, the invaded cell tips off the host that there is this foreign protein that needs to draw an immune response in order to maintain a condition of health. But in our viral example, the virus is inside the cell, hiding – if you will – from our neutrophil in the example above. Not that our neutrophil could do anything about it, because in this situation, the host cell itself needs to be destroyed, and our neutrophil protagonist cannot engage and kill a cell from the host it resides in.

The Role of Lymphocytes

In these situations, the other immune system is called in: the lymphoid system and its cells – lymphocytes. While our myeloid cells can do some potent cell-killing in response to very unusual protein such as that derived from bacteria, in other cases these cells will “present” protein to lymphocytes. Myeloid cells with names like macrophages, monocytes, and dendritic cells (together, “antigen-presenting cells”) can adopt a stance where they might be thought of as saying: “we don’t know what to do with this one… maybe there’s something you lymphocytes can do”.

Lymphocytes are far more discriminating than the myeloid cells, and they have an important capacity that myeloid cells don’t: they can directly kill their host’s cells that are deemed to bear protein that the lymphocytes find foreign. (In the interest of simplicity, we are ignoring some important cells here, such as natural killer cells.)

Lymphocytes (also called T and B cells) are of a very different lineage from the myeloid cells, which are made in the bone marrow. Lymphocytes are produced early in gestation via a very complicated process not to be described here. But, importantly, lymphocytes inhabit a set of tissues and organs known as lymphoid tissues (Figure 3), which include the lymph nodes, lymphoid-associated tissues, and the spleen (in case you ever wondered just what your spleen was for).

Figure 3. Various lymphoid tissues, where lymphocytes reside.

By and large, lymphocytes reside in lymphoid tissues, waiting for myeloid cells to wander in with protein that might require lymphocytic intervention. In the scenario of our virally infected cell above, some of these infected cells will be “sampled” by antigen presenting cells of the myeloid variety, and some of these cells will find their way to lymphoid tissues, and thus lymphocytes. Should the viral antigen brought by the antigen presenting cells find a “match” among these lymphocytes, the lymphocytes will expand greatly in number. Among these expanded numbers will be (1) lymphocytes that can make antibodies (plasma cells), (2) those that can direct other cells to kill the offending cells (T helper cells), and (3) those that can directly kill the offending cells (cytotoxic T cells). Keep in mind that the offending cells here are the host’s own cells that happen to be occupied by virus.

What has been described here, the lymphocytic immune response, is also called the adaptive or the specific immune response. It takes longer than the innate immune response in the example of the neutrophil and the bacteria above, but it is far more precise, and – importantly – it can result in the death of “self” – or host – cells. It also requires the participation of the innate, myeloid cells. This response also has a long memory.

Events Involved in Common Immunizations

As illustrations of the lymphoid immune system, consider the sequence of events involved in the immunization against cowpox and polio viruses.

In both cases, a virus that (intentionally) is not capable of causing serious disease is injected into a host. A local inflammatory response takes place, mediated by the innate, myeloid cells, which sense something is amiss. Antigen-presenting cells from this crowd take some of the injected viral protein, and move it to the lymphatic tissues in order to see if the lymphocytes are interested.

The lymphocytes are most definitely interested, since the viral protein is the kind of molecule that they can act against. The lymphocytes expand in number and disseminate through the host’s circulation. After some time passes – remember that there are no severely virally infected cells – the lymphocytes decrease their numbers. However, some sentinel lymphocytes remain in the lymphoid tissues that “remember” that protein, or antigen, that was provided in the vaccination. When the polio or the smallpox virus actually does parasitize the host cells, the antigen-presenting cells again sample these cells and visit the lymphoid tissues, where this time they find the “memory” lymphocytes against the viral antigen. These lymphocytes, which are much more attuned than the naïve lymphocytes that have never seen the virus or its protein, quickly expand and vanquish the virus, host cells and all.

