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Immune Therapy to Fight Cancer

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    Posted: Feb 21 2012 at 8:43pm
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Clinical Trials Network Aims to Strengthen Cancer Immunotherapy Pipeline

Later this year, the first clinical trials will be launched under a new NCI-funded initiative to spur the development of cancer treatments that work by revving up the immune system's response to tumors. The Cancer Immunotherapy Trials Network Exit Disclaimer (CITN) includes the foremost researchers in cancer immunotherapy from 27 top U.S. cancer centers and universitieswho are working collectively to identify promising agents and to formulate and run the trials in which they will be tested.

The first immunotherapy agents to enter CITN trials have been selected, and several trials are moving closer to launch. The first two agents, interleukin-15(IL-15) and CP-870,893, were selected "based on broad consensus and the field's collective experience and 'wisdom,'" explained Dr. Martin A. "Mac" Cheever, the CITN's principal investigator and director of the CITN Central Operating and Statistical Center (COSC), located at the Fred Hutchinson Cancer Research Center in Seattle.

All CITN trials will be phase I or phase II trials. The network's aim is to establish a pipeline of agents to test in the large phase III trials that ultimately determine whether a new treatment will make it to the clinic, said Dr. Cheever, who, along with co-investigator Dr. Kim Margolin, runs the network's day-to-day operations. Correlative science studies, such as those that look for biomarkers that indicate which patients are likely to respond to a treatment and that assess the extent to which treatments stimulate an immune response, will be built into the trials. These studies will be performed under the direction of Dr. Cheever's other co-investigator, Dr. Mary L. "Nora" Disis.

"The goal," Dr. Cheever explained, "is to design trials that can quickly demonstrate proof of concept and patient benefit, ultimately helping to define a path toward regulatory approval."

The Field Comes Together

The concept of using a patient's own immune system to destroy tumors has enticed researchers for decades. Until quite recently, however, regimens focused on boosting patient immune responses to their own cancers, although effective in some patients, have failed to produce many broadly effective treatments. (For years, blood and bone marrow transplants, which restore or replace patients' immune systems, have been highly effective treatments for leukemia and lymphoma, and some monoclonal antibodies, such as trastuzumab [Herceptin], are believed to work, in part, by stimulating an antitumor immune response.)

But a confluence of events has propelled the field forward, said Dr. William Merritt of NCI's Division of Cancer Treatment and Diagnosis (DCTD) and NCI program director for the CITN. Chief among them has been the "vastly improved understanding of tumor immunology and the number of agents known to modify the immune response to tumors," Dr. Merritt said.

A major tipping point was the first NCI-sponsored Immunotherapy Agents Workshop, held in 2007, which brought together leading cancer immunologists to identify the most promising immunotherapy agents for further study and development. From more than 120 candidates, 20 agents were chosen. NCI held additional workshops to help further prioritize agents for development, with an emphasis placed on agents with the greatest potential for broad usage by multiple investigators in different regimens, Dr. Cheever explained.

"Everything that's happened progressed from that first workshop," Dr. Cheever added.

Not long after the series of prioritization workshops, a group of immunotherapy researchers approached then-NCI Director Dr. John E. Niederhuber and urged him to increase the institute's support for efforts to facilitate the development of high-priority agents, Dr. Merritt recalled. Dr. Niederhuber and DCTD leaders agreed, and the CITN concept was born.

Cancer Immunotherapy Trials Network logo

In addition, the Food and Drug Administration last year approved two cancer immunotherapies: ipilimumab (Yervoy)to treat advanced melanoma and sipuleucel-T (Provenge) for the treatment of advanced prostate cancer.

The impact of those approvals was enormous, said Dr. Jedd Wolchok, a CITN investigator at Memorial Sloan-Kettering Cancer Center. "For pharmaceutical companies and the industry to see a successful immunotherapy that can be administered in a doctor's office has really changed the field," Dr. Wolchok said.

Researchers have historically had difficulty gaining access to the diverse array of investigational immunotherapy agents that have shown significant promise in laboratory testing as well as early phase clinical trials. In some cases, the company that developed an agent prioritized its development for a disease other than cancer, or the agent needed to be developed in combination with other agents as part of a multi-component regimen.

Availability has "definitely been a major bottleneck," said Dr. Thomas Gajewski, a CITN investigator at the University of Chicago Medical Center. 

That is now beginning to change. Numerous companies are more interested in making agents available for study and developing new investigational immunotherapy agents, Dr. Wolchok said. Several are even establishing immuno-oncology departments.

"And we, as a community of cancer immunotherapy investigators, need to be prepared to help them test [these agents] in a thoughtful way," he continued. "And that's where the CITN can play a major role."

