A new ally against cancer / Eric von Hoff

The US Food and Drug Administration recently approved the first therapeutic component against cancer, and these days other drugs that mobilize the immune system against tumors are being studied

For decades, cancer experts have been offering cancer patients three main types of treatment: surgery, chemotherapy, and radiation. Some of the people who have recovered refer to this difficult trinity as "shredding, poisoning, and burning."

Over the years, these blunt treatment methods have been refined, and the more serious side effects have become tolerable. At the same time, the effectiveness of treatments increased greatly, and new highly targeted drugs (Herceptin and Gleevec) were developed to treat several types of cancer. Overall, the five-year survival rate for invasive cancer has increased from 50% to 66% over the past 30 or so years. Despite this progress, many cancer patients will not have a normal life expectancy.

For many years, researchers thought of a way that might significantly increase the survival rate without causing serious side effects, if only they could figure out how to make the patient's own immune system fight the malignant cells better. But decades of efforts ended in bitter failures. In the 80s of the 20th century, for example, excessive hopes were raised that a molecule of the immune system called interferon would stimulate the body's systems so that they would succeed in eradicating most types of cancer, or even all of them. These hopes were dashed after a few years of research.

Today, interferon plays a role in the treatment of cancer patients, but it is not the miracle cure they were hoping for. Until the last decade, clinical trials tested many different types of vaccine-related approaches to treat cancer, but nothing worked. The feeling was that the vision of the general weapon, which everyone expected would work against a wide variety of crops, would never materialize.

Indeed it has not yet happened. But in the summer of 2010, something happened to suggest that the era of failed starts and dead ends in the effort to stimulate the immune system may finally be coming to an end: the US Food and Drug Administration approved the first compound to treat cancer. The treatment, known as Provenge, is not a cure, but when combined with standard chemotherapy it has already given several months of life to hundreds of men with advanced stages of prostate cancer.

This positive turn occurred after scientists re-examined some basic assumptions about the way the immune system attacks cancer cells and about the way the cancerous tumors fight back. Today, cancer researchers are expressing cautious optimism about the prospect of developing additional specific treatments that will stimulate the immune system, will be used as a routine treatment alongside surgery, chemotherapy and radiation to suppress the cancer and will weaken the side effects associated with them until they are not as severe as a bad cold.

A new ally

Many of us focus on ingredients for cancer treatment. Unlike the familiar ingredients, which prevent infection in the first place that can cause brain damage (measles), paralysis (polio) or liver cancer (hepatitis B), a cancer treatment ingredient teaches the body to recognize and destroy cancer cells that are already present in the tissues and continue to kill these malignant cells for a long time after the end of the treatment.

But developing such components is more difficult than one might imagine. Most of the preventive components induce a simple antibody response, which is usually sufficient to protect against a wide variety of infections. The antibodies simply stick to the flu viruses, for example, and prevent them from infecting cells. But in general, an antibody response is not strong enough to kill cancer cells. To achieve this goal, the immune system must stimulate a group of cells called T cells.

There are two main types of T cells in the body. Scientists usually distinguish between them based on unique proteins, called receptors, such as the CD4 and CD8 receptors, located on the cell membrane. T cells that excel at destroying cancer cells - assuming they recognize the cancer cells as dangerous - are those that display CD8 receptors on the cell membrane. (That's why these T cells are called CD8+ cells)

Despite these complexities, developing a compound for cancer is not a new idea. In the late 19th century, many years before anyone had heard of CD8+ cells, William B. Cooley began
injecting cancer patients with a substance called, in the end, "Coley's toxin". Cooley, who was an orthopedic surgeon at what is now known as Memorial Sloan-Kettering Cancer Center in New York City, was intrigued by reports of cancer patients who were cured of their disease, apparently after a brief bout of a life-threatening infectious disease. In an effort to simulate the infection without endangering the patients' lives, Cooley prepared a mixture of two deadly strains of bacteria. He gently heated the preparation, and thus the bacteria were killed and rendered harmless. But the bacterial proteins remained in the solution and caused a significant increase in the body temperature of the patients.

High heat hair sonics can activate the suppressed immune system of the patients and make it recognize and attack the abnormal tumors in their body. He extended the duration of the artificial heat of his patients by daily injections of increasing concentrations of dead bacteria. Amazingly, the survival of cancer patients who received the toxin was longer than that of untreated patients. Cooley claimed, and with some justification, that his toxin was used as a kind of compound against cancer.