Consider also the case of influenza, which almost everyone has experienced. As influenza virus spreads cyclically around the world, constant mutations in its antigenic make-up prevent effective memory lymphocytes from being resident in our lymphoid organs. Therefore, we must mount a primary, lymphocytic immune response via flu shots every season or so, although the flu shots that are distributed represent an effort to develop memory lymphocytes before the actual mutated influenza virus appears.

If the immunization against the flu is unsuccessful, the virally infected cells in the pharyngeal tissues of our throats and the tracheal tissues of our windpipes are sampled by our antigen-presenting cells, which arrive at the lymphoid tissues to contact the lymphocytes. When the antigen-presenting cells, loaded with viral antigen, make contact with the lymphocytes in the lymph tissue, the number of lymphocytes that match this antigen increases. Where these lymph tissues are close to the skin in the head and neck, we can often feel this tissue as “swollen lymph nodes”, or “swollen glands”. This tissue is swelling under the massive division of lymphocytes, which will go on to attack our own pharyngeal and tracheal tissue, destroying the infected cells and giving us the common flu symptoms of sore throats and hoarse coughs.

Immunotherapy Against Cancer

So, now that we’ve gone over the basics, where does all this get us with regard to treating cancer?

While somewhat controversial, a long-held contention holds that our lymphocytic immune system is continuously pruning back cells that produce antigen that contributes to cancer development and growth1. Although a difficult hypothesis to prove, the concept does make a lot of sense. For instance, consider that the radiation from the sun, especially the ultraviolet frequencies, is known to induce a certain sort of mutation in DNA called a “thymine dimmer”. Since we essentially bathe in the sun’s radiation on a continuous basis, it is entirely likely that our skin cells, which are rapidly dividing, are undergoing a fairly large number of mutation events over the course of our lives.

However, when we’re young, not many cancers develop, at least not as many as we would assume given the potentially mutagenic effect of environmental insults – like solar radiation and other carcinogens. Later in life, as with most cancers, the incidence of basal cell (skin) carcinomas begins to increase. But relatively early in life, we seem to be protected from the development of cancer, and it is likely that this protection is afforded by the monitoring, or “surveillance”, of our cells by the lymphocytic system.

In all likelihood, this immunosurveillance also curtails the growth of cells in dividing tissues that are improperly formed or otherwise dysfunctional. These cells, along with cells that have DNA encoding improper protein due to mutation, are expected to express protein that the lymphocytic immune system finds problematic. Through the constant sampling process described above, the lymphocytes are primed against the problem antigen and see to the destruction of the problem cells that are making that protein.

But it appears that something goes wrong with this scenario when aggressive cancers achieve the capability to grow and spread unabated. With cancer, it is largely understood that we are dealing with cells that have for some reason undergone significant changes. Some of these changes are likely at the DNA level, and by implication, at the protein level. That is, cancer cells are making protein that should not be made. This protein may be the result of mutated DNA (DNA that has changed over what it originally was, and therefore encodes erroneous protein); or it may be the result of viral infection (some cancers are known to be caused by viral infection and therefore contain viral protein); or there could be other, unknown reasons for cancerous cells to “turn on” certain inappropriate or destructive pathways of behavior that are mediated by faulty or improper protein manufacturing.

In any of these events, we know that protein (or antigen) is the target, and that this protein is manufactured by self-, or host-, cells. Therefore, in order to vaccinate against cancers the way we vaccinate against viral or bacterial disease, we will need to use protein contained in the cancer in order to stimulate the specific, cell destroying capability of the lymphoid – or adaptive, or specific – immune system. Approaches that utilize these principles are called “active immunotherapies” or “cancer vaccines”, and the desired objective is the creation of cell-killing lymphocytes that will eradicate the cancer that contains the protein contained in the vaccine (Figure 4).

Figure 4. Cancer eradication by the immune system,

with lymphocyte activation by antigen presenting cells (APCs)

Theoretically, the problem with vaccinating ourselves against our own cancers is that the immune system, especially in the advanced cancer patient, seems to have learned to “tolerate” the cancer. Somehow, the cancer – despite its anarchic and pathologic nature – has achieved a certain protection from the lymphoid system that should be responsible for eradicating it. This contention seems to be reflected in the fact that one of first sites of metastasis of advanced cancers is found in the lymphoid immune system itself, in the form of lymph node metastases.