Collaboration Pushing Science Forward

Having a network of investigators and centers "means that we can initiate trials in a timely way," Dr. Merritt explained. "We don't have to wait for individual grants to get funded, with  [researchers] doing their own trials at their own institutions." And having multiple centers involved in each trial, he added, will significantly improve how quickly trials can accrue patients and be completed.

But the potential benefits go well beyond speedier trials, Dr. Gajewski stressed.

"With a network, data are shared, and data management and statistical analysis are all uniform," he explained. "Before data are published, we'll all be exchanging this information, so the cross-fertilization potential will be huge. Ideas will move much more readily among investigators and among projects."

The CITN has benefitted greatly from the support of staff from another NIH-funded clinical trials initiative run out of Fred Hutchinson, the HIV Vaccine Trials Network Exit Disclaimer supported by the National Institute of Allergy and Infectious Diseases, Dr. Cheever noted. And potential research collaborations are already being discussed between the CITN and a similar international cancer immunotherapy trials network led by Dr. Wolchok, the Cancer Vaccine Collaborative.

The CITN is funded for 5 years, Dr. Cheever said, and he has had encouraging discussions about obtaining additional funding from industry and philanthropy groups.

Getting the initial trials up and going is an important step, Dr. Merritt said. But it's just the beginning. "Several CITN working groups and its steering committee are now discussing the trial concepts for the next group of agents to move forward," he noted. "I'm very encouraged by the progress so far."

Carmen Phillips

The First Agents

Numerous types of immunotherapeutic agents have been developed, including T-cell and NK-cell growth factors like IL-15, others that stimulate T cells or activate dendritic cells, so-called immune checkpoint inhibitors like ipilimumab, and others that inhibit or neutralize factors secreted by tumors that suppress the immune system.

The first two agents to be tested in CITN-led trials, selected from the 20 identified in the 2007 workshop, will be IL-15 and a dendritic cell-activating  monoclonal antibody called CP-870,893.

The first human trial of IL-15 was recently launched at NCI by Dr. Thomas Waldmann, who co-discovered IL-15 nearly 18 years ago, and Dr. Kevin Conlon. For these first trials, NCI is manufacturing IL-15 at its drug production facility on the NCI-Frederick campus. The CITN trial of IL-15 is separate from Dr. Waldmann and Dr. Conlon's trial, but CITN investigators are working closely with Dr. Waldmann on IL-15's development, Dr. Cheever noted.

The Pfizer-developed CP-870,893—which targets the CD40 antigen on certain immune cells—has alreadyshown efficacy in a small phase I trial of patients with advanced pancreatic cancer. The CITN trial, to be led by Dr. Robert Vonderheide of the University of Pennsylvania, will test the CD40-targeted antibody as a presurgical treatment in patients with operable pancreatic cancer.

Planning and negotiations are underway to test several other treatment strategies, including the cytokineIL-7 and an agent in development that targets the immune checkpoint protein PD-1 on the surface of certain immune cells.

http://www.cancer.gov/ncicancerbulletin/022112/page6



Edited by 123Donna - Jun 16 2012 at 3:44pm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: May 01 2012 at 3:55pm

Pitt aims to prove therapy can offer new cancer hope

David Templeton
Pittsburgh Post-Gazette

04-27-12

April 27--A human clinical trial under way at UPMC's Hillman Cancer Center in Shadyside will help determine whether a combination of approved drugs based on a new theory of cancer can "revolutionize cancer therapy."

That's the explanation of lead researcher Michael T. Lotze, who says his team has combined interleukin 2 (IL-2) with hydroxychloroquine in a new therapy designed to be more effective and less toxic in curing cancer than IL-2 alone.

The new cancer theory, how the two drugs work in tandem and how the treatment works involve complicated science. The Pitt team starts with IL-2, a drug that strengthens the immune response to cancer but doesn't work in the majority of patients, in part, due to severe toxicity. It then adds an inexpensive drug, hydroxychloroquine, to serve a different role -- to reduce the cancer drug's toxicity and increase its cancer-killing efficiency.

IL-2, a hormone that promotes immune T cells that fight infections and cancer at local sites, is considered the only cancer cure available. But it's effective in only 10 percent of the patients with renal-cell (kidney) cancer and melanoma who qualify for the treatment.

One chief concern is IL-2's toxicity in high doses sent bodywide to fight cancer. The drug causes healthy tissue and organ cells to begin consuming themselves in a process known as autophagy -- Greek for "self-eating" -- that leads to vascular leakage among other serious side effects.

But a new Pitt theory about cancer says autophagy also helps explain how cancer cells produce tumors.

