Immunological Research: A multi-faceted approach to curing disease

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If you're considering monoclonal antibody therapy as part of your cancer treatment, learn about these drugs and carefully weigh the benefits against the potential side effects.

By Mayo Clinic staff

Monoclonal antibody drugs are a relatively new innovation in cancer treatment. While several monoclonal antibody drugs are available for treating certain cancers, the best way to use these new drugs isn't always clear.

If you and your doctor are considering using a monoclonal antibody as part of your cancer treatment, find out what to expect from this therapy. Together you and your doctor can decide whether a monoclonal antibody treatment may be right for you.

What is a monoclonal antibody?

A monoclonal antibody is a laboratory-produced molecule that's carefully engineered to attach to specific defects in your cancer cells. Monoclonal antibodies mimic the antibodies your body naturally produces as part of your immune system's response to germs, vaccines and other invaders.

How do monoclonal antibody drugs work?

When a monoclonal antibody attaches to a cancer cell, it can:

Make the cancer cell more visible to the immune system. The immune system attacks foreign invaders in your body, but it doesn't always recognize cancer cells as enemies. A monoclonal antibody can be directed to attach to certain parts of a cancer cell. In this way, the antibody marks the cancer cell and makes it easier for the immune system to find.

The monoclonal antibody drug rituximab (Rituxan) attaches to a specific protein (CD20) found only on B cells, one type of white blood cell. Certain types of lymphomas arise from these same B cells. When rituximab attaches to this protein on the B cells, it makes the cells more visible to the immune system, which can then attack. Rituximab lowers the number of B cells, including your healthy B cells, but your body produces new healthy B cells to replace these. The cancerous B cells are less likely to recur.

Block growth signals. Chemicals called growth factors attach to receptors on the surface of normal cells and cancer cells, signaling the cells to grow. Certain cancer cells make extra copies of the growth factor receptor. This makes them grow faster than the normal cells. Monoclonal antibodies can block these receptors and prevent the growth signal from getting through.

Cetuximab (Erbitux), a monoclonal antibody approved to treat colon cancer and head and neck cancers, attaches to receptors on cancer cells that accept a certain growth signal (epidermal growth factor). Cancer cells and some healthy cells rely on this signal to tell them to divide and multiply. Blocking this signal from reaching its target on the cancer cells may slow or stop the cancer from growing.

Stop new blood vessels from forming. Cancer cells rely on blood vessels to bring them the oxygen and nutrients they need to grow. To attract blood vessels, cancer cells send out growth signals. Monoclonal antibodies that block these growth signals may help prevent a tumor from developing a blood supply, so that it remains small. Or in the case of a tumor with an already-established network of blood vessels, blocking the growth signals could cause the blood vessels to die and the tumor to shrink.

The monoclonal antibody bevacizumab (Avastin) is approved to treat a number of cancers, not including breast cancer. Bevacizumab targets a growth signal called vascular endothelial growth factor (VEGF) that cancer cells send out to attract new blood vessels. Bevacizumab intercepts a tumor's VEGF signals and stops them from connecting with their targets.

Deliver radiation to cancer cells. By combining a radioactive particle with a monoclonal antibody, doctors can deliver radiation directly to the cancer cells. This way, most of the surrounding healthy cells aren't damaged. Radiation-linked monoclonal antibodies deliver a low level of radiation over a longer period of time, which researchers believe is as effective as the more conventional high-dose external beam radiation.

Ibritumomab (Zevalin), approved for non-Hodgkin's lymphoma, combines a monoclonal antibody with radioactive particles. The ibritumomab monoclonal antibody attaches to receptors on cancerous blood cells and delivers the radiation.

A number of monoclonal antibody drugs are available to treat various types of cancer. Clinical trials are studying monoclonal antibody drugs in treating nearly every type of cancer.

How are monoclonal antibody drugs used in cancer treatment?

Monoclonal antibodies are administered through a vein (intravenously). How often you undergo monoclonal antibody treatment depends on your cancer and what drug you're receiving. Some monoclonal antibody drugs may be used in combination with other treatments, such as chemotherapy and hormone therapy. Others are administered alone.

Monoclonal antibody drugs were initially used to treat advanced cancers that hadn't responded to chemotherapy or cancers that had returned despite treatment. However, because these treatments have proved to be effective, certain monoclonal antibody treatments are being used earlier in the course of the disease. For instance, rituximab can be used as an initial treatment in some types of non-Hodgkin's lymphoma, and trastuzumab (Herceptin) is used in the treatment of some forms of early breast cancer.

Many of the monoclonal antibody therapies are still considered experimental. For this reason, these treatments are usually reserved for advanced cancers that aren't responding to standard, proven treatments.

