The Ludwig Institute for Cancer Research (LICR) announced today the launch of a private biotechnology enterprise, iTeos Therapeutics SA, to develop a novel pre-clinical pipeline of immunomodulators to stimulate the immune system’s ability to attack cancer. Founded by LICR with the de Duve Institute at the Université catholique de Louvain (UCL), iTeos is led by a team experienced in tumor immunology, immunotherapy, drug discovery, business development and entrepreneurship. iTeos is the ninth new company formed based on innovative cancer research discoveries licensed from LICR.

The field of cancer immunotherapy has come to the fore in the last two years with the approval of drugs and vaccines that harness the power of the immune system to treat cancer patients more safely, efficiently and effectively. However, therapeutic uses of these treatments can be limited as the tumors often develop mechanisms that enable them to escape the immune system. iTeos brings together world-class expertise in tumor immunology and immunotherapy, with a focus on developing small molecule immunomodulators to counteract cancer immunosuppression.

“Immunotherapy – boosting the body’s natural immune system to fight cancerous tumors – is the next frontier in life-extending cancer treatment,” said Benoît Van den Eynde, M.D., Ph.D., Brussels Branch Director at LICR, UCL Professor and co-founder of iTeos. “Effective immunotherapy treatments enable the body’s immune system to ‘re-engage’ in destroying tumor cells, thereby potentially creating better patient outcomes with fewer side effects when compared to conventional cancer treatments.”

“iTeos’ mission is to translate pioneering scientific discovery into meaningful treatments for people living with cancer,” said iTeos co-founder and CEO Michel Detheux, Ph.D. “We now know that combination treatments are likely to be more effective than single therapies in controlling and eventually eliminating cancer. iTeos will pursue this approach by combining existing vaccines with new immunodulatory compounds based on research that has just emerged from the Ludwig Institute.”

iTeos’ initial goals are to reach a proof of concept in humans by completing a Phase I/IIa study for the first compound program and to submit an Investigational New Drug application for a second candidate in four years.

Ludwig and UCL scientists, led by Dr. Van den Eynde, recently made the breakthrough discovery of the potential role of TDO in immunotherapy. TDO is a critical enzyme that is produced by a significant number of human tumors. In research published in the 30 January 2012 issue of Proceedings of the National Academy of Sciences, Dr. Van den Eynde’s team showed that blocking TDO with a novel inhibitor promotes tumor rejection in mice. This team was also responsible for recognizing the role that a similar enzyme, IDO, plays in tumor growth. TDO and IDO inhibitors are now in preclinical development at iTeos.

“Preclinical studies suggest that TDO inhibition may be beneficial in treating bladder, liver and melanoma skin cancers. Suppressing IDO may help to positively impact ovarian, prostate, pancreatic and colorectal cancer treatment among others,” said Dr. Detheux. “iTeos’ focus is to bring these and other truly novel compounds to become part of the standard of care for cancer treatment.”

“LICR has the expertise to conduct and administer its own early phase clinical trials as part of its technology development process,” said Jonathan Skipper, Ph.D., Executive Director of Technology Development at LICR. “Spin-off companies, such as iTeos, have access to this infrastructure so that candidate therapeutics can be further tested. This allows LICR to continue to have input into the development of its discoveries and, more importantly, ensure promising new therapies will eventually reach patients.”

Strong third-party endorsement is behind iTeos, including early funding by the Belgian Walloon Government. In fact, the creation of the spin-off was made possible by the grant from a Walloon FIRST spin-off mandate. Then, in December 2011, the Walloon Government awarded iTeos a research grant for $8M (€6M). This support builds upon the progress of an earlier government program, the Biowin Pole of “Plan Marshall,” aimed at the development of small molecule inhibitors.

Provided by Ludwig Institute for Cancer Research

By Sharon Begley

NEW YORK (Reuters) – Prostate cancer vaccine Provenge has long incited passions unlike any other cancer therapy.

Doctors who raised doubts about it received death threats. Health regulators and lawmakers faced loud protests at their offices. A physician at the American Cancer Society was so intimidated by Provenge partisans that he yanked a skeptical discussion of it from his blog.

The vitriol dissipated in April 2010, when the U.S. Food and Drug Administration approved Provenge for advanced prostate cancer, satisfying investors in manufacturer Dendreon and patients who for years had demanded it be put on the market.

But the bell on Round Two sounded when Marie Huber, a trained scientist and former hedge-fund analyst, made it her mission in the last year to analyze what she believes are deadly flaws in the studies that led to the approval of Provenge by the FDA.