Dr. Lotze, professor of surgery, immunology and bioengineering at the University of Pittsburgh School of Medicine, said cancer patients who undergo IL-2 immunotherapy experience extreme influenza-like symptoms that many can't tolerate for the few days they receive it. But the oral medication hydroxychloroquine, originally used to treat patients with malaria and now used to treat patients with systemic lupus erythematosus, rheumatoid arthritis, HIV and other diseases, reduces IL-2 toxicity by inhibiting autophagy without hindering the drug assault on cancer.

The drug combination in mice with cancer proved to be "dramatically more effective" than IL-2 alone. Published April 3 in Cancer Research, the study was performed by Xiaoyan Liang, a UPMC scientist on the Lotze team at the cancer center.

Clinical-trial success could increase IL-2's use in treating kidney cancer and melanoma and expand that use to other major cancers.

With the two drugs already approved for use by the U.S. Food and Drug Administration, Pitt's Cancer Institute team hopes to test the new drug regimen on 60 renal-cell (kidney) patients. Those interested in participating should call 877-470-7241.

Michael Wong, professor of medicine at the Norris Comprehensive Cancer Center at the University of Southern California, said he's familiar with the study but was not involved in it.

The key problem with IL-2, he said, is that patients must be admitted to a hospital because of blood pressure problems and vascular leakage it causes, along with impacts on the liver, kidneys and other organs.

"The holy grail," he said, would be reductions in IL-2's toxic side effects so more patients could undergo the treatment.

"One in 10 people have a tremendous response from IL-2 -- a complete response where the tumor melts away," he said, describing it as a cure in that small percentage. But the1-in-10 success rate in those able to undergo the therapy has not budged for many years.

"In the Lotze trial, if they can get more patients in and move the needle to 2 out of 10 or 3 out of 10 -- if it truly works -- it's going to be dramatic," Dr. Wong said. "Any improvement would be mind-boggling because we've been stuck here for quite a while."

The traditional theory of cancer says a genetic mutation causes uncontrolled cell growth. But the Pitt team says cancer isn't just a disorder of cell growth, but just as much a disorder in cell death.

Rather than die in an organized, natural way through a process known as "apoptosis," as occurs with normal cells, a genetic mutation causes cancer cells to die through the process of necrosis following autophagy. Dr. Lotze describes necrosis as "a terrible, horrible, screaming-out-loud, blood-in-the-streets type of death."

In the process, cancer cells consume themselves and shed cellular parts into the tissue to keep other cancer cells alive. It also provides biological infrastructure to sustain tumor growth.

"Tumors just want to die," Dr. Lotze said. But those dying cancer cells promote autophagy and set the stage for their survival by recruiting immune cells and new cells to develop blood vessels. Those vessels help sustain the cancer cells that otherwise would die.

"What's new is our understanding of autophagy," he said. "Our innovation was to marry tumor immunology to autophagy."

The Pitt team's goal is to kill cancer cells naturally through immunology rather than allow autophagy to continue. Even with its toxic side effects, IL-2 remains "the closest to a [cancer] cure that we have," Dr. Lotze said.

Traditional chemotherapy, which can reduce tumor size and knock back cancer growth temporarily, also can promote rather than halt autophagy, which allows cancer to return with a vengeance, he said.

The Pitt team's theory about autophagy's role in cancer "is a novel one" that could make scientists "rethink what holds true" with cancer, Dr. Wong said. "It can shake the ground you stand on, and this is the first step in that direction."

If the clinical trial shows that the combination drug treatment is less toxic and more effective, Dr. Lotze said, "We think this can potentially revolutionize cancer therapy."

David Templeton: dtempleton@post-gazette.com or 412-263-1578.

___

(c)2012 the Pittsburgh Post-Gazette

Visit the Pittsburgh Post-Gazette at www.post-gazette.com

Distributed by MCT Information Services

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jun 03 2012 at 7:01pm
While not breast cancer related, promising research on immunotherapy clinical trials.

Cancer therapy that boosts immune system ready for wider testing

Two clinical trials led by Johns Hopkins Kimmel Cancer Center researchers in collaboration with other medical centers, testing experimental drugs aimed at restoring the immune system’s ability to spot and attack cancer, have shown promising early results in patients with advanced non-small cell lung cancer, melanoma, and kidney cancer. More than 500 patients were treated in the studies of two drugs that target the same immune-suppressive pathway, and the investigators say there is enough evidence to support wider testing in larger groups of patients

http://www.breakthroughdigest.com/medical-news/cancer-therapy-that-boosts-immune-system-ready-for-wider-testing/
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jun 08 2012 at 9:31pm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jun 16 2012 at 3:45pm

Drug Helps Immune System Fight Cancer, Study Says

William Weir, The Hartford Courant, Conn. 
The Hartford Courant, Connecticut

06-04-12

June 02--NEW HAVEN -- A study conducted in part by researchers at the Yale School of Medicine suggests that a new drug that bolsters the immune system can shrink tumors in certain cancers -- including lung cancer, which has been resistant to treatment.

