Immunotherapy is Slowly Gaining Ground
In Conventional Cancer Treatment
June 14th, 2015 by Holly Cornish
The outlook for Vicky looked bleak. The malignant melanoma had spread to her lungs and she wasn’t expected to live more than six months.
But Vicky was lucky. She was offered the chance to take part in a major international trial to test the effectiveness of several new drugs.
Just weeks after she started taking the medications, the lump at the base of her neck disappeared, the two to three centimeter lung tumors vanished. Today she is no longer on any medication. She has remained clear of cancer for more than a year.
Oncologists are very enthusiastic about this new form of cancer therapy. . .
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It’s called immunotherapy.
In a recent medical journal the authors write, “It is not a question of ‘if’ but for many cancers ‘when’ immunotherapy will be the main treatment modality.”
The idea of utilizing the body’s own immune system to overcome cancer is not new. In fact it goes back to ancient Egyptian times, when swellings and tumors were wrapped in moist salves with open incisions to induce infections at the site. The theory was also put into practice in the 18th and 19th centuries.
But it wasn’t until the late 19th century when someone focused on the idea as an important therapy. His name was William Coley, a New York surgeon. Arguably he’s one of the most important figures in the history of cancer treatment.
Dr. Coley induced severe bacterial infections in cancer patients with the aim of revving up their immune systems to fight the tumor. The infectious agents would generate a fever that cancer cells often could not survive.
Although the records of 894 cases he treated were impressive, Coley’s toxins gradually fell into disuse after his death in 1936.
Cancer is not foreign to the body, or is it?
One of the problems conventional oncologists had with focusing on the immune system was that since it sees the cancer as ‘self’ — not foreign to the body –it won’t attack it. They believed that the inability of the immune system to recognize and attack cancer tumors was inherent and could not be fixed.
A major breakthrough came about when it was discovered that proteins on the cancer cell’s surface can be differentiated from normal cells. If immune cells could identify these proteins, they could target them.
With this and other discoveries, immunotherapy became a very popular research topic for a time, but it was undermined by repeated failures. For instance, one of three main types of immunotherapy called “nonspecific,” which activates the immune system as a whole, did not meet with great success.
Because it failed to live up to its promise, immunotherapy fell out of favor and there was little interest in researching further.
Then along came Dr James Allison of the University of California, Berkeley.
Dr Allison focused on another main type of immunotherapy that makes use of monoclonal antibodies.
Antibodies defend against substances called antigens that provoke an immune response. Virtually anything can be an antigen. Pollen is a familiar example.
Antibodies are able to latch on to specific proteins on the outside of the invading cell to stop it from functioning, trigger a chemical response to shut it down, or signal other immune cells to kill it.
In the late 1970s Dr Allison identified a receptor on a T cell (an antibody-producing immune cell that is the body’s “first responder” to cancer) that is able to recognize the proteins on a cancer cell. Because of this receptor’s ability to identify cancer cells, it became possible to create single man-made antibodies in the laboratory that can attach to the specific cancer protein.
His next discovery was a support molecule – a co-stimulatory receptor called CD28 – that activates the T cell to actually go on the attack.
Dr Allison had found the ‘on your marks’ and ‘get set’ part of the puzzle but the ‘go’ won’t take place as long as the immune system thinks it is attacking its own body.
It wasn’t until 2005 that Allison made his major groundbreaking discovery.
He found that a surface marker on the T cell called cytotoxic T-lymphocyte antigen-4 (CTLA-4) is what puts the brakes on, stopping the antigens that would otherwise attack the body’s own tissues. Allison then created an antibody to shut off CTLA-4. His drug, ipilimumab (Yervoy) is the first to do this. T cells now had the ‘go’ which allowed them to attack cancer cells.
Since then, another receptor called PD-1 has been found on activated T cells which downregulates the immune system.
Since this is a receptor not just on T cells but also on another aspect of the immune system — B lymphocytes — it makes for a more powerful and widespread attack.
The PD-1 signal-blocking antibody drug called nivolumab (Opdivo) plus Yervoy were combined in a study of 53 late-stage melanoma patients.
