Immunological Research: A multi-faceted approach to curing disease

[gdpawel]

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

[gdpawel]

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.

[gdpawel]

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