The tumors of about one-fourth of the study's 300 patients with non-small cell lung cancer, renal cell cancer and advanced melanoma significantly decreased in size after the patients were given the drug.

The study -- which was also authored by researchers from Johns Hopkins University, Harvard University, Bristol-Myers Squibb and other institutions -- appears Saturday in the New England Journal of Medicine. Several of the researchers are also presenting their findings at the annual meeting of the American Society of Clinical Oncology in Chicago this weekend.

The drug, known as BMS-936558, was developed by Bristol-Myers Squibb and is still in the study phase.

The drug is an antibody designed to restore the functions of lymphocyte cells, known as T-cells, and to foil tumors' ability to fight off the immune system.

"What happens is that the T-cells look for things that shouldn't be in the body," said co-author Scott Gettinger, associate professor of medicine at Yale.

But sometimes, Gettinger said, "there's a communication between the T-cell and the tumor, which tells the T-cell to not attack it." The drug, he said, "binds to the T-cell, which doesn't allow the negative communication."

Tumors shrank by at least 30 percent in 28 percent of the melanoma patients; a slightly smaller percentage of renal cancer patients had similar reductions in tumors. And 18 percent of the lung cancer patients had tumor reductions of 30 percent or more.

Gettinger said the progress made in the lung cancer tumors was most surprising.

"Immunotherapy has been tried for a long time in lung cancer in prior studies and it never amounted to much," he said.

Gettinger said the drug has to go through the U.S. Food and Drug Administration approval process so it could be years before it is widely available.

___

(c)2012 The Hartford Courant (Hartford, Conn.)

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jan 03 2013 at 8:38pm

Revolutionary techniques could help harness patients’ own immune cells to fight disease


The human body contains immune cells programmed to fight cancer and viral infections, but they often have short lifespans and are not numerous enough to overcome attacks by particularly aggressive malignancies or invasions. Now researchers reporting in two separate papers in the January 4th issue of the Cell Press journal Cell Stem Cell used stem cell technology to successfully regenerate patients’ immune cells, creating large numbers that were long-lived and could recognize their specified targets: HIV-infected cells in one case and cancer cells in the other. The findings could help in the development of strategies to rejuvenate patients’ exhausted immune responses.

The techniques the groups employed involved using known factors to revert mature immune T cells into induced pluripotent stem cells (iPSCs), which can differentiate into virtually any of the body’s different cell types. The researchers then expanded these iPSCs and later coaxed them to redifferentiate back into T cells. Importantly, the newly made T cells were “rejuvenated” with increased growth potential and lifespan, while retaining their original ability to target cancer and HIV-infected cells. These findings suggest that manipulating T cells using iPSC techniques could be useful for future development of more effective immune therapies.

In one study, investigators used T cells from an HIV-infected patient. The redifferentiated cells they generated had an unlimited lifespan and contained long telomeres, or caps, on the ends of their chromosomes, which protect cells from aging. This is significant because normal aging of T cells limits their expansion, making them inefficient as therapies. “The system we established provides ‘young and active’ T cells for adoptive immunotherapy against viral infection or cancers,” says senior author Dr. Hiromitsu Nakauchi, of the University of Tokyo.

The other research team focused on T cells from a patient with malignant melanoma. The redifferentiated cells they created recognized the protein MART-1, which is commonly expressed on melanoma tumors. “The next step we are going to do is examine whether these regenerated T cells can selectively kill tumor cells but not other healthy tissues. If such cells are developed, these cells might be directly applied to patients,” says senior author Dr. Hiroshi Kawamoto, of the RIKEN Research Center for Allergy and Immunology. “This could be realized in the not-so-distant future.”

###

Nishimura et al.: “Generation of rejuvenated antigen-specific T cells by pluripotency reprogramming and redifferentiation.”

Vizcardo et al.: “Regeneration of human tumor antigen-specific T cells from iPS cells derived from mature CD8+ T cells.”

Contact: Mary Beth OLeary
moleary@cell.com
617-397-2802

http://www.breakthroughdigest.com/medical-news/revolutionary-techniques-could-help-harness-patients-own-immune-cells-to-fight-disease/

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jun 24 2013 at 9:06pm

Targeted viral therapy destroys breast cancer stem cells in preclinical experiments


A promising new treatment for breast cancer being developed at Virginia Commonwealth University Massey Cancer Center and the VCU Institute of Molecular Medicine (VIMM) has been shown in cell culture and in animal models to selectively kill cancer stem cells at the original tumor site and in distant metastases with no toxic effects on healthy cells, including normal stem cells. Cancer stem cells are critical to a cancer’s ability to recur following conventional chemotherapies and radiation therapy because they can quickly multiply and establish new tumors that are often therapy resistant.

