(c. 2007)
Introduction
Most “high-tech” medicines are not the life-savers they are believed to be. The advent of modern sanitation, especially toilets and clean water, has saved more lives than all medicines combined. As a designer of new drugs this statement dismays me, but its accuracy cannot be questioned.
Among modern medicines, vaccines and antibiotics have undoubtedly saved the most lives. These agents have been so successful because they boost or assist natural defense mechanisms rather than attempting to supplant them.
Virtually any disease defense system designed by Nature, with more than 150 million years of practice, must be intrinsically more effective than so-called “rationally designed” drug, whose discovery is based on the current state of understanding of biology. The selection system for achieving the very best defense system is harsh; a high price is paid for coming in second. Nature’s grading scale rewards a few A+ students with survival, and punishes those receiving lower marks with death or extinction.
Mother Nature’s grading scale rewards the most adaptable mechanisms with survival, and punishes the rest with death or extinction.
Arguments that we can substantially improve on nature, regardless of whether it’s the handiwork of God or of evolution, defies common sense. Even the remarkable products of animal husbandry, plant genetics, and transgenics derive from manipulation of genetic materials already present in nature.
Paradoxically, even the recognized miracle drugs, antibiotics and vaccines, do not cure bacterial or viral diseases. Antibiotics merely hold the microbial invaders at bay until the host’s own defenses can clear the infection. This mechanism holds for most, but not all infectious diseases. Drug cocktails have transformed AIDS, for example, from a universally fatal infection into a chronic, manageable disease. But AIDS is incurable – not due to any shortcoming of AIDs drugs, but because the human body never evolved a home-grown mechanism for curing the disease.
Similarly, vaccines enhance natural immunity by stimulating the host’s normal defenses in anticipation of meeting a microbial or viral invader. Vaccines have little effect, if any, once the host is infected. One can gauge the potential success of a proposed vaccine treatment simply by testing whether the host can mount an immune response, even a weak one, on its own.
A great deal of time and effort have gone into creating an AIDS vaccine. One need not be a world-class immunologist or virologist to predict the probable success in creating such a vaccine. Instead, one only needs ask one or two questions. The first question to ask is, “Can HIV-positive individuals survive infection (presumably as a result of developing natural immunity)?” The answer is “No!” since humans have not yet evolved immune mechanisms capable of significantly altering the course of HIV infection. So what are the chances of developing an AIDS vaccine? Not zero, but most likely quite poor. The human immune system, developed over 150 million-plus years of evolution, is far more effective than our feeble attempts at creating drug-induced immunity. It is more likely that HIV will evolve into a less deadly form than that our immune systems will develop a means for countering this catastrophic infection.
Our approaches to treating cancer directly defy the rationales underlying the effectiveness of vaccines and antibiotics. This may explain the relative lack of success in effecting long-term remissions and cures through conventional cancer therapies, principally chemotherapy and radiation. And it clearly explains, at least in part, the severe side effects resulting from conventional cancer treatments.
Chemotherapy remains primarily a regimen of administering highly toxic agents targeted toward cancer cells’ reproductive mechanisms. An unfortunate side effect almost always is damage to the cells’ genetic material. Chemotherapy agents are among the most potent mutagens, and carcinogens known, so even if these agents clear the disease, a long-term consequence may be a new cancer induced by the treatment itself.
It’s a long, boring flight between London and Charlotte, NC. Normally I try to read, write, or watch whatever movies are available on the plane. On a recent flight I ran out of material to keep me entertained and picked up my neighbor’s Time Magazine. Thumbing through, I noticed the obituary section and a prominently displayed entry on the passing of a world-class viral pathologist who had trained me. Among the greatest lessons I learned from him were to value scientific integrity and to place scientific data above political or economic pressure. The obituary described my mentor’s death from cancer. With tears streaming down my face, I returned the magazine to the man in the next seat. By the time I landed, many calls were awaiting me from virologists and immunologists locate all over the world. When I answered one, he said, “We knew you would want to be at the funeral but we couldn’t find you.” “London.” was all I said, before asking, “What happened?” The answer was that a new cancer had developed as a result of cancer therapy he had received 30 years prior to defeat colon cancer. The new cancer was so virulent that nothing could stop it. It was so bizarre that the pathologists were puzzled as to what exactly it was and what its origins were. So he really hadn’t completely defeated his initial cancer, but was quite lucky that he had 30 years before the new cancer developed due to the treatments he received.
I would argue that the effects of toxic, carcinogenic cancer treatments might do more damage to anti-cancer defenses than to the cancer itself. Any high-affinity immune cell clone, when it recognizes its target, becomes highly activated, which makes it highly susceptible to death by radiation or chemotherapy. In many cases, immune system mechanisms are affected more than the tumor itself, and often the cancer-fighting clones become fully depleted and never return. Therefore, the first casualty of toxic cancer drugs may very well be the defenses that have been evolving for millions of years to fight cancer.