In the 50s, doctors began to get more consistent results with chemotherapy. The dose of Coley's toxin decreased, and the very idea of ​​a compound as a cancer treatment faded away.

But the study of the immune system and its possible role in cancer continued to progress. Researchers have gradually found evidence to support the idea first proposed by Paul Ehrlich in 1909, that the immune system constantly scans for and destroys cancer cells as soon as they are formed. The immune surveillance theory gained further support in the 80s, when researchers calculated and found that the high level of spontaneous mutations that appeared in the human cells they tested should have caused many more cancers than observed. Somehow the body found and permanently destroyed many cancer cells on its own.

Even after a random tumor manages to escape extinction, the evidence shows that the immune system continues to fight, though not as effectively. Pathologists have long noticed that cancerous tumors often contain cells of the immune system, and this finding underlies the notion that tumors are "wounds that do not heal." In addition to this, experiments have shown that as the tumor develops, it releases more and more substances that actively suppress T cells. The question is therefore how to design vaccines against cancer that will be able to tip the scales in favor of the T cells and allow them to destroy the tumor.

An answer to this began to emerge in 2002, when a group of scientists at the American Cancer Institute (NCI) showed that another type of T cell, known as the CD4+ cell, serves as an essential component of an effective response against cancer. CD4+ cells are like the commanders of the immune system: they decide for the common soldiers, in this scenario CD8+ cells, who and what to attack and eliminate. The team from NCI, led by Steven Rosenberg, took T cells from 13 patients who had advanced melanoma and whose tumors had metastasized, meaning spread throughout their bodies. The researchers activated these T cells and made them attack melanoma cells in vitro. Then the scientists grew large quantities of the activated cells and infused them back into the patients' bodies. This approach of the NCI group is called adoptive immunotherapy, and it is actually a kind of self-implantation of immune cells (artificially modified outside the body).

Therefore, it is not a component that causes the immune system to produce immune cells within the body that focus on a specific target.

Previous cellular immunotherapy treatments, which used only CD8+ cells, were ineffective. But when the NCI group added CD4+ cells to the mix, the results were amazing. Tumors shrunk dramatically in six subjects, and blood tests in two of the six showed that they were producing their own cancer-fighting immune cells even nine months after the treatment ended. The treatment caused flu-like symptoms in the subjects, and four of them also suffered from a complex autoimmune reaction that caused a loss of pigment in parts of their skin.

The results of the research from NCI were a convincing proof of principle that it is possible to induce a T-cell-based immune response that is precise enough to destroy tumors. The number of immune cells cloned for each patient in this experiment is astounding: more than 70 billion CD8+ and CD4+ cells, which means a volume of several hundred milliliters. The scientific community now believes that cancer immunotherapy can be effective.

The next step will be to figure out how to achieve a similar result in a simpler way, that is, without extracting cells from the body, growing large amounts of them and then returning them. In other words, the body needs to be made to grow most of the additional cells it needs on its own, and this is exactly what happens in the body in response to an effective ingredient.

Many strategies

My colleagues and I at Antigen Express felt satisfied when Rosenberg's group showed that an effective anticancer compound had to activate both CD4+ and CD8+ cells. We also believed this based on animal experiments, and in fact the future of our company relies on this belief.

When developing a compound against cancer three aspects must be taken into account. The first is to decide exactly which molecular component, or antigen, in the malignant tumor will be recognized as foreign by the immune system and serve as a target for attack. The second is to decide how to present the stimulus (ie the compound) to the immune system to encourage it to attack cancer cells. And the third aspect is to decide which cancer patients to treat and when during their illness should be vaccinated.

In recent years, researchers in the biotechnology industry have considered many proteins and protein fragments (called peptides) as possible starting points for creating an immune response that will be strong enough to kill cancer cells. (Other possibilities for stimulating the system were, among others, the use of pieces of genetic material that code for cancer proteins, or even whole cancer cells that have been irradiated).

It turns out that the genetic changes that allow cancer cells to proliferate uncontrollably also cause them to produce certain proteins in far greater quantities than anywhere else in the body. About ten companies, including our company, chose a variety of such peptides to fulfill the first two requirements in the development of an anti-cancer compound: the selection of the starting point and the presentation mechanism to the immune system.

What makes the components based on peptides particularly tempting is that they are small protein fragments that are cheap to produce and very easy to change, meaning that they can easily be developed into a component that can be produced in large quantities. Furthermore, since the selected peptides appear in many people with different types of cancer, they can be used in compositions that will help many people without doctors having to prepare an individual composition for each person, as must be done in cellular immunotherapy methods.