The study, published in the International Journal of Cancer, focuses on a gene originally cloned in the laboratory of primary investigator Paul B. Fisher, M.Ph., Ph.D. The gene, melanoma differentiation associated gene-7 (mda-7), also known as interleukin (IL)-24, has been shown to directly impact two forms of cell suicide known as apoptosis and toxic autophagy, regulate the development of new blood vessels and also play a role in promoting cancer cell destruction by the immune system. In the present study, the researchers used a recombinant adenovirus vector, an engineered virus with modified genetic material, known as Ad.mda-7 to deliver the mda-7/IL-24 gene with its encoded protein directly to the tumor.

“Therapy with the mda-7/IL-24 gene has been shown to be safe in a phase I clinical trial involving patients with advanced cancers, and prior studies in my laboratory and with collaborators have shown that the gene could also be effective against breast, prostate, lung, colorectal, ovarian, pancreatic and brain cancers,” says Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics program at VCU Massey, chairman of VCU School of Medicine’s Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine. “Our study demonstrates that this therapy may someday be an effective way to eradicate both early and advanced stage breast cancer, and could even be used to reduce the risk of cancer recurrence.”

The researchers found that infection of human breast cancer cells with the adenovirus decreased the proliferation of breast cancer stem cells without affecting normal breast stem cells. It was also shown to induce a stress response in the cells that led to apoptosis by disrupting Wnt/B-catenin signaling, a process cells rely upon to transmit signals that initiate biological functions critical to survival. In mouse models, the therapy profoundly inhibited the growth of tumors generated from breast cancer stem cells and also killed cancer cells in distant, uninjected tumors.

Since discovering the mda-7/IL-24 gene, Fisher and his team have worked to develop better ways to deliver it to cancer cells, including two cancer “terminator” viruses known as Ad.5-CTV and Ad.5/3-CTV. Cancer terminator viruses are unique because they are designed to replicate only within cancer cells while delivering immune-modulating and toxic genes such as MDA-7/IL-24. Coupled with a novel stealth delivery technique known as ultrasound-targeted microbubble destruction (UTMD), researchers can now systemically deliver viruses and therapeutic genes and proteins directly to tumors and their surrounding tissue (microenvironment) at both primary and metastatic tumor sites. UTMD uses microscopic, gas-filled bubbles that can be paired with viral therapies, therapeutic genes and proteins, and imaging agents and can then be released in a site and target-specific manner via ultrasound. Fisher and his colleagues are pioneering this approach and have already reported success in experiments utilizing UTMD technology and mda-7/IL-24 gene therapy in prostate and colorectal cancer models.

“We are hopeful that this targeted gene therapy could be safely combined with conventional chemotherapies to significantly improve outcomes for patients with breast cancer and potentially a variety of other cancers,” says Fisher. “When paired with promising new delivery techniques such as UTMD, physicians may one day be able to better target site-specific cancers and also monitor the effectiveness of these types of therapies in real time.”

http://www.breakthroughdigest.com/medical-news/targeted-viral-therapy-destroys-breast-cancer-stem-cells-in-preclinical-experiments/

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Post Options Post Options   Thanks (0) Thanks(0)   Quote denise07 Quote  Post ReplyReply Direct Link To This Post Posted: Jun 24 2013 at 10:51pm
Donna,
Thank you so much for this information you are one fighting trooper who has our backs covered.
Love ya,
Denise
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Ditto! Thanks Donna!!!
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jun 28 2013 at 9:50pm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jul 03 2013 at 8:51am
This is the clinical trial, Phase 1 for MPDL3280A:


Engineered Antibody Demonstrated Safety, Efficacy in Wide Range of Advanced Tumors

  • The PD-L1 antibody MPDL3280A displayed antitumor activity across a range of cancer types, including lung, kidney, colon and stomach cancers.
  • MPDL3280A was well tolerated.
  • Phase I study results demonstrated no limiting toxicities.
WASHINGTON, D.C. — The engineered antibody MPDL3280A, which targets a protein called programmed death-ligand 1 (PD-L1), was safe and effective for several cancers, according to phase I study results presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.

“Our PD-L1 antibody was well tolerated, and there were no limiting toxicities,” said Michael S. Gordon, M.D., research director at Pinnacle Oncology Hematology in Scottsdale, Ariz. “It was active with antitumor activity across a broad range of cancers, and we have developed biomarker tools that we are testing, which may allow us to optimize patient selection for this novel therapy.”