There is increasing evidence that, in addition to the lymphocytes that lead to the destruction of invading organisms (and probably cancer), there is another set of lymphocytes that exerts the exact opposite effect; that is, their interaction with specific antigens leads to a suppression of the lymphocytic immune response. These lymphocytes are called “regulatory” lymphocytes, and numerous experiments have demonstrated that this strain of lymphocyte is designed to turn off an immune response once it is created, and to protect our own cells and tissues from our destructive lymphocytes.

An attractive theory2 at present holds that there is a balance in our bodies between the destructive lymphocytes and the regulatory lymphocytes. This balance ensures that our immune systems are mobilized in time of disease, but that this mobilization does not end up attacking us (the host). Interestingly, it is currently thought that when there are too few regulatory cells, a condition called auto-immunity develops. It seems t h a t these regulatory lymphocytes buffer our own normal tissues from their aggressive cousins. If this buffer is diminished, the surly lymphocytes that normally attack disease end up attacking our own tissues and organs.

Many reports of late indicate the number of regulatory lymphocytes is significantly increased in cancer patients3. These “regs” can be found in the circulation and at the site of the tumor, and they can be demonstrated to counter the activity of the killer lymphocytes. These facts have led many in the tumor immunology field to hypothesize that cancers – especially those cancers that end up spreading and growing unabated – are in fact protected by the regulatory immune system. In this case, the buffer has become too extensive, and prevents the proper destruction of cancer cells (Figure 5).

Against this extensive background (and assuming you’ve made it this far), let’s look at some of the current research that seeks to take the most up-to-date knowledge of the immune system and put it to work against cancer.

Figure 5. Regulatory lymphocytes can inhibit the ability of activated lymphocytes to destroy cancer.

Provenge®

The Dendreon Corporation’s Provenge®4 (sipuleucel-T) has made headlines of late in its quest for approval by the U.S. Food and Drug Administration. This method of treatment involves drawing myeloid cells from the circulation and turning them into antigen-presenting cells. Remember, our myeloid cells are the ones that couldn’t do anything about the invading virus, but were able to “sample” the infected cells and deliver protein from them to the doorstep of the lymphoid immune system. Using modern methods, these antigen-presenting cells (APCs) can be developed in the laboratory to make many, many millions.

The trick is that these cells, prior to processing in the laboratory, have to be drawn from a specific patient, and given back to the same patient. This feature makes these kinds of treatments “personalized”, or “autologous” immunotherapies. Once these cells are available, they can be fed an antigen from one source or another (specifically an antigen that is known to come from the cancer) and can then be put back into the patient. Theoretically, these APCs, once introduced back into the patient, will find the lymphatic tissues and nodes, where they can contact the lymphocytes, which in turn will expand, circulate, and attack the cancer (which ideally will contain the antigen loaded into the APCs).

In the case of Provenge®, the antigen delivered into the APCs taken from the patients is prostatic acid phosphatase (PAP), an enzyme made by the cells of the prostate. Because prostate cells produce PAP, it is thought that metastases from the prostate will manufacture it as well. By introducing PAP into APCs and injecting these cells back into the cancer patient, the lymphocytic immune system is given a head start. Many variations on this theme loading cancer-associated antigen into APCs are being studied world-wide.

Provenge® has shown promising signs of activity, including signs of (1) activating lymphocytes against PAP, (2) decreasing PSAs, and (3) extending survival by an average of 4.5 months over placebo treatment in men with metastatic prostate cancer. However, Provenge® failed to prove its primary trial goal and significantly slow the recurrence of cancer as compared to placebo. Thus it is not currently available commercially. Data to be released later in 2008 may provide further, compelling evidence of Provenge’s effectiveness, although this data remains to be seen. Importantly, as with many immunotherapies of this sort, side effects of therapy were minimal, especially when compared to established treatments such as chemotherapy.