Finally, all the peptide compounds tested so far cause relatively mild side effects, such as temporary irritation in the injection area and sometimes fever or flu-like symptoms.

Ten years ago, scientists at Antigen Express made some fundamental changes to a peptide that was used in an experimental formulation against breast cancer. The peptide, known as HER2, is also the target protein of Herceptin, a monoclonal antibody used in the treatment of certain types of breast cancer. Our researchers found that adding four amino acids to the peptide dramatically increased its ability to activate CD8+ and CD4+ cells against breast cancer cells that produce the HER2 protein. This finding was the innovative basis on which we bet in our company.

Preliminary findings published in early 2011 from an independent study comparing our improved HER2 component to two peptide components designed to activate only CD8+ cells indicate that we are on the right track.

Some companies, such as Dendreon, which makes Provenge, which was recently approved by the FDA, bet differently. Dendron and other companies are introducing unique targets for cancer cells directly to cells of the immune system called dendritic cells. These cells are scattered throughout the body, mainly in the tissues that come into contact with the outside world (such as the skin and the walls of the digestive system). These are the sentinels of the immune system, and are among the first to alert the T cells that something is not right.

But since the immune cells receive their orders from other immune cells that are genetically identical to them, it is necessary to extract the dendritic cells from each patient separately, load them with the proteins unique to cancer and then return them to the patient's body. The total cost of the process is approximately $93,000.

The side effects are, among others, chills, fever, headaches, and less frequently, stroke. But a short-term clinical study showed that people with advanced prostate cancer treated with Provenge lived an average of four months longer than people who did not receive the treatment.

next steps

The approval given by the FDA to Dendron's Provenge and the promising preliminary results of clinical tests conducted by other companies, including our company, indicate the beginning of a new era in the development of ingredients against cancer. But as scientists venture and advance in this promising journey, we find that we cannot use the metrics used to estimate the success of chemotherapy or radiation treatments.

With normal treatments, you can see a relatively fast improvement: within a few weeks, the tumors shrink, if it is a good result, or they do not shrink, if it is a bad result. But data obtained from several clinical tests indicate that after treatment with an anti-cancer compound, even a year may pass before the immune system really begins to affect the tumor.

This length of time is not surprising, because the immune system needs an arduous campaign of persuasion to attack cells that look remarkably similar to normal body cells, as opposed to a bacterium or virus.

Overcoming immune tolerance, that is, the reluctance of the immune system to attack cells originating from the body itself, is probably the biggest obstacle on the way to creating effective therapeutic compounds against cancer. Another surprise is that sometimes the tumors even grow following treatment with an anti-cancer compound. But an examination of the tumor tissues shows that this growth is the result of the invasion of immune system cells, and not of the culture of the cancer cells themselves.

The measured rate at which the immune system has so far reacted to the therapeutic components against cancer leads to two important intermediate conclusions. First, in the near term, anti-cancer compounds will probably be most effective for treating people in the early stages of the disease, if their tumors are not large enough to suppress the immune system, and if they have enough time to wait until a stronger immune response develops. And second, people with advanced stages of the disease will likely have to first undergo conventional treatments to shrink the tumors before receiving an anti-cancer compound.

A small tumor as a starting point or shrinking a larger tumor is essential because well-developed and old tumors suppress the immune system more efficiently and evade it better than small tumors do. They have more cells capable of releasing greater amounts of immune-suppressing chemicals and more types of these chemicals. Even a healthy immune system may not be able to deal with the amount of cancer cells found in advanced cancer patients.

Despite these obstacles and complexities, the direction is clear: it is possible to mobilize the patient's own immune system to fight cancer. This recognition is a tremendous shot of encouragement to researchers in academia and industry who continued and persevered despite the many failures. Previous clinical trials that were considered failures are re-examined to see if there were immune responses after all.

Indeed, one such test of a possible compound for prostate cancer, Prostvac, showed that although the compound failed to deliver the predetermined goal - stopping the growth of the tumor - it prolonged the survival of the subjects. It is understood that this finding was discovered after the small biotech company that developed Frostvac lost its life due to the failure of clinical trials. Fortunately, another company acquired the rights to develop the drug.

And as for the survivors in the industry, after years of disappointing results we've gotten used to looking beyond the obstacles and under-promising. But the evidence from research and clinical tests conducted over the past two years leads a growing number of researchers to believe that in the coming decade, therapeutic components against cancer will play an important role alongside surgery, chemotherapy and radiation and will serve as an effective treatment for some of the most common types of cancer affecting humanity.