PD-L1, a protein found on the surface of many cancer cells, impairs the immune system’s ability to fight cancer, according to Gordon. 

“PD-L1 is essentially a plug, which inserts into an outlet (PD-1) on the surface of the immune T cells,” Gordon said. “As the T cells come close to the tumor, for example, they are engaged by PD-L1, which inserts into the outlet on the surface of the T cell. That starts a signal inside the T cell that blocks the T cell’s ability to kill the cancer cell.” 

MPDL3280A, a human monoclonal antibody under development by Genentech, a member of the Roche Group, binds to PD-L1 and blocks this action.

Gordon and colleagues administered an escalating intravenous dose of MPDL3280A once every three weeks to 30 patients with a variety of locally advanced or metastatic solid tumors. They escalated the dose from 0.01 mg/kg to as high as 20 mg/kg. The data being presented are the preliminary data from the dose escalation cohorts of the ongoing phase I trial. 

No dose-limiting toxicities or grade 4 adverse events have been reported. “We were able to escalate to the top dose without being limited by any serious side effects,” Gordon said.

“From a therapeutic standpoint, we were able to identify a number of patients with a broad range of diseases, including lung cancer, kidney cancer, colon cancer and stomach cancer, who responded to the treatment,” he said. 

A second protein, called PD-L2, fits into the same T-cell “outlet” as PD-L1, according to Gordon. MPDL3280A is specific for PD-L1; it does not block PD-L2, which is expressed in noncancerous tissues including the lung, he added. 

“One would anticipate, compared with drugs being developed to specifically block the T-cell outlet (PD-1) and, therefore, block the relationship between the outlet and both PD-L1 and PD-L2, that we might see less lung or pulmonary toxicity with MPDL3280A. But we need to conduct larger studies to confirm this.”
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jul 13 2013 at 11:27pm
Could this be what we've been waiting for?  I hope we don't have to wait 5 or 10 years to find out.

Exclusive: Cancer - A cure just got closer thanks to a tiny British company - and the result could change lives of millions

A revolution is brewing on an English business park as scientists harness our natural-born killers – the T cells – to target malign tumours

A single-storey workshop on a nondescript business park in Oxfordshire is not the sort of place where you would expect scientific revolutions to take place. But behind the white-painted walls of this small start-up company, scientists are talking about the impossible – a potential cure for cancer.

For the past 20 years, the former academics who set up Immunocore have worked hard on realising their dream of developing a totally new approach to cancer treatment, and finally it looks as if their endeavours are beginning to pay off. In the past three weeks, the company has signed contracts with two of the biggest players in the pharmaceuticals industry which could lead to hundreds of millions of pounds flowing into the firm's unique research on cancer immunotherapy – using the body's own immune system to fight tumour cells.

Immunocore is probably the only company in the world that has developed a way of harnessing the power of the immune system's natural-born killer cells: the T-cells of the blood which nature has designed over millions of years of evolution to seek out and kill invading pathogens, such as viruses and bacteria. T-cells are not nearly as good at finding and killing cancer cells, but the hard-nosed executives of the drugs industry – who are notoriously cautious when it comes to investments – believe Immunocore may have found a way around this so that cancer patients in future are able to fend off their disease with their own immune defences.

"Immunotherapy is radically different," said Bent Jakobsen, the Danish-born chief scientific officer of Immunocore who started to study T-cells 20 years ago while working at the Medical Research Council's Laboratory of Molecular Biology in Cambridge. "It doesn't do away with the other cancer treatments by any means, but it adds something to the arsenal that has one unique feature – it may have the potency to actually cure cancer," Dr Jakobsen said.

It is this potency that has attracted the attention of Genentech in California, owned by the Swiss giant Roche, and Britain's GlaxoSmithKline. Both companies have independently signed deals with Immunocore that could result in up to half a billion pounds being invested in new cancer treatments based on its unique T-cell therapy.

It is no understatement to say that cancer immunotherapy, or immuno-oncology as it is technically called, represents a sea change in terms of cancer treatment. Cancer in the past has been largely treated by slicing (surgery), poisoning (chemotherapy) or burning (radiotherapy). All are burdened with the inherent problem of how to spare healthy tissue from irreparable damage while ensuring that every cancer cell is killed, deactivated or removed.

Now there is another approach based on the immune system, a complex web of cells, tissues and organs that constantly strive to keep the body free of disease, which almost certainly includes keeping cancerous cells in check.

For many years, scientists have realised that the immune system plays a key role in cancer prevention. There is ample evidence of this, not least from patients who are immune-suppressed in some way – they are more likely than other patients to develop cancer.