GVAX®

As discussed earlier, antigen (protein) is the target against which an immune response is mounted. Cancer vaccine researchers have long been attempting to isolate cancer antigen – so-called “tumor-associated antigen” – and to use this antigen for cancer vaccines. Another, more ambitious, means of providing cancer antigen as a vaccine is to take actual cancer cells, disable them by using radiation to destroy the cells’ potential for multiplication, and use these cells as a cancer vaccine, much like early viral vaccinations.

GVAX®5, manufactured by Cell GeneSys, Inc., is an example of this approach. Further, these cancer cells are engineered such that they make a molecule called GM-CSF. GM-CSF (granulocyte-macrophage colony stimulating factor) is a powerful immune molecule, and in this case serves as a signal to the immune system akin to “come get me” (“me” being the cancer cells). Because cells express vast numbers of antigens, using whole cells may be superior to using individual proteins.

GVAX® is not personalized; it is a combination of two cell lines (LNCaP and PC-3) that have been grown in a laboratory, but were originally isolated from human prostate cancer. So while this cellular vaccine is prostate cancer, and the immune response generated should be against prostate cancer, the cells used being laboratory grown) may not be exactly related to the cancer in the patient.

Early studies have shown some success, and GVAX® is entering Phase III trials in order to carefully determine its effectiveness. Results presented at a prostate cancer meeting in 2007 showed very impressive results, including significant drops in serum PSAs, when GVAX® was combined with anti-CTLA4 antibody6 (discussed next).

As with all trials of cancer immunotherapies and cancer vaccines, the patients who will be treated as part of these trials will have hormone-refractory (a.k.a. androgen-independent) metastatic prostate cancer.

anti-CTLA4 antibody

So we know now that antigen is the basis for all vaccines, and cancer vaccines as well, and that antigen is necessary to stimulate a lymphoid or lymphocytic response – the only response that can kill cancer cells in our bodies. If we can find and isolate the antigen that is contained in cancer and not in any other cells, we should be able to vaccinate against cancer. The problem is that very little in the way of such cancer- specific antigen has been found. So, as with the Provenge® studies, we must try and vaccinate against antigen that may be normal to us.

But remember, in addition to the lymphocytes that are designed to kill unwanted cells, it seems that we have a second set of lymphocytes (the regs) that are designed to protect the cells that we need the immune system to leave alone. It thus has occurred to cancer immunologists – “What if we knock down the regulatory lymphocytes?” By reducing the effect of the regs, and therefore the buffer against the destructive lymphocytes, perhaps the immune system will stop tolerating the cancer and will attack it outright.

Better yet, perhaps we should combine antigen-based vaccines with regulatory lymphocyte reducing therapy at the same time.

Several approaches are being developed to accomplish this latter part, the reduction of the regulatory lymphocytes. One approach is a monoclonal antibody against a molecule called CTLA4 or Cytotoxic T Lymphocyte Antigen 4)7. The antibody blocks this molecule on the regulatory lymphocyte that mediates tolerance, and thus can reduce the effect of regs.

Keep in mind that reducing the activity or number of regulatory lymphocytes can have drastic adverse effects, since the regs protect us from our own killer lymphocytes. In early studies, one anti-CTLA4 antibody (called MDX-010 or ipilimumab, from Medarex, Inc.) seemed to increase the effectiveness of an ovarian cancer vaccine, ostensibly by reducing the activity of regulatory cells. This same antibody has been used along with the GVAX® prostate vaccination, and positive results have been presented.

However some toxicities were also noted.

Because targeting regulatory lymphocytes seems to increase the effectiveness of cancer vaccines, you can expect to hear more about these agents in the future, as the combination strategies of these two treatment modes enter additional clinical trials.