Furthermore, relatively ineffective chemotherapies and radiation are more likely to train the immune system to tolerate the cancer (similar to low-dose tolerance therapy used to treat allergies), as opposed to stimulating a full-scale attack on it. We commonly treat cancer with systemic doses of chemotherapy or fractionated doses of radiation. While almost immediate ablation of the anti-tumor defenses is likely to occur, tumors generally shrink slowly over time. The immune system responds in direct proportion to the strength of a threat. Thus, to maximize their effectiveness, killed-virus vaccines usually contain an adjuvant designed to stimulate a robust immune response, usually through limited tissue damage. Absent this tissue insult, the immune system may simply ignore a vaccine antigen. Similarly, the immune system may not be prompted to attack slowly-shrinking tumors, and in the worst case may be coaxed into leaving the tumor alone.
To become safer and more effective, cancer therapies need to engage the natural anti-cancer defenses instead of destroying them. As radical as it may sound, we need treat cancer like an infectious disease.
As radical as it may sound, we need treat cancer like an infectious disease.
While the etiology of many cancers remains unknown, more and more appear to have a link to infectious agents. We know that certain viruses can transform cells to a cancerous state. Hepatitis B virus is associated with liver cancer; human T-cell leukemia virus is known to cause human leukemia, papilloma viruses are associated with nasopharyngeal and cervical carcinomas. There is evidence that both prostate and breast cancers may be caused by viruses as well. One wonders how many other serious cancers possess a link to viruses (or even bacteria). The recently approved vaccine against human papilloma virus, believed to be the causative agent in cervical cancer, may serve as a model for the state of tomorrow’s cancer prevention strategies.
It will be interesting to observe whether the incidence of prostate cancer in men declines as the use of the papilloma virus vaccine becomes prevalent. While no virus has yet been associated with prostate cancer, researchers have not identified any relevant genetic aberration that explains this disease affecting almost 220,000 men annually in the U.S.
How to Engage the Immune System
One way to stimulate natural anti-cancer defenses is to kill the tumor rapidly, thereby stimulating the immune system via the destruction of tissue. A simple way to do this is to treat the tumor by intralesional injection of a suitable anti-tumor agent. However, such drugs must possess high specificity for tumors. Previous attempts to ablate tumors directly using standard chemotherapy agents have been unsuccessful because these drugs show little or no preference for tumors over normal tissues. Intralesional injection with such agents produces the same toxic damage to natural anti-cancer immunity as occurs with systemic treatment.
A second way to engage the immune system is to present antigens to the cells responsible for selecting the best antigens, which then present these antigens to high-affinity clones of both effector cells and cells that function as “Concert Masters” by maintaining immunologic memory (a mixed populace of cells so named based on their common function as orchestrators of the immune system). Photodynamic anti-cancer agents are superior in delivering antigens to antigen presenting cells (APCs), allowing these cells to process the antigens, select appropriate targets, present selected antigens to immune system cells with high affinity for the targets, and stimulate cancer-killing cells to replicate .In other words, they are allowed to do the job for which nature prepared them.
Finally, tumor antigens must be viewed in context. Physical ablative techniques, such as heating or freezing tissue, are likely to destroy fragile antigens and disrupt their relevant contextual structures. Disruption of cell membranes and removal of lipids, proteins, and complex carbohydrates destroys the antigens’ context, which is what immune system cells respond to. Thermal destruction may also denature potential antigens, changing their chemical structure so that they are no longer representative of the tumor cell. In order to work, rapid destruction of tumors must preserve antigenic structure and biological context.
Clinical-stage cancer vaccines based on antigen presentation are likely to fail for many of the reasons given above. The antigen chosen by drug developers is very likely not the best one, or the only one, that the immune system would choose on its own. Further, only one antigen has been selected whereas natural presentation of a potpourri of cellular antigens allows the selection of multiple targets, perhaps on an individual basis, and their subsequent presentation to high affinity T and B cells. Finally, generating the response in vitro, compared with normal antigen-presenting mechanisms, hinders the ability to generate an effective immune response.
The cancer antigen approach suffers from a complete loss of contextual presentation of the tumor targets. When I was first taught immunology, the prevailing dogma held that there was never an anti-self response. However, this is now known to be incorrect. In addition to targeting “foreign” threats such as bacterial infections, the immune system targets things it recognizes as “altered-self.” The immune system can be thought of has having a very highly specific and nearly perfect “picture” of what “self” looks like. Anything different is subject to attack. Therefore, generating the optimal anti-tumor response through a target antigen requires cells to experience the antigen in vivo, in its natural conformation and context.
While we have learned many things about how the immune system works, much still remains a “black box.” We know what goes into the box, and can quantify outputs, but we are clueless of the intervening mechanisms, particularly how to harness the natural immune response for treating cancer.