FDA-approved monoclonal antibodies for cancer treatment
Name of drug Type of cancer it treats

Alemtuzumab (Campath) Chronic lymphocytic leukemia
Bevacizumab (Avastin) Brain cancer
Colon cancer
Kidney cancer
Lung cancer

Cetuximab (Erbitux) Colon cancer
Head and neck cancers

Ibritumomab (Zevalin) Non-Hodgkin's lymphoma

Ofatumumab (Arzerra) Chronic lymphocytic leukemia
Panitumumab (Vectibix) Colon cancer

Rituximab (Rituxan) Chronic lymphocytic leukemia
Non-Hodgkin's lymphoma

Tositumomab (Bexxar) Non-Hodgkin's lymphoma

Trastuzumab (Herceptin) Breast cancer
Stomach cancer

Source: Food and Drug Administration (FDA), Center for Drug Evaluation and Research

What types of side effects do monoclonal antibody drugs cause?

In general, monoclonal antibody treatment carries fewer side effects than do traditional chemotherapy treatments. However, monoclonal antibody treatment for cancer may cause side effects, some of which, though rare, can be very serious. Talk to your doctor about what side effects are associated with the particular drug you're receiving.

Common side effects

In general, the more-common side effects caused by monoclonal antibody drugs include:

Allergic reactions, such as hives or itching
Flu-like signs and symptoms, including chills, fatigue, fever, and muscle aches and pains
Nausea
Diarrhea
Skin rashes

Serious side effects

Serious, but rare, side effects of monoclonal antibody therapy may include:

Infusion reactions. Severe allergy-like reactions can occur and, in very few cases, lead to death. You may receive medicine to block an allergic reaction before you begin monoclonal antibody treatment. Infusion reactions usually occur while treatment is being administered or soon after, so your health care team will watch you closely for a reaction.

Dangerously low blood cell counts. Low levels of red blood cells, white blood cells and platelets may lead to serious complications.

Heart problems. Certain monoclonal antibodies may cause heart problems, including heart failure and a small risk of heart attack.

Skin problems. Sores and rashes on your skin can lead to serious infections in some cases. Serious sores can also occur on the tissue that lines your cheeks and gums (mucosa).

Bleeding. Some of the monoclonal antibody drugs are designed to stop cancer from forming new blood vessels. There have been reports that these medications can cause bleeding.

What should you consider when deciding on monoclonal antibody drug treatment?

Discuss your cancer treatment options with your doctor. Together you can weigh the benefits and risks of each treatment and decide whether a monoclonal antibody treatment is right for you.

Questions to ask your doctor include:

Has the monoclonal antibody drug shown a clear benefit? Some monoclonal antibody drugs are approved for advanced cancer, though they haven't been shown to extend lives. Instead, some drugs are more likely to slow a cancer's growth or stop tumor growth temporarily.

What are the likely side effects of monoclonal antibody treatment? With your doctor, you can determine whether the potential side effects of treatment are worth the likely benefit.

How much will monoclonal antibody treatment cost? Monoclonal antibody drugs can cost thousands of dollars per treatment. Insurance doesn't always cover these costs.

Is monoclonal antibody treatment available in a clinical trial? Clinical trials, which are studies of new treatments and new ways to use existing treatments, may be available to you. In a clinical trial, the cost of the monoclonal antibody drug may be paid for as a part of the study. Also, you may be able to try new monoclonal antibody drugs. Talk to your doctor about what clinical trials may be open to you.

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Cancer immunology has been selected as the "Breakthrough of the Year" by the editors of Science, the flagship journal of the American Association for the Advancement of Science. A report on the subject was published in the December 20 issue.

"Immunotherapy marks an entirely different way of treating cancer — by targeting the immune system, not the tumor itself," according to the report. It beat out scientific advances in areas such as human stem cells from cloning and the understanding of sleep.

The choice was not without debate and worry about "hyping" an approach to cancer treatment that has only touched a "tiny fraction" of patients, according to the editors.

Nonetheless, in 2013, "clinical trials have cemented [cancer immunology's] potential in patients and swayed even the skeptics," reads the report. "A corner has been turned and we won't be going back."

In fact, this year, investigators of paradigm-making clinical trials presented results involving a number of agents and tumor types.

For example, the concurrent combination of the approved immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb) and the experimental agent nivolumab (Bristol-Myers Squibb) yielded an objective response rate of 53% in patients with metastatic melanoma. That is better than either drug alone, and higher than any rate seen before the advent of immunotherapy.

In addition, in patients with metastatic melanoma, the experimental anti-PD-1 antibody MK-3475 (Merck) had an objective response rate of 52% in one cohort of a phase 1 trial.