Ontak®

Another means by which to decrease the regulatory immunity, and thereby increase the effectiveness of cancer vaccination therapy, is to directly kill these lymphocytes. A drug that has shown early promise in this regard is Ontak® (denileukin diftitox, Eisai Pharma). Ontak®8 takes advantage of a receptor on the surface of reg cells by sending a specific molecule to this receptor. Attached to this molecule is a fragment of diphtheria toxin (a kind of toxic substance created by the diphtheria bacterium). Once the molecule reaches the regulatory lymphocyte, it attaches to the surface and thereby delivers its toxic payload.

Therefore, this approach seeks to reduce the number of regulatory cells (as opposed to anti-CTLA4, which merely blocks their activity). Ontak® has shown very promising results in animals, and is being used in humans for regulatory lymphocyte depletion in metastatic ovarian cancer, renal cancer, and melanoma.

Since Ontak® has already been approved for certain cancers of lymphocytes (known as lymphomas), it may be slower to be deployed as a combination therapy with cancer vaccines under study. However, as with the anti-CTLA4 antibodies above, you can expect to hear more about this approach in the next few years.

Low-Dose Cyclophosphamide

Interestingly, it has been noted for several years that a long-standing chemotherapy drug, cyclophosphamide (Cytoxan®), can also measurably reduce the number of regulatory lymphocytes in animals and humans9. However, this depletion of regulatory cells only occurs at very low doses of the drug. At higher doses, cyclophosphamide (Cy) can decrease the number of all lymphocytes, including those that might potentially participate in eradicating cancer.

 

The reason that low-dose Cy can selectively kill off regulatory cells is not known. Full-dose Cy has been used for decades to treat lymphomas, and for some reason it seems that when the dose is reduced, the regulatory cells remain susceptible to the drug while the other lymphocytes do not. The idea that Cy can be used in this way has been suggested for some twenty years, but only recently has the research community become interested in the approach. This is largely due to the fact that regulatory, or “suppressive” lymphocytes – once considered phantoms unsupported by scientific research – have become demonstrated as important modulators of immune activity. The perceived need to reduce the activity or numbers of these cells has, to some extent, brought this role of Cy back into research contexts, and it is widely studied currently for this purpose.

Leukine® (GM-CSF)

Leukine® is a human injectable form of the immune molecule granulocyte-macrophage colony stimulating factor. GM-CSF has long been known to be an important cytokine (a chemical messenger among immune cells), and Immunex Corporation (now Amgen) first manufactured it for use in bone marrow transplantation in the early 1990s.

GM-CSF is a very potent stimulant to bone marrow, especially to the white blood cells of bone marrow origin, or myeloid cells. As such, it is a very non-specific immune treatment; the myeloid cells mentioned earlier, including neutrophils, monocytes, macrophages, and dendritic cells, all increase greatly in number following injection with Leukine®. In theory, a greater number of these cells in circulation and in body tissues may increase antigen presentation to the lymphoid system, or there may be direct action by myeloid cells against cancer.

Although the mechanism of its effects is not known, one published series from the University of California San Francisco, describes 29 patients with biochemical (PSA-only) relapse of their prostate cancers were treated by Leukine® therapy alone. Seven of these patients (24%) were free of prostate cancer progression at five years, suggesting that Leukine® therapy may have a role in these patients10.

Unlike many of the topics described to this point, the patients in this study were non-metastatic, androgen-sensitive patients whose only sign of disease relapse following treatment was a rising PSA. And cytokine therapy, while a form of immunotherapy, does not represent a vaccine strategy nor is it as “active” as those described above. However, the availability in recent years of cytokines for human treatment, such as GM-CSF, interleukin-2, and others, has led to their study in cancer patients.

Combination Therapy

There has been some interest of late in combining vaccine therapies with other currently used treatments for cancer. As previously mentioned, many current investigators are of a mind that some sort of regulatory lymphocyte-defeating strategy will need to be combined with cancer vaccine therapy in order to see the kinds of clinical responses desired.

