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  • richardmitnick 10:42 am on July 31, 2017 Permalink | Reply
    Tags: , , , , Immunotherapy, It wouldn’t have been obvious that PTPN2 is a good drug target for the immunotherapy of cancer, , PD-1 checkpoint inhibitors have transformed the treatment of many cancers   

    From HMS: “Attack Mode “ 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School


    Genetic screening for cancer immunotherapy targets. Cancer cells (colored shapes), each with a different CRISPR-Cas9-mediated gene knocked out. T cells (red) destroy the cancer cells that have had essential immune evasion genes knocked out. Image: Haining Lab, Dana-Farber/Boston Children’s.

    A novel screening method developed by a team at Harvard Medical School and Dana-Farber/Boston Children’s Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has revealed new drug targets that could potentially enhance the effectiveness of PD-1 checkpoint inhibitors, a promising new class of cancer immunotherapy.

    In findings published online today by Nature http://www.nature.com/nature/journal/v547/n7664/full/nature23270.html the Dana-Farber/Boston Children’s team, led by pediatric oncologist W. Nick Haining, reports that deletion of the PTPN2 gene in tumor cells made them more susceptible to PD-1 checkpoint inhibitors. PD-1 blockade is a drug that “releases the brakes” on immune cells, enabling them to locate and destroy cancer cells.

    “PD-1 checkpoint inhibitors have transformed the treatment of many cancers,” said Haining, HMS associate professor of pediatrics at Dana-Farber/Boston Children’s, associate member of the Broad Institute of MIT and Harvard, and senior author on the new paper. “Yet despite the clinical success of this new class of cancer immunotherapy, the majority of patients don’t reap a clinical benefit from PD-1 blockade.”

    That, Haining said, has triggered a rush of additional trials to investigate whether other drugs, when used in combination with PD-1 inhibitors, can increase the number of patients whose cancer responds to the treatment.

    “The challenge so far has been finding the most effective immunotherapy targets and prioritizing those that work best when combined with PD-1 inhibitors,” Haining said. “So, we set out to develop a better system for identifying new drug targets that might aid the body’s own immune system in its attack against cancer.

    “Our work suggests that there’s a wide array of biological pathways that could be targeted to make immunotherapy more successful,” Haining continued. “Many of these are surprising pathways that we couldn’t have predicted. For instance, without this screening approach, it wouldn’t have been obvious that PTPN2 is a good drug target for the immunotherapy of cancer.”

    Sifting through thousands of potential targets

    To cast a wide net, the paper’s first author Robert Manguso, a graduate student in Haining’s lab, designed a genetic screening system to identify genes used by cancer cells to evade immune attack. He used CRISPR-Cas9, a genome editing technology that works like a pair of molecular scissors to cleave DNA at precise locations in the genetic code, to systematically knock out 2,368 genes expressed by melanoma skin cancer cells. Manguso was then able to identify which genes, when deleted, made the cancer cells more susceptible to PD-1 blockade.

    Manguso started by engineering the melanoma skin cancer cells so that they all contained Cas9, the cutting enzyme that is part of the CRISPR editing system. Then, using a virus as a delivery vehicle, he programmed each cell with a different single-guide-RNA (sgRNA) sequence of genetic code. In combination with the Cas9 enzyme, the sgRNA codes—about 20 amino acids in length—enabled 2,368 different genes to be eliminated.

    By injecting the tumor cells into mice and treating them with PD-1 checkpoint inhibitors, Manguso was then able to tally up which modified tumor cells survived. Those that perished had been sensitized to PD-1 blockade as a result of their missing gene.

    Using this approach, Manguso and Haining first confirmed the role of two genes already known to be immune evaders—PD-L1 and CD47, drug inhibitors that are already in clinical trials. They then discovered a variety of new immune evaders that, if inhibited therapeutically, could enhance PD-1 cancer immunotherapy. One such newly found gene of particular interest is PTPN2.

    “PTPN2 usually puts the brakes on the immune signaling pathways that would otherwise smother cancer cells,” Haining said. “Deleting PTPN2 ramps up those immune signaling pathways, making tumor cells grow slower and die more easily under immune attack.”

    Gaining more ground

    With the new screening approach in hand, Haining’s team is quickly scaling up their efforts to search for additional novel drug targets that could boost immunotherapy.

    Haining says the team is expanding their approach to move from screening thousands of genes at a time to eventually being able to screen the whole genome and to move beyond melanoma to colon, lung, renal carcinoma and more. He’s assembled a large team of scientists spanning Dana-Farber/Boston Children’s and the Broad to tackle the technical challenges that accompany screening efforts on such a large scale.

    In the meantime, while more new potential drug targets are likely around the corner, Haining’s team is taking action based on their findings about PTPN2.

    “We’re thinking hard about what a PTPN2 inhibitor would look like,” said Haining. “It’s easy to imagine making a small molecule drug that turns off PTPN2.”

    This work was supported by the Broad Institute of Harvard and MIT (BroadIgnite and Broadnext10 awards) and the National Institute of General Medical Sciences (T32GM007753).

    See the full article here .

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    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

  • richardmitnick 3:27 pm on June 25, 2017 Permalink | Reply
    Tags: , Immunotherapy, , , , TACC Lonestar supercomputer, TACC Stampede supercomputer   

    From Science Node: “Computer simulations and big data advance cancer immunotherapy” 

    Science Node bloc
    Science Node

    09 Jun, 2017 [Where has this been?]
    Aaron Dubrow

    Courtesy National Institute of Allergy and Infectious Diseases.