She argues that the main reason Provenge seemed to extend survival – a crucial factor in the FDA’s decision – was that older men in the study who did not receive Provenge died months sooner than similar patients in other studies.

She raises the possibility the “placebo” they received was actually harmful and made Provenge, known scientifically as sipuleucel-T, look better by comparison.

As Huber gains traction, most notably with a February paper in the prestigious Journal of the National Cancer Institute, she, too, is receiving threats. One post on an investors’ message board last month suggested that “somebody smack her with a rubber hose.” An email said “don’t think you will be unscathed in this battle you waged on Provenge.”

Provenge is Dendreon’s only product and the company’s stature with investors has waned with disappointing sales. In 2011, product revenues totaled $213.5 million, far from the $400 million Dendreon initially projected.

The company insists Huber’s analysis is flawed and that Provenge has helped thousands of men with prostate cancer.

“I’m looking forward to getting this to patients around the world,” said President and Chief Executive John Johnson.

FIRST CANCER VACCINE

Since it won FDA approval two years ago, Provenge has been Exhibit A for the idea that a patient’s immune system can control or cure cancer. The first therapeutic cancer vaccine to reach the market, Provenge tries to engineer white blood cells, part of the immune system, to vanquish prostate cancer, which killed an estimated 33,720 men in the United States last year.

Its path to approval has all the features of a heavyweight healthcare fight – desperate patients demanding access to a promising therapy, a very expensive drug that extends life only a few months and efficacy data open to interpretation.

The FDA declined to approve the drug in 2007, when a clinical trial failed to show it slowed tumor growth. That incited protests, lawsuits and death threats against physicians on the FDA advisory panel who did not recommend approval, breaking with the 13-4 majority in favor.

“Provenge came along when we didn’t have much to offer for prostate cancer,” said Dr. Len Lichtenfeld of the ACS. “The advocacy community was bursting at the seams for something that worked. When you have that situation, it inflames passions and that can overtake the science.”

In the pivotal trial called IMPACT, published in July 2010, but shared with the FDA months earlier, Provenge extended median survival by 4.1 months to 25.8 months from 21.7 months. That was sufficient for FDA approval. The vaccine costs $93,000 and patients also incur physician and other charges. Medicare agreed to cover Provenge last year, as have private insurers, but doctors initially balked at a long wait for reimbursement.

Huber had long been “utterly intrigued” by Provenge and its “huge promise of harnessing the immune system to battle cancer,” she said in an interview.

In documents JNCI requires authors to sign, she declared no financial conflicts of interest. Neither she nor her former firm nor anyone else she is connected to stands to benefit financially from her analysis, she said.

Instead, she says she is motivated to help “vulnerable and desperate patients” – so much so that she gave up her job, salary and health insurance. Arguing that Provenge is harming these men, she called “the whole thing utterly horrific. The company got away with hiding data and doctors making $7,000 per prescription won’t even engage in discussion” about whether it helps their patients.

After receiving degrees in biochemistry and bioscience enterprise from Cambridge University, Huber began working as an analyst for a hedge fund in 2007. A Thomson Reuters analysis of securities filings confirmed her former firm has not held any positions in Dendreon.

LACK OF EVIDENCE

Each dose of Provenge is custom-made. A nurse or technician withdraws white blood cells from a man’s arm in a three-to-four hour procedure called leukapheresis.

The cells are shipped to a Dendreon manufacturing facility, where for two days they are incubated with a “fusion protein:” One protein that stimulates the cells’ growth and maturation and another called PAP, or prostatic acid phosphatase. PAP is an antigen that studs prostate cancer cells like antennae, pieces of it sticking out of the cells’ surfaces.

Dendreon says the patients’ white blood cells take up the antigen and within hours their surfaces bristle with fragments of the telltale molecule. The cells are then shipped back to the physician and infused into the patient. A full treatment includes three such procedures, two weeks apart.

Back inside the body, Dendreon claims the modified cells trigger the immune system to produce T cells that kill any cell sporting the PAP antigen — namely, prostate cancer cells.

In principle, that should eliminate the cancer, but Provenge does not shrink either the primary tumor or metastases.

Steven Rosenberg of the National Cancer Institute, a leading tumor immunologist, says that raises doubts over whether Provenge helps patients live longer, as the IMPACT trial reported.

“We have a lot of data that supports the idea that the product works the way it was designed to,” said Dr. Mark Frohlich, Dendreon’s chief medical officer. “We’re seeing evidence of immune-system activation. The only question is whether the T cells are killing the tumor.”