In keeping with the “personalized” vaccine therapy, and the use of cancer antigen highly specific to the individual cancer, several ongoing studies seek to use cancer material from the patient in order to design the vaccine. Examples of this approach are most numerous in studies where cancers are surgically removed from patients; they are then processed for, or stripped of, the antigen that resides in the cancer. This antigenic material can then be loaded into dendritic cells, or other antigen presenting cells, and given back to the patient with the aim of generating a specific, lymphocyte-based response against the cancer remaining in the patient – or against cancer that might re-grow following the surgery.

It is also thought that cytotoxic, or cell-killing, treatments such as chemotherapy and radiation might also cause a cancer to become disrupted in such a way that the injection of immune cells – such as antigen-presenting cells – into the damaged cancer might provoke the all-important lymphoid response. Also, by destroying some of the cancerous mass, these therapies can decrease the amount of cancer that the immune system must deal with.

Bostwick Therapeutics is planning to begin a study in 2008 which combines cryotherapy of cancerous tissue with the injection into the cryo-damaged tumor of a patient’s own dendritic cells. When the cancer is frozen and thawed, the antigen that is contained in the cancerous cells is released and therefore available to dendritic cells injected into the site. This treatment will be combined with regulatory lymphocyte depletion as well, with the objective of “tilting” the balance of the immune system against the cancer, using the antigen from the cancer as it exists in the host as the vaccine.

Editor’s note: see “Cancer Cryo-Immunotherapy”, from Insights February 2006

Conclusion

The key to developing the kinds of immunotherapies capable of attacking aggressive, metastatic prostate cancers will likely require well thought out combinations that stimulate the patient’s own immune system to launch volleys of lymphocytes against the cancer, while carefully reducing the immune system’s tendency to protect the body’s tissues – including the cancer – against such immune attacks.

Each year sees an increasing number of scientific studies in both animals and humans that suggest successful immunotherapy of cancer is somewhere on the horizon. The attractiveness of active immunotherapy of cancer lies in the extraordinary precision practiced by adaptive, or lymphocytic, immune system. Where a scalpel can remove a tumor with the millimeter precision of the blade and skill of the surgeon, and a radiation treatment can treat cancer with a centimeter margin of damage to normal tissue, these kinds of immunotherapies may be able to eradicate a cancer cell living right next to a normal cell.

Thus, the promise is not only in a therapy that can address disease spread metastatically through the body, but one that can spare patients the aggregate injury and toxicity of the multiple, current cancer treatments usually endured by patients with advanced disease. The field is moving quickly and with a great sense of purpose in this direction. We can all hope this determination and effort will yield the kind of results that are desperately needed in the very near future.

References

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3. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nature Reviews. Immunology 2006;6:295-307.

4. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. Journal of Clinical Oncology 2006;24:3089-3094.

5. Small EJ, Sacks N, Nemunaitis J, et al. Granulocyte macrophage colony-stimulating factor–secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer. Clinical Cancer Research 2007;13:3883-3891.

6. Gerritsen W, Van Den Eertwegh AJ, De Gruijl TD, et al. A dose-escalation trial of GM-CSF-gene transduced allogeneic prostate cancer cellular immunotherapy in combination with fully human anti-CTL4 antibody (MDX-010, ipiluminab) in patients with metastatic hormone-refractory prostate cancer (MHRPC). ASCO 2007 Prostate Cancer Symposium. Abstract #262. Orlando, FL; 2007.

7. Peggs KS, Quezada SA, Korman AJ, et al. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Current Opinion in Immunology 2006;18:206-213.

8. Dannull J, Su Z, Rizzieri D, et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. Journal of Clinical Investigation 2005;115:3623-3633.

9. Ghiringhelli F, Menard C, Puig PE, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunology, Immunotherapy 2007;56:641-648.

10. Rini BI, Fong L, Weinberg V, et al. Clinical and immunological characteristics of patients with serologic progression of prostate cancer achieving long-term disease control with granulocyte-macrophage colony-stimulating factor. Journal of Urology 2006;175:2087-2091.