The immune system has two basic ways of fighting invading pathogens and the body's own cells that have gone awry. One involves the release of free-floating proteins, or antibodies, that lock on to an invader, triggering other immune cells to come in and sweep them away.

Many organisations have tried to develop anti-cancer treatments based on antibodies, with limited success, Dr Jakobsen said. Part of the problem is that antibodies are not really designed to recognise cells. What Immunocore has done is to build a therapy around the second arm of the immune system, known as cellular immunity, where T-cells seek out and destroy invading pathogens.

"There are a lot of companies working with antibodies but we are virtually the only company in the world that has managed to work with T-cells. It has taken 20 years and from that point we are unique," Dr Jakobsen said.

Immunocore has found a way of designing small protein molecules, which it calls ImmTACs, that effectively act as double-ended glue. At one end they stick to cancer cells, strongly and very specifically, leaving healthy cells untouched. At the other end they stick to T-cells.

The technology is based on the "T-cell receptor", the protein that sticks out of the surface of the T-cell and binds to its enemy target. Immunocore's ImmTACs are effectively independent T-cell receptors that are "bispecific", meaning they bind strongly to cancer cells at one end, and T-cells at the other – so introducing cancer cells to their nemesis.

"What we can do is to use that scaffold of the T-cell receptor to make something that is very good at recognising cancer even if it doesn't exist naturally," said Dr Jakobsen. "Although T-cells are not very keen at recognising cancer, we can force them to do so. The potential you have if you can engineer T-cell receptors is quite enormous. You can find any type of cell and any kind of target. This means the approach can in theory be used against any cancer, whether it is tumours of the prostate, breast, liver or the pancreas.

The key to the success of the technique is being able to distinguish between a cancer cell and a normal, healthy cell. Immunocore's drug does this by recognising small proteins or peptides that stick out from the surface membrane of cancer cells. All cells extrude peptides on their membranes and these peptides act like a shop window, telling scientists what is going on within the cell, and whether it is cancerous or not.

"All these little peptides tell you the story of the cell. The forest of them on the cell surface is a sort of display saying 'I am this kind of cell. This is my identity and this is everything going on inside me'," Dr Jakobsen explained.

Immunocore is building up a database of peptide targets on cancer cells in order to design T-cell receptors that can target them, leaving healthy cells alone and so minimising possible side effects – or that is the hope.

The first phase clinical trial of the company's therapy, carried out on a small number of patients in Britain and the United States with advanced melanoma, has shown that people can tolerate the drug reasonably well and preliminary results suggest there are "early signs of anti-tumour activity", the company said.

A danger with deploying T-cells against cancer is their potency. Yet it is this very potency that it is so exciting because it could lead to a cure for metastatic disease that has spread around the body, Dr Jakobsen said. "You can never make a single-mechanism drug that would come anywhere near a T-cell in terms of its potency.

"If you want to make an impact on cancer you need something that is incredibly potent – but when something goes wrong, it goes badly wrong. I think the honest truth about all cancer treatments is that no matter how much we test and do beforehand, it will continue to go wrong sometimes."

One infamous case of something going disastrously wrong was a clinical trial in 2006 at Northwick Park Hospital in London where scientists were testing a powerful immuno-regulatory drug on six volunteers. All suffered serious side effects caused by the overstimulation of their immune systems.

But Dr Jakobsen said the clinical trial of Immunocore's T-cell drug, as well as future trials, are inherently safe because they are based on incremental rises in dose. All indications suggest it will lead to the expected breakthrough.

He added: "All the pharma companies have come to the realisation that immunotherapy may hold the ultimate key to cancer; it is the missing link in cancer treatment that can give cures."

"They have seen this technology develop. It has come over the mountain top, if you like. With our melanoma trial they have seen it is safe – and it is working."

T-cell therapy

Using the body's immune system to fight cancer is one of the most promising areas of therapy, and could prove particularly helpful in the treatment of metastatic disease, when the cancer has spread from its original site.

The immune system is complex and is composed of many kinds of cells, proteins and chemical messengers that modulate how it works. Scientists are working on ways of exploiting the immune defences to recognise and eliminate cells that have become cancerous.

One of the most interesting examples is ipilimumab, a "monoclonal antibody" made by Bristol-Myers-Squib. It recognises and binds to a molecule, called CTLA-4, which is found on the T-cells of the immune system. CTLA-4 normally keeps T-cells from proliferating, but in the presence of ipilimumab, it becomes blocked, allowing T-cells to increase in numbers, so leading them to attack cancer cells.

Other drugs based on monoclonal antibodies are designed to attack tumours more directly. When they bind to a cancerous cell, it serves as a signal for other cells of the immune system to come in and sweep the cancer cells away.