The FDA acknowledges that data supporting Provenge’s approval did not show the drug shrank tumors, but says the overall survival benefit was enough to bring it to market. Spokeswoman Rita Chapelle, citing data submitted by Dendreon, said there is a “lack of evidence of anti-tumor activity,” the reason for which “is unclear.”

SUSPICIONS OVER SURVIVAL BENEFIT

Huber’s analysis comes from data showing that men who received the placebo had very different survival times based on their age. Men older than 65 lived 17.3 months on placebo and 23 months with Provenge. Men younger than 65 lived 28 months after receiving placebo and 29 months after Provenge.

Other studies have shown that age generally does not affect how long a man survives with this form of prostate cancer, says Peter Iversen, a urologist and prostate-cancer surgeon at the University of Copenhagen and co-author of the paper with Huber.

Combining these findings led to the new paper’s conclusion: The four-month edge in median survival from Provenge for all patients was due to longer survival among older men who got the vaccine.

“There is no efficacy in the younger patients, the primary group where you would expect it,” said Huber.

Since the immune system weakens with age, an immune-based therapy should work better in younger men.

Some experts agree.

“If it was really a vaccine, you’d think younger men would show more response, since they are more immunocompetent,” said NCI’s Rosenberg.

On that basis, Huber and her co-authors, including two prostate-cancer specialists, argue the placebo used in the trial may have harmed the older men, cutting months off their lives and inadvertently making Provenge seem beneficial.

One way that could have occurred was through leukapheresis. That process removed about 90 percent of certain kinds of circulating white blood cells, according to calculations by immunologist Laura Haynes of the Trudeau Institute, a co-author of the JNCI paper.

The Provenge men got back about 32 percent of those cells, which had been stored at body temperature. The placebo men got back 12 percent, which had been incubated at near-freezing temperatures. Cold storage has been reported to kill “most, if not all, of those cells,” notes the JNCI paper. Moreover, said Haynes, “if you return dead and dying cells to older men you are likely to cause inflammation,” which can stoke the growth of cancerous cells.

Younger men were better able to replace the lost white blood cells, argued Iversen. Older men could not, resulting in early death.

“These cells are very specialized and there is research suggesting that removing them can harm older men,” he said.

Earlier this month, DynaMed, an online database used by physicians, added to its Provenge entry a note on the JNCI paper, but calls the concern “not substantiated.” ACS’s Lichtenfeld says the analysis “might inhibit some patients and doctors from going ahead with a very expensive drug.”

Huber says she plans to approach European regulators as they consider Dendreon’s application to approve Provenge.

Investor message boards have lit up in response to the new paper. In February, an anonymous commentator on InvestorVillage.com warned that Huber’s work was about to be published “a few days before our earnings. Her agenda is obvious.”

IFFY STATISTICS

Critics of the new analysis argue the number of cells removed is too small to suppress the immune system. Charles Drake, an oncologist and immunologist at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, said there is no evidence the placebo men in IMPACT suffered more infections or other effects of a depleted immune system than the Provenge men.

The scientist who led IMPACT, oncologist Philip Kantoff of Dana Farber Cancer Center, said colleagues in immunology “dismissed as nonsense the idea that leukapheresis could hurt individuals.”

He takes issue, too, with the statistics. Dividing the men by whether they are older or younger than 65, he said, is “arbitrary” and to pick apart data retrospectively is a statistical no-no.

Dendreon’s Frohlich also criticizes the statistics: “If you do enough of these (post-hoc analyses) then by chance alone you’d expect to get one positive finding.”

In other words, it is almost always possible to find a subset of patients who do better than others.

When Dendreon divided the men by whether they were older or younger than about 71, he added, they found no red flags.

The FDA agrees that such post-hoc statistical analyses “are exploratory” and their results “must be interpreted with caution, as acknowledged by the authors.” Yet a paid consultant to Dendreon before the IMPACT trial agreed with many of Huber’s concerns.

“The control vaccine used in IMPACT and in the predecessor trial had never been used anywhere for anything and may well have been detrimental to patients,” said Donald Berry of MD Anderson Cancer Center, a leading biostatistician. “Here’s a great way to get your drug approved: Kill the control patients.”

Despite the heated rhetoric, Provenge may go out with a whimper more than a bang. Promising new agents for advanced prostate cancer include an oral drug from Medivation Inc called enzalutamide, in the final phase of clinical trials, and Zytiga from Johnson & Johnson, which won FDA approval in 2011. A vaccine that targets PSA, from Bavarian Nordic Immunotherapy, is in late-stage trials.