One-year survival was 85% and two-year survival was 79%. These are impressive results.
According to Mario Sznol, M.D., lead study author and Professor of Medical Oncology at Yale School of Medicine, “Concurrent therapy with nivolumab and ipilimumab results in what I believe to be an unprecedented 2-year survival.”
Opdivo is FDA-approved for metastatic melanoma and lung cancer. Yervoy is approved for metastatic melanoma only.
Cancer treatment vaccines
The third main type of conventional immunotherapy removes the patient’s white blood cells from the body and loads them with an antigen or a substance derived from the patient’s tumor. These are then injected back into the patient to create a strong and targeted immune response to kill specific proteins on the cancer cell.
The type of immune cell most frequently employed for this purpose is called a dendritic cell. Cells of this type make up less than one percent of white blood cells, but they are able to stimulate other aspects of the immune system. They scan the environment to provide T cells with an early warning system for potential threats.
When the vaccine is given to the patient, the new, loaded dendritic cells make their way to the patient’s lymph nodes. Once that happens, the T cells and other immune cells know exactly what to look for. They can seek out and attack the tumor. For a more complete description of dendritic cell vaccines, see Issue #414.
This is an individualized treatment. Each vaccine is uniquely cultured for each patient. A few alternative cancer clinics have been using dendritic cell vaccines for years, reportedly with some success. They use it in conjunction with other alternative treatments. It’s not a standalone “magic bullet.”
In conventional medicine, the only FDA-approved dendritic-cell drug at this time is Provenge for the prostate. The approved drug extended life in those with metastatic prostate cancer by an average of 4.1 months in the study that led to its approval.
However some have criticized this study and do not believe there is enough evidence to support it.
In the U.K., in February, 2015, the National Health Service was unable to approve its use because it was not considered to be an improvement on existing procedures and was not proven to delay the development of the disease. I would agree that a 4.1-month extension in life is not impressive.
In a recent paper, medical oncologist Gerald Linette, M.D., Ph.D., together with Beatriz Carreno, Ph.D., wrote that “Dendritic cell based anticancer vaccines have yielded disappointing results in a multitude of clinical trials.”
Personalized genetic targeting
In their own research with dendritic cells, Linette and Carreno take immunotherapy one step further. They not only remove and reinfuse dendritic cells, but also target specific gene mutations within the patient’s tumor.
In a small trial with seven stage 4 melanoma patients, six had a positive T cell response, in three the tumor shrunk significantly, one went into complete remission and after five years another had minimal disease.
Dr Linette said, “In principle, we are creating a personalized vaccine based on the patient’s own cancer genome.”
A similar approach is being conducted by researchers led by Carl June, M.D. at the University of Pennsylvania.
Dr. June’s team removed a billion T cells from a patient suffering from chronic lymphocytic leukemia. They gave the cells new genes and then returned them to the patient. Two weeks later there was no trace of the disease. Two pounds of cancer cells had just disappeared. A year later the patient was still in complete remission.
A larger study by the same group included five adults and 25 children with leukemia. It concludes: “The complete remission rate of 90% and sustained remissions of up to 2 years that were seen in this study are encouraging.”
Vicky is melanoma free today, but she was fortunate. She reacted so badly to Opdivo and Yervoy that they were stopped after only a few doses. It was her good fortune that the drugs destroyed the cancer very early into the procedure.
Immunotherapy can come with some serious side effects. The high stimulation of T cells can sometimes cause them to attack the liver, the gut and other body systems.
Dr. Steven Rosenberg at the National Cancer Institute articulated a major hurdle: “It’s the search for targets expressed by the cancer and not the normal tissue that represents a major obstacle to progress.”
Although this is one of many challenges to overcome, immunotherapy is an important advance and will be increasingly utilized by conventional oncologists. It could well become the main treatment modality for some cancers, but that is not likely to occur for many years into the future.
Hard to believe that for two issues in a row we’ve had articles about conventional oncology making moves in an alternative direction – but we did. And the treatment covered in our last issue is much more promising than the stumbling moves in immunotherapy I just described. If you missed our article on Novocure, you can scroll down and read it right now.