In another phase 1 trial, involving multiple tumor types that had metastasized or were incurable, the experimental anti-PD-L1 antibody MPDL3280A (Genentech) produced an overall response rate of 21%, with the best responses seen in patients with non-small cell lung cancer, kidney cancer, and melanoma. In the lung cancer group, responses were seen in patients who had a history of smoking. Those phase 1 results were comparable to results from an early trial of nivolumab in patients with a variety of cancer types.

Proven advances from clinical trials conducted this year have also involved a different experimental approach in the treatment of hematologic cancers. The personalized treatment involves extracting T-cells from the patient, subjecting them to chimeric-antigen receptor (CAR) cell engineering, and then infusing the engineered T-cells back into the patient.

In early December, results from the unprecedented research involving CAR therapy were presented at the annual meeting of the American Society of Hematology, as reported by Medscape Medical News.

A team from the University of Pennsylvania reported that 19 of 22 pediatric patients with acute lymphocytic leukemia (ALL) who were treated with CAR had a complete response, which was ongoing in 14 patients (5 have relapsed). Also, all 5 adults with ALL who were treated with CAR had a complete response, which was ongoing in 4.

The team also reported that 15 of 32 adults with chronic lymphocytic leukemia had partial responses and 7 had complete responses, all of which were ongoing.

In addition, a team of researchers from the National Cancer Institute reported that of the 13 adults with advanced B-cell lymphomas who were treated with CAR and evaluable for response, 12 responded; 7 had complete remissions and 5 had partial remissions.

Years of Research

The Science report chronicles some of the early research stories leading to the development of cancer immunotherapy, one of which begins in France and then jumps the pond to the United States.

In 1987, French researchers, who were not engaged in cancer research, identified a new protein receptor on the surface of T-cells, called cytotoxic T-lymphocyte antigen 4, or CTLA-4.

Cancer immunologist James Allison, PhD, then at the University of California, Berkeley, subsequently found that CTLA-4 "puts the brakes on T-cells, preventing them from launching full-out immune attacks. He wondered whether blocking the blocker — the CTLA-4 molecule — would set the immune system free to destroy cancer."

It would take 2 more decades for an anti-CTLA-4 antibody, eventually called ipilimumab, to demonstrate results in phase 3 trials. In 2010, at the American Society of Clinical Oncology annual meeting, researchers reported that, for the first time, a therapy (ipilimumab) had significantly improved survival in patients with metastatic melanoma, as reported by Medscape Medical News.

Some of these patients with metastatic melanoma are still alive 10 years later. Apparently, ipilimumab has "reset" patients' immune systems and turned a deadly cancer into a chronic disease.

The Science report emphasizes that immunotherapies do not work in all patients, and might not work in all cancer types.

Nevertheless, for "physicians accustomed to losing every patient with advanced disease," the results now being seen in clinical trials "bring a hope that they couldn't have fathomed a few years ago," according to the report.

Science. 2013:342:1432-1433.

http://www.sciencemag.org/content/342/6165/1432.full

Citation: Cancer Immunology Named 'Breakthrough of the Year'. Medscape. Dec 20, 2013.

The Role of Anti-PD-L1 Immunotherapy in Cancer

http://www.onclive.com/web-exclusive...py-in-cancer/1

Jim Allison confronts cancer, critics with immunotherapy

http://m.sfgate.com/health/article/J...th-5405290.php

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The potential to harness the body's immune system to fight cancer may finally prove itself on a large scale in the next couple of years. Scores of new immunotherapy vaccines and other immune system modifiers are being tested against a variety of cancers. At least a dozen therapies are set to have key late- or mid-stage trial data.

The concept of using the immune system against cancer dates back to the 1890s when Dr. William Coley, a New York surgeon, noted that some patients who got infections after cancer surgery fared better. He surmised that the immune response triggered by the infection was also working to eradicate cancer.

According to Dr. Glenn Dranoff, co-director of the Dana-Farber Cancer Vaccine Center in Boston, although the idea of a vaccine or cancer immunotherapy has been around really for at least 100 years, we now know a lot more about what are the requirements to generate an effective anti-cancer immune response than we ever did.

Researchers had previously believed that only melanoma and kidney cancer had the right properties to respond to immune system therapy. They were eventually proven wrong. Clinical trials now are taking on lung, breast, liver, prostate, pancreatic, ovarian, head and neck and brain cancers.

The basic idea remains the same: train a patient's immune system to attack the cancer. But new approaches based on more recent knowledge of the immune system's components include activating a variety of cells to go after tumors and modifying mechanisms that keep either the immune system in check or turn it loose.

There appears to be near universal agreement that to achieve optimal benefit, immunotherapies should be combined with targeted cancer drugs or other immunotherapies in a multi-pronged attack.