Dendreon does not disclose how many patients have been prescribed Provenge. CEO Johnson said that about 70 percent of its Provenge revenue comes from sales to community hospitals and doctors and 30 percent from academic medical centers. Some of the latter decline to use Provenge, deterred by lingering concerns over whether it provides a meaningful benefit.

Three such facilities in the Midwest, contacted at random by Reuters, confirmed they do not recommend Provenge. All asked not to be named for fear of receiving threats.

“It is my policy not to make public comments about this drug,” said one oncologist. Patients who ask for it “are referred to another facility.”

(Editing by Michele Gershberg, Ed Tobin and Andre Grenon)

Saturday, March 31, 2012

In a potential breakthrough for cancer research, Stanford immunologists discovered they can shrink or even get rid of a wide range of human cancers by treating them with a single antibody.

The experiments were done on cancerous tumors transplanted into mice, but the researchers hope to move to human clinical trials within the next couple of years.

“We have made what we think is a big advancement … and we’re going to push as hard as we can and as fast we can,” said Dr. Irving Weissman, pathology professor at the Stanford University School of Medicine and director of Stanford’s Institute of Stem Cell Biology and Regenerative Medicine.

The researchers focused on blocking a protein, which they refer to as the “don’t eat me” molecule because it sits on tumor cells signaling the body’s immune system not to attack it. By introducing the antibody, the scientists were able to block the protective signal, otherwise known as CD47, allowing the immune system to go after the cancer cells.

Broad range of cancers

Researchers say CD47 is the only target found so far on the surface of all cancer cells. That means the antibody offers hope as a weapon against a broad range of cancers – breast, ovarian, colon, bladder, brain, liver and prostate.

The research involved taking cells from Stanford cancer patients, planting them into matching locations in the bodies of mice, and then administering the antibody. The antibody completely destroyed the tumor in some cases but also prevented the cancer from spreading.

“The most common result was the tumor growth was inhibited – not fully cured – but in a few weeks dramatically decreased,” said Stephen Willingham, postdoctoral researcher and co-lead author of the study.

The study, published online this week in the journal Proceedings of the National Academy of Sciences, has drawn praise from other researchers.

“The data is indeed exciting, and the effects are significant,” said Tyler Jacks, director of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, who was not involved in the study.

Research on mice

But Jacks noted that the research has been limited to mice, and disease in humans tends to be much more complex.

“That’s a commonly used preclinical model, but there are other examples when therapeutic effectiveness in such models has not translated well in real disease,” Jacks said. “We need to see what happens when the treatments are (used) in patients.”

The Stanford team said the “don’t eat me” CD47 signal has long been identified and is associated, in particular, with the treatment of leukemia. CD47 is found in healthy cells but tends to be expressed in higher levels in cancerous cells.

Limited side effects

The researchers were concerned that any treatment would single out normal cells as well as malignant ones. They discovered, however, that the antibody selected older, red blood cells, causing mild but temporary anemia and no other adverse side effects.

“That was the best moment. We found a way to utilize this antibody to treat (the cancer) without having major toxicity,” said Dr. Jens-Peter Volkmer, the study’s other lead author.

The Stanford team’s continuing research is being funded by a grant from the California Institute for Regenerative Medicine. The organization was created by Proposition 71, passed by voters in 2004 to support stem cell research.

Victoria Colliver is a San Francisco Chronicle staff writer. vcolliver@sfchronicle.com

In a review article posted online March 16 in Cell, the researchers say that refinements and modifications of monoclonal antibody drugs — several of which have already revolutionized the care of breast and colon cancer –are now being tested in most tumor types.

These modifications allow antibody drugs to bind to more than one target on a cell, and to directly stimulate the body’s immune response to promote vaccine-like antitumor effects. Others have been designed to boost their killing power by carrying a payload of radiation, toxins, or other chemicals.

‘We are heading into an era where antibodies will not just be components of an effective therapeutic strategy, they will be at the core of an oncologist’s treatment plan for patients,” says the review’s lead author, Louis M. Weiner, M.D., director of Georgetown Lombardi Comprehensive Cancer Center, an internationally recognized expert in immunotherapy research.

“Advancement in antibody cancer treatment is not a minor advance or a trivial victory. This is big time stuff,” Weiner said in an interview.

His co-authors on the review are Joseph Murray and Casey W. Shuptrine, both graduate students in the Tumor Biology Training Program at Georgetown Lombardi.

A good example of the new class of antibody-based therapies is ipilimumab, a drug approved in 2011 to treat patients with metastatic melanoma, says Weiner. Ipilimumab is a fully human antibody which binds to an immune antigen (CTLA-4) on cancer cells that transmits a signal inhibiting other immune cells from destroying the tumor. Ipilimumab blocks CTLA-4, thereby inducing an active immune response.