The trouble is that cancer cells are notoriously mutational. Eliminating 99.9 per cent of cancer cells in a patient may be an improvement, but it still leaves 0.1 per cent that could "escape".

One hope of using T-cells, is that this possibility of escape is narrowed down, or even eliminated. Of course, these are still early days. This is only just beginning to go through the first clinical trials. It could take five or 10 years before we know whether or not they work.

http://www.independent.co.uk/news/science/exclusive-cancer--a-cure-just-got-closer-thanks-to-a-tiny-british-company--and-the-result-could-change-lives-of-millions-8707590.html

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Oct 01 2013 at 12:36pm
Another Immunotherapy drug trial to keep our eye on.


Scancell reports progress across a number of trials

Scancell, which develops novel immunotherapies for the treatment of cancer, on Tuesday revealed that four out of the six evaluable patients treated with either the 2mg or 4mg dose of its SCIB1 drug still remain alive.

It said the mean survival time in this group of five Stage IV and one Stage IIIb patients is currently 21 months from trial entry.

As a result of the positive developments and minimal sideeffects seen with the 4mg dose, Scancell has initiated evaluation of an 8mg dose in up to six patients with measurable tumours, and is currently seeking the appropriate regulatory approval to treat a further 10 patients.

The group also reported that planning is underway for the preclinical and clinical development of SCMod1 as an immunotherapeutic, provisionally for the treatment of triple-negative breast cancer, ovarian and endometrial cancers. First-in-man clinical studies are scheduled to start in 2016.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Nov 22 2013 at 11:48am
Immune system mutations found in breast cancers
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Mar 07 2014 at 9:07am
Some cancers evade detection by silencing parts of immune system cells
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: May 26 2014 at 11:35pm
Research Worth Watching: Immunotherapy
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jun 03 2014 at 10:41pm
Immunotherapy May Be an Option in Challenging Breast Cancer, Mayo Clinic Study Finds

 A promising new study from Mayo Clinic, in conjunction with Caris Life Sciences, points to immunotherapy as a possible treatment option for patients with the difficult-to-treat triple negative breast cancer mutation. The study was presented this week at the 50th annual meeting of the American Society of Clinical Oncology in Chicago.

“This study may change our ability to treat triple negative breast cancer patients,” says Barbara Pockaj, M.D., lead investigator of the study and Mayo Clinic surgeon. “We may have signs that these patients can be treated with immunotherapy. We don’t have a lot of options for these patients and this would really expand our options.”

Triple negative breast cancer is an aggressive form of breast cancer that evades the immune system because it lacks expression of genes for estrogen receptor, progesterone receptor and HER2. This limits treatment options. The study examined biomarkers involved in immune evasion including the gene PD-L1 and its association with other biological pathways as potential treatment options. In other cancers, patients who have the PD-L1 gene have been treated with immunotherapy – enhancing the body’s immune system – and some of the results have been dramatic, Dr. Pockaj says.

“This is important because immunotherapy is evolving as an effective treatment for patients with cancer,” she says. “We’ve seen remarkable results with patients with melanoma, renal cell carcinoma and even lung cancer. The question is, ‘Can we expand this type of treatment to patients with breast cancer?’”

The study analyzed 511 triple negative breast cancer samples using a multiplatform approach, including whole genome mRNA expression, protein expression, gene copy number changes and gene sequencing. The study found that 25 to 30 percent had the PD-L1 gene, which means those patients may be candidates for immunotherapy. There is a suggestion that the percentage may be even higher for patients who carry the BRCA1 gene, which produces tumor suppressor proteins. While the results need further investigation, they illustrate how molecular profiling can be used to identify potential treatment targets in triple negative breast cancer and other difficult-to-treat cancers.

“We now want to do validation studies in which we would hope to determine whether those patients who overexpress PD-L1 also have changes in their DNA repair genes,” Dr. Pockaj says. “And if they have both, it suggests the combination immunotherapy and chemotherapy may work.”

http://www.newswise.com/articles/immunotherapy-may-be-an-option-in-challenging-breast-cancer-mayo-clinic-study-finds


http://truebluetribune.com/caris-life-sciences-biomarker-research-suggests-role-for-immune-targeted-therapies-in-subsets-of-patients-with-triple-negative-breast-cancer-tnbc/3134



Edited by 123Donna - Jun 03 2014 at 10:42pm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote MomMom44 Quote  Post ReplyReply Direct Link To This Post Posted: Jun 04 2014 at 5:27pm
This looks so promising!  Thank you for making us aware of it Donna.  Wonder how far off this is?
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Mark4Lori Quote  Post ReplyReply Direct Link To This Post Posted: Jun 11 2014 at 1:02pm
I agree.  This looks great! 
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