According to the researchers at Anderson, our immune cells are like little tanks that travel round the body to shoot bacteria and viruses that are hurting us, but you can't let them go unregulated. When the body has cancer you want the tanks to go a little bit wild, so they want to lift those brakes and let them go after the enemy.

Some believe that companies would do well to test immunotherapies at an earlier stage of the disease, perhaps to prevent recurrence. Such trials take years longer to produce results, so companies tend to start trials with advanced cancer patients with limited life expectancy that yield results sooner.

The body's immune system is constantly trying to keep tumors from forming or coming back. If you can give the immune system a boost in terms of helping out with that long-term surveillance, it could make more sense biologically.

The immune system may take some months to ratchet up its anti-cancer armaments researchers say, so giving immunotherapy to a patient with just a few months to live may be futile.

Early disappointment in the field may have been due to testing on patients with very advanced disease whose immune systems were severely compromised by chemotherapy and radiation, and such failures are to be expected.

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An old idea for treating cancer is yielding impressive results on cancer patients—and lots of attention from drug companies.

New medicines that shrink tumors and have beneficial effects lasting for months to years in some cancer patients are helping breathe new life into an old idea: using a patient’s own immune cells to attack malignant cells.

Several drug makers are trying to prove the safety and efficacy of new medicines that harness the body’s own lines of defense. Merck, for one, is testing an immune-modulating compound in patients with metastatic, or spreading, melanoma. In an early-stage trial, half of the patients receiving the highest-attempted dose of the drug saw their tumors shrink or disappear, and more than a year later, the vast majority of those patients who responded to that dose and lower doses were still alive. On average, the prognosis for survival a patient with late-stage metastatic melanoma is less than a year.

“This is not a garden-variety cancer treatment development program,” says Roger Perlmutter, an immunologist who heads R&D at Merck. “This looks special at this stage,” he says.

Merck’s compound is an antibody, a Y-shaped biological molecule that grabs onto a specific protein. The target protein normally prevents immune cells from attacking cancer. By blocking the activity of that protein, the antibody frees the immune cell to fight the disease. Roche, GlaxoSmithKline, Bristol-Myers Squibb, and others are also developing antibodies to release such brakes on the immune system.

New details of how these compounds work and for whom will be presented by many groups involved in the new push for cancer immunotherapy at this year’s American Association for Cancer Research meeting, in San Diego. The conference, which started on Saturday, is the largest meeting of oncologists and oncology researchers in the world. Although researchers express excitement about the potential for immune-modulating medicines to combat cancer—some experts even use the word “cure”—many caution that it will take time to fully understand how well the treatments are working.

Just a few years ago, many in the biomedical community would have been skeptical. Numerous attempts to induce the immune system to attack cancer had proved ineffective in humans, says Charles Link, CEO of New Link Genetics, a biotech company that has been developing immunotherapies for years. “But as the sophistication of our understanding of immunology increased, new strategies evolved to attack the disease, and those strategies are turning out to work in the clinic,” says Link.

“It is exciting—we have been working on this for so long, and now finally human results show it clearly works,” says Jianzhu Chen, a biologist at the Koch Institute for Integrative Cancer Research at MIT, who studies cancer immunotherapy. “This will have a major impact on cancer treatment.”

In 2011, Bristol-Myers Squibb began to sell Yervoy, also an antibody, which was the first marketed medicine to disrupt the process that prevents immune cells from attacking cancer. The treatment has shown to nearly double the survival rate of metastatic melanoma patients, enabling 20 percent of patients to live up to four years after diagnosis. The clinical trial of Yervoy was the first ever to show that life could be extended for advanced melanoma patients.

The antibody medicines represent just one part of the renaissance of cancer immunotherapy. There’s also been progress in a form of cellular therapy that engineers a patient’s own immune cells to better recognize cancer cells, after which they are infused back into the patient. Other companies, such as Amgen, are developing virus-based gene therapies that selectively kill cancer cells while simultaneously making the cells better targets for the immune system.

The immune system can be a powerful ally for doctors, but they must tread carefully. “We know the immune system is capable of killing any cell. If we aren’t careful, we could trigger systemic autoimmune disease of major consequences,” says Perlmutter. “We have to take advantage of the enormous potential of immune recognition and response and at same time leave ourselves in a position where we can control that activity,” he says.

So far, the treatments have been tested on only a subset of cancer types—mostly melanoma but also lung cancers and breast cancers, among others. Researchers will have to test the treatments on more cancer types to know how wide a range of malignancies they can attack, and whether certain targets, or even combination of targets, are needed. “It may be that in different tumor types, different immune modulators will have different importance,” says Deborah Law, who heads one of Merck’s biologics research units. “Combination approaches might be most effective,” she says.

Citation: The Revival of Cancer Immunotherapy. Susan Young Rojahn. MIT Technology Review. April 7, 2014