“This agent turns off the brakes of an immune response against melanoma, liberating the body to set up long term protectiion against the cancer,” Weiner says. “About 10 percent of patients with metastatic melanoma who use it go into long-term remission, and may well be cured.”

Antigens are substances, often a cell surface receptor, which causes the immune system to produce an antibody against it, as a way to target and kill the cell. Therefore, antibody agents targeted to a receptor on a cancer cell have the unique capacity to target and kill cancer cells while activating an immune response. A monoclonal antibody (mAb) is an artificially produced antibody designed to bind to a specific cancer antigen, and currently 11 mAbs are approved for use in oncology, Most of these were approved in the last decade. The most commonly used are trastuzumab (Herceptin) to treat HER2-positive breast cancer and rituximab (Rituxan) for specific forms of lymphoma and leukemia.

Advanced antibody engineering techniques are being used to create more effective treatments, Weiner says. One group, known as bispecific antibodies (bsAbs) can bind to two different tumor antigens, or to a tumor antigen and another target in the tumor microenvironment, such as an immune system killer cell. Other mAbs are being designed as “conjugates” to carry a toxic payload, which can be a radionuclide, other drugs, toxins, or enzymes. Researchers are also now increasing the capacity of antibodies to be absorbed by cancer cells so that they can bind to antigens inside the cell – not just on the outside of the cell surface.

“The field of cancer antibodies is definitely maturing. There are scores of new cancer antibody agents now being tested in virtually every kind of solid cancer, and oncologists, researchers and pharmaceutical companies are excited about their promise,” Weiner says. “To me this is like watching a child grow up and do well — very well — in young adulthood.”

The work was supported by funding from the National Cancer Institute. Weiner serves as an expert consultant on cancer immunotherapy to several pharmaceutical companies, none of whose products are mentioned in this article.

About Georgetown Lombardi Comprehensive Cancer Center

Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and MedStar Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Georgetown Lombardi is one of only 40 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington, DC, area. For more information, go to http://lombardi.georgetown.edu.

About Georgetown University Medical Center

Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or “care of the whole person.” The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization (BGRO), which accounts for the majority of externally funded research at GUMC including a Clinical Translation and Science Award from the National Institutes of Health. In fiscal year 2010-11, GUMC accounted for 85 percent of the university’s sponsored research funding.

Peter MacCallum Cancer Centre’s Jane Oliaro has deciphered the mechanics in how T-cells – the “soldiers” of the immune system – divide to produce “killer” and “memory” cells that track down and kill infected or cancerous cells.

Dr Oliaro’s work has been honoured in the top 10 research projects by the National Health and Medical Research Council in its annual awards, recognising her work as among the most important in the country.

Dr Oliaro has for the first time shown T-cells divide into two different daughter cells – “killer” and “memory” cells – which are activated by an “antigen-presenting cell” to start killing a particular infection or cancer.

“The antigen-presenting cell engulfs the bacteria and displays it to the T-cell which tells it there’s a foreign pathogen in the body,” she said.

“The T-cell gets woken up and starts multiplying cells that are designed to recognise, target and kill any cell with that bacteria inside it. That’s why our immune system doesn’t deal well with cancer, because cancer arises from our own cells and T-cells are trained not to attack anything that looks like our own cells.”

She is investigating the signals that “switch on” T-cells which determine what types of daughter cells are generated in preparation to fight.

“Our immune system does an excellent job about getting rid of infections in general, and we want to apply that knowledge to fighting cancer,” Dr Oliaro said.

“If these signals can be artificially recreated, scientists could develop a blueprint to reproduce more killer and memory cells.

“With research it’s baby steps, but the more we can learn about this, the more we can manipulate our immune system to produce more killer cells, or more memory cells the body needs to fight cancer without chemotherapy, surgery or radiation therapy.”

oconnellb@heraldsun.com.au

Photo: AP

A Sand Tiger Shark swims in its aquarium, File November 9, 2010.

Australian scientists investigating the cancer-fighting qualities of shark blood have been given a significant funding boost from an international pharmaceutical giant.  The team from La Trobe University in Melbourne says trials indicate shark antibodies can be a potent weapon against malaria and breast cancer.

International pharmaceutical company Roche is funding Australian research into shark blood for six months.  During that time scientists will try to determine if shark-blood antibodies are able to lock onto and neutralize cancer cells.

Shark antibodies are very small, which researchers say makes them particularly good at seeking out and binding to target cells.   Thanks in part to funding from the Bill Gates Foundation, trials have already shown they can be an effective treatment against malaria.