Another technique currently under development for enhancing anti-tumor response entails harvesting high-affinity immune cells which are stimulated and amplified in vitro. For example, white cells exhibiting tumor antigen are harvested, stimulated by chemokines, then re-introduced into the patient. Killed tumor antigens may also be delivered to the patient in the form of a “vaccine” which in theory should help generate a maximum immune response.
This approach, while more ingenious and practical than the cell-based treatment, still suffers in that the response generated in vitro may not fully mimic that produced in vivo.
The last liability of current anti-tumor immunotherapies is their novelty, which often relegates them to last-ditch rescue therapy after surgery, radiation and chemotherapy cease to provide a response. By this time, the patient’s natural immune response may have been completely destroyed. Additionally, late-stage patients generally have very high tumor loads, making cancer eradication that much more difficult. Thus, stimulating a patient’s innate anti-tumor defenses should have a much better chance of working before conventional therapies are employed.
Anti-tumor immunotherapies are often relegated to last-ditch rescue therapy after surgery, radiation and chemotherapy cease to provide a response. By this time, the patient’s natural immune response may have been completely destroyed. Stimulating a patient’s innate anti-tumor defenses should have a much better chance of working before conventional therapies are employed.
How to Generate a Practical Anti-tumor Response
Recently PV-10 (Provecta™), a small-molecule agent, was shown by Provectus Pharmaceuticals to have an almost absolute specificity for tumor cells. PV-10 partitions into the hydrophobic membranes of cancer cells but does not penetrate the cell membranes of normal cells. Figure 1a illustrates the penetrating ability of PV-10 in tumors, while figure Fig. 1b shows a more typical agent with comparable affinity for normal and diseased cells. PV-10 was diluted for this demonstration because at therapeutic concentrations all tumors in the mice would be completely destroyed within 24 hours post injection (Table 1
-- No Table Available).
Subsequent light activation of the control agent, a green photodynamic dye, failed to cure any mice, only partially damaging the tumors while inflicting significant damage on normal tissue. In contrast, mice treated with PV-10 (with or without light) were all cured of their tumors and sustained no damage to healthy tissue or other side effects.
PV-10 has a high affinity for the highly fluid lysosomal membranes of cancer cells and the very low pH (pH-4.0) of the intra-lysosomal environment. Once trapped in this membrane, PV-10 causes the lysosomes to leak or rupture. The cancer cell is quickly destroyed from within by autophagy as the lysosomal hydrolases are released into the cytosol of the cell. Hersey and coworkers described this process, in a landmark paper in (
Not Available) as possibly a new pathway of chemo-induced apoptosis, through which cancer cells destroy themselves. PV-10 therefore fulfills the criteria for an anti-cancer agent in having almost absolute specificity for tumor tissue, with very rapid clearance from normal tissue. PV-10 shows a half-life after iv injection of 7 hours, but has been detected in significant quantities intratumorally days after intralesional delivery (unpublished data).
Generation of Anti-tumoral Response by PV-10
Table 2 (
No Table Available) shows data for immunocompetent mice cured of melanoma tumors by intralesional delivery of PV-10. When challenged 6 months later with transplanted cancer cells, these animals fail to develop tumors. Immunodeficient mice, by contrast, are cured of their initial tumor but fail to develop this protective anti-tumor response. Similarly, mice treated for melanoma by PV-10 treatment, when challenged with an MHC-matched renal adenocarcinoma, develop intradermal tumors produced by these unrelated cancers. Therefore, intralesional treatment with PV-10 produces a highly effective and specific response remarkably similar to that of a vaccine. Furthermore, in immunocompetent mice, tumor removal by intralesional PV-10 can result in remission of distant untreated tumors (called the “bystander effect”) whereas no similar effect occurs in immunodeficient mice.
Recently completed Phase 1 clinical trials have highlighted the safety and efficacy of PV-10 in patients with Stage III-IV metastatic melanoma. Besides being highly effective against the injected tumors (successful treatment being defined as stable disease, partial regresssion, or complete disappearance of treated lesions), many study participants also exhibited the bystander effect in untreated tumors (Data to be published). PV-10’s high level of effectiveness against melanoma is in stark contrast to that of approved agents and other new experimental treatments (such as anti-melanoma monoclonal antibodies).
*****
The effectiveness of PV-10 in early human trials is likely a product of its fulfilling the criteria postulated here for effectively engaging the host’s highly evolved immune defenses. PV-10 targets only tumor cells and can generate a long-lasting protective response in immunocompetent animals while failing to do so when the host’s anti-tumor immunity is compromised. PV-10 stimulates anti-tumor defenses in vivo and allows the natural systems to choose the best antigens that generate the most effective response.
With more than one hundred million years of practice, Nature knows best how to fight cancer. PV-10 appears to activate natural immunologic defenses, which in most cases represent the only real chance to beat cancer.
Surgery is the first line of defense when early stage cancer first strikes, while therapies and treatments and repetitions and combinations of them are fall back positions as cancer progresses and recurs towards its later stages.