The research started a decade ago and a team from Melbourne’s La Trobe University has created the world’s first ‘test-tube library’ of millions of antibodies from shark blood that could fight cancer and other diseases.  Trials into breast cancer have also started, work that will be accelerated following the deal with Roche.

“There are several-thousand million different anti-bodies,” explained associate professor Mick Foley, explaining the funding deal.  “Really we have just got to find in our library one that will bind to their target and give that to them.  We will license it to them,” he explained. “But we are hoping that, you know, this is just a sort of vote of confidence, if you like, in big pharma (large pharmaceutical companies) that we have something interesting that might be very useful to the broader pharmaceutical industry.”

Foley says his team’s work could provide a breakthrough. “We are researching into sort of, for example, cancers,” Foley said. “So, we have several antibodies that we are looking at, one of which we know in vitro, again in the laboratory, if you put it into breast cancer cells it will stop those breast cancer cells from growing.”

Sharks have immune systems similar to humans, but their antibodies – the molecules that actually fight disease – are different to human anti-bodies and are extremely resilient.

The team in Melbourne found that shark antibodies can withstand high temperatures as well as extremely acidic or alkaline conditions.

A rarely seen phenomenon in cancer patients — in which focused radiation to the site of one tumor is associated with the disappearance of metastatic tumors all over the body — has been reported in a patient with melanoma treated with the immunotherapeutic agent ipilimumab (Yervoy). Researchers at Memorial Sloan Kettering Cancer Center shared their findings in a unique single-patient study, which could help shed light on the immune system’s role in fighting cancer. Their observations suggest that the combination of ipilimumab and radiation may be a promising approach for the treatment of melanoma. The findings are published as a brief report in the March 8 issue of the New England Journal of Medicine. The work was done at Memorial Sloan Kettering’s Ludwig Center for Cancer Immunotherapy.

They say they boosted the effectiveness in melanoma patients by carefully selecting and cloning T cells from patients’ blood.

In a bid to make cancer immunotherapy more effective, researchers report they have succeeded in halting the progress of aggressive melanoma in its tracks — at least briefly — in seven patients treated with an army of cloned cancer-fighting immune cells. In one of those patients, the treatment resulted in complete remission of his metastatic melanoma and evidence that his immune system stands ready to fight any return of the cancer after three years.

The study, published Monday in the Proceedings of the National Academies of Science, contributes to hopes that a tumor-fighting strategy called immunotherapy can slow, halt or even reverse the growth of a range of cancers — and do so with fewer dangerous side effects.

Immunotherapy is one of medicine’s most promising — and most problematic — approaches to cancer treatment. It aims to charge up the patient’s immune system to attack cancer cells and halt their out-of-control growth.

The approach outlined in the new study by researchers from the Fred Hutchinson Cancer Research Center in Seattle identifies several ways to make it better, said Dr. Cassian Yee, the study’s senior author. The key is to identify specific cancer-fighting cells already circulating in the blood of patients and make thousands of copies of them in the lab.

This type of “adoptive immunotherapy” could be effective against a wide range of cancers, Yee said. His research group is making plans to try the technique on patients with advanced ovarian cancer and sarcomas — rare tumors that arise from connective tissue in bones and muscle.

Several independent researchers said the study results were promising. But they also noted that the trial involved only 11 patients and said the therapy was less effective than in other published trials.

“Someday, cell-based therapy will be mainstream in cancer therapy,” said Dr. Jeff Miller of the University of Minnesota’s cell therapy core laboratory. “Each article that shows clinical activity is giving us a piece of the puzzle” that will make it safer and more effective, he said.

Immunotherapy usually starts with clinicians harvesting immune system cells called T cells that have attached themselves to a tumor in an effort to attack. They then coax the cells to multiply, either in the lab or in the body, and let them loose in the bloodstream so they can attack cancer wherever they find it.

Yee’s team tried to do this more precisely. The researchers hoped that by choosing T cells more selectively and cloning only those judged most likely to vanquish their foe, the treatment would be more effective. Sorting through the body’s vast and diverse population of T cells to select just the right ones is a painstaking process. But Yee bet that the extra effort would pay off with better results and fewer side effects.

Researchers drew blood from patients and scoured it to find the rare type of immune cell — a melanoma-specific cytotoxic T lymphocyte cell — that specifically homes in on proteins expressed by the cancer. Then they put their harvest — as few as a few hundred cells — into a test tube and cloned them, creating millions. The last step was to infuse the resulting army of cancer-fighting clones back into the patient.

In six of the 11 patients in the trial, the melanoma stopped progressing for 12 to 19 weeks. Another patient was declared in remission because his cancer ceased to spread and, after several months, disappeared altogether. Three years later, researchers continue to detect the presence of the cloned cells they infused into the patient, 61-year-old high school history teacher Gardiner Vinnedge of North Bend, Wash.

For six years, Vinnedge endured painful rounds of chemotherapy, only to have his melanoma return. The immunotherapy allowed him to return to work three weeks after treatments began. The only side effect, he said, was a raging rash that lasted for three days.

“My back, my legs were just covered with a hot red rash,” Vinnedge said. “It meant the treatment was working — the war was on between my T cells and the melanin in my skin.” Now he says he is optimistic he may live to see retirement age, though he’s not sure he’ll ever stop teaching.

For immunotherapy to work, the manufactured T cells must survive for the months it takes to reach a tumor and dismantle it, as well as to round up migrating cancer cells and kill them. Currently, the T cells have limited staying power and often die off before their work is done. Doctors give them a boost by administering a growth factor called interleukin-2. But at high doses, it can cause dangerously low blood pressure, breathing problems, kidney failure and heart arrhythmias.

Yee’s group showed that by choosing T cells more selectively, patients can get by with much lower doses of interleukin-2, making the treatment less toxic.

The researchers also discovered another way to reduce their dependence on interleukin-2 — by selecting the most youthful T cells, which survived the longest when infused into patients.

Dr. Patrick Hwu of the MD Anderson Cancer Center in Houston said the study “adds to the wealth of what we know” about using the body’s immune system to fight cancer. But immunotherapy pioneer Dr. Steven A. Rosenberg was highly critical of the methods and results.

“Cloned cells don’t work,” said Rosenberg, who heads the National Cancer Institute’s tumor immunology section. In larger immunotherapy trials that used cultured cancer-fighting immune cells taken from patients’ tumors, Rosenberg and his colleagues achieved “durable and complete regression” in as many as 40% as patients with advanced metastatic melanoma. “These results,” he said, “are inferior.”

melissa.healy@latimes.com

Enlarge

This is the Universal Immune Receptor Platform. Credit: Daniel J. Powell Jr., Ph.D., Perelman School of Medicine, University of Pennsylvania

(Medical Xpress) — Researchers from the Perelman School of Medicine at the University of Pennsylvania report this month in Cancer Research a universal approach to personalized cancer therapy based on T cells. It is the first time a system for making an adaptable, engineered T-cell to attack specific tumor types has been proposed, depending on which abnormal proteins, called antigens, are expressed by individual patients’ tumor cells.

For now, the system is being refined in experiments using healthy donor T cells and animal models of human cancer, with the aim to introduce the personalized cells into patients in the future, explains senior author Daniel J. Powell Jr., Ph.D., a research assistant professor of Pathology and Laboratory Medicine with Penn’s Ovarian Cancer Research Center.

Tumor antigens are potential targets of an immune response, and identifying which antigens a patient’s tumor cells express would be helpful in designing cancer therapy for that individual. Any mutated protein produced in a tumor cell can act as a tumor antigen. Many tumor cells have surface proteins that are inappropriately expressed for the cell type, or are only normally present during embryonic development. Still other tumor cells display cell surface proteins that are rare or absent on the surfaces of healthy cells and are responsible for activating molecular pathways that cause uncontrolled replication of cells. In most cancers, not all patients have tumor cells that express the exact same antigen, and sometimes tumor cells from a single patient can express different antigens. Because of this complexity, it is important to properly choose which antigen to target with cancer therapy.

T cells engineered to express an engineered antigen, called a chimeric antigen receptor (CAR), offer an attractive strategy for targeting antigens and treating cancer, says Powell. CARs are engineered receptors that graft, for example, the portion of a tumor-specific antibody onto an immune cell. This allows the patients’ T cells to recognize tumor antigens and kill their tumor cells.

For therapy, a large number of tumor-specific, cancer-fighting CAR T cells can be generated in a specialized lab using patients’ own T cells, which are then infused back into them. This approach has shown promising results in patients whose tumors all express the same antigen.

Despite these encouraging findings, currently made CARs have a fixed antigen specificity, which means only one type of tumor antigen can be targeted at a time. Tumor cells that lack that selected antigen can then escape recognition by immune cells and replicate, limiting what might otherwise have been an effective therapy if multiple tumor antigens had been targeted. For this reason, the team sought to make a more generalized receptor framework that is able to produce T cells capable of targeting large panels of known tumor antigens.

To that end, the team developed a new platform from which they could eventually target a variety of tumor antigens, either simultaneously or sequentially. So far, they have engineered T cells against the antigens mesothelin, present on several tumor cell types; epCAM, present on epithelial cell cancers; alpha folate, present on ovarian cancer cells; and, more recently, CD19 on lymphoma cells.

The universal immune receptor recognizes molecules attached to tumor antigens on the surface of tumor cells. When this happens, the T cells produce inflammatory response proteins called cytokines and pore-forming proteins. Those proteins cause the release of enzymes through those pores into tumor cells, thereby killing them.

The new engineered T cells described in the Cancer Research paper recognize and bind exclusively to cancer cells pre-targeted with biotin-labeled molecules, such as antibodies. Biotin is a B complex vitamin necessary for cell growth that can be bound by a molecule called avidin, which is contained in the universal immune receptor. Since nearly any molecule can be biotin labeled, the number of antigens that can be targeted by T cells carrying the biotin-binding immune receptor is nearly infinite. The versatility afforded by this biotin-binding receptor permitted the targeting of a combination of distinct antigens all at once, and even one after another, notes Powell.

The findings demonstrate that a universal T cell can significantly extend conventional CAR approaches, allowing the team to generate T cells of unlimited antigen specificity. This process is geared to make T cell therapy more available to patients and to improve the effectiveness of T-cell immunotherapies for cancer.

First author post-doctoral fellow Katarzyna Urbanska, Ph.D. continues optimization of the universal receptor approach by looking for different ways to improve the interaction of T cells with tumor cells, and how to better direct the T cells and the biotin-labeled molecules to tumor cells in the body.

In the future, Powell and colleagues predict a highly personalized platform for cancer therapy that begins when patient tumors are analyzed for their expression of specific antigens at the Department Pathology and Laboratory Medicine’s new Center for Personalized Diagnostics. When the antigens expressed by a patient’s tumor cells are determined, their T cells will be engineered to express the universal immune receptor, which will be given back to them in combination with biotin-labeled molecules to attach to patients’ tumor antigens for an individualized tumor attack.

More information: http://cancerres.a … 890.abstract

A team of 18 researchers at Moffitt Cancer Center in Tampa, Fla., have found that treating high-risk, soft tissue sarcoma patients with a combination of implanted dendritic cells (immune system cells) and fractionated external beam radiation (EBRT) provided more than 50 percent of their trial patients with tumor-specific immune responses lasting from 11 to 42 weeks.

Their study was published in a recent issue of the International Journal of Radiation Oncology * Biology * Physics (Vol. 82, No. 2), the journal of the American Society for Radiation Oncology (ASTRO).

“Sarcomas are relatively rare forms of cancer with about 10,000 new cases in the U.S. annually,” said study co-author Dmitry Gabrilovich, M.D., Ph.D., senior member of the Moffitt Department of Immunology.

The authors note that because 50 percent of patients with large, high-grade soft tissue sarcomas develop distant metastasis, new, effective treatments are needed.

“Unfortunately, conventional therapy for large, high-grade tumors is frequently systematically ineffective, making this a very deadly problem,” Gabrilovich said.

According to the researchers, administration of dendritic cells has been found to be a promising method for producing an immune response because dendritic cells process antigen material and present it to other immune cells. Dendritic cells act as immune system messengers.

“Many studies have shown that preoperative radiotherapy and surgery is effective in treating many soft tissue sarcomas with high-risk features,” said Gabrilovich. “We designed our study to investigate the effect of combining the administration of dendritic cells and EBRT for patients with soft tissue, high-risk sarcomas.”

The researchers hypothesized that if dendritic cell implants were combined with EBRT (the most common kind of radiotherapy treatment that not only can kill tumor cells but release tumor antigens) the combination therapy might be complimentary when the dendritic cells helped process tumor antigens released by the EBRT treatment.

“The combination treatment resulted in dramatic increases in immune T cells in the tumors,” explained Gabrilovich. “The presence of T cells in the tumors positively correlated with the development of tumor-specific immune responses.”

An important finding in this study was that no patient had significant tumor specific immune responses before the combined therapy. After the combination treatment, tumor specific responses were observed in 52.9 percent of trial patients.

The researchers reported that the combination treatment was “well tolerated” and that 12 of the 17 patients in the clinical trial were “progression free” after one year.

The authors concluded that given that the combination therapy proved effective in creating a potent anti-tumor response and was safe, producing no adverse side effects, larger trials with greater numbers of patients were warranted.

Provided by H. Lee Moffitt Cancer Center & Research Institute