    Supercomputers help classify immune response, design clinical trials, and analyze immune repertoire data.
    Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. Immunotherapy fights cancer by supercharging the immune system’s natural defenses (include T-cells) or contributing additional immune elements that can help the body kill cancer cells. [Credit: NIAID]

    The body has a natural way of fighting cancer – it’s called the immune system, and it is tuned to defend our cells against outside infections and internal disorder. But occasionally, it needs a helping hand.

    In recent decades, immunotherapy has become an important tool in treating a wide range of cancers, including breast cancer, melanoma and leukemia.

    But alongside its successes, scientists have discovered that immunotherapy sometimes has powerful — even fatal — side-effects.

    Identifying patient-specific immune treatments

    Not every immune therapy works the same on every patient. Differences in an individual’s immune system may mean one treatment is more appropriate than another. Furthermore, tweaking one’s system might heighten the efficacy of certain treatments.

    Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. Immunotherapy fights cancer by supercharging the immune system’s natural defenses (include T-cells) or contributing additional immune elements that can help the body kill cancer cells. [Credit: NIAID]

    Researchers from Wake Forest School of Medicine and Zhejiang University in China developed a novel mathematical model to explore the interactions between prostate tumors and common immunotherapy approaches, individually and in combination.

    In a study published in Nature Scientific Reports, they used their model to predict how prostate cancer would react to four common immunotherapies.

    The researchers incorporated data from animal studies into their complex mathematical models and simulated tumor responses to the treatments using the Stampede supercomputer at the Texas Advanced Computing Center (TACC).

    Dell Poweredge U Texas Austin Stampede Supercomputer. Texas Advanced Computer Center 9.6 PF

    “We do a lot of modeling which relies on millions of simulations,” says Jing Su, a researcher at the Center for Bioinformatics and Systems Biology at Wake Forest School of Medicine and assistant professor in the Department of Diagnostic Radiology.

    “To get a reliable result, we have to repeat each computation at least 100 times. We want to explore the combinations and effects and different conditions and their results.”

    TACC’s high performance computing resources allowed the researchers to highlight a potential therapeutic strategy that may manage prostate tumor growth more effectively.

    Designing more efficient clinical trials

    Biological agents used in immunotherapy — including those that target a specific tumor pathway, aim for DNA repair, or stimulate the immune system to attack a tumor — function differently from radiation and chemotherapy.

    Because traditional dose-finding designs are not suitable for trials of biological agents, novel designs that consider both the toxicity and efficacy of these agents are imperative.

    Chunyan Cai, assistant professor of biostatistics at UT Health Science Center (UTHSC)’s McGovern Medical School, uses TACC systems to design new kinds of dose-finding trials for combinations of immunotherapies.


    Writing in the Journal of the Royal Statistics Society Series C (Applied Statistics), Cai and her collaborators, Ying Yuan, and Yuan Ji, described efforts to identify biologically optimal dose combinations for agents that target the PI3K/AKT/mTOR signaling pathway, which has been associated with several genetic aberrations related to the promotion of cancer.

    After 2,000 simulations on the Lonestar supercomputer for each of six proposed dose-finding designs, they discovered the optimal combination gives higher priority to trying new doses in the early stage of the trial.

    TACC Lonestar Cray XC40 supercomputer

    The best case also assigns patients to the most effective dose that is safe toward the end of the trial.

    “Extensive simulation studies show that the design proposed has desirable operating characteristics in identifying the biologically optimal dose combination under various patterns of dose–toxicity and dose–efficacy relationships,” Cai concludes.

    Whether in support of population-level immune response studies, clinical dosing trials, or community-wide efforts, TACC’s advanced computing resources are helping scientists put the immune system to work to better fight cancer.

    See the full article here .

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    Science Node is an international weekly online publication that covers distributed computing and the research it enables.

    “We report on all aspects of distributed computing technology, such as grids and clouds. We also regularly feature articles on distributed computing-enabled research in a large variety of disciplines, including physics, biology, sociology, earth sciences, archaeology, medicine, disaster management, crime, and art. (Note that we do not cover stories that are purely about commercial technology.)

    In its current incarnation, Science Node is also an online destination where you can host a profile and blog, and find and disseminate announcements and information about events, deadlines, and jobs. In the near future it will also be a place where you can network with colleagues.

    You can read Science Node via our homepage, RSS, or email. For the complete iSGTW experience, sign up for an account or log in with OpenID and manage your email subscription from your account preferences. If you do not wish to access the website’s features, you can just subscribe to the weekly email.”

  • richardmitnick 3:28 pm on May 26, 2017 Permalink | Reply
    Tags: , , Immunotherapy, ,   

    From Hopkins: “FDA approves cancer drug for personalized immunotherapy approach” 

    Johns Hopkins
    Johns Hopkins University

    Vanessa Wasta

    T-cells attacking a cancer cell. Image credit: istock

    Earlier this week, for the first time, a drug was FDA-approved for cancer based on disease genetics rather than type.

    Developed from 30 years of basic research at Johns Hopkins and its Bloomberg–Kimmel Institute, the drug, pembroluzimab, now can be used for colon, pancreatic, stomach, ovarian, and other cancers if genetic testing reveals defects in so-called mismatch repair genes.

    Experts at the Bloomberg–Kimmel Institute designed the first clinical trial to test the theory that patients whose tumors have defects in mismatch repair genes may respond better to immunotherapy. Results of the trial were presented and published in 2015 at the American Society of Clinical Oncology Annual Meeting and published online by The New England Journal of Medicine.

    See the full article here .

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    Johns Hopkins Campus

    The Johns Hopkins University opened in 1876, with the inauguration of its first president, Daniel Coit Gilman. “What are we aiming at?” Gilman asked in his installation address. “The encouragement of research … and the advancement of individual scholars, who by their excellence will advance the sciences they pursue, and the society where they dwell.”

    The mission laid out by Gilman remains the university’s mission today, summed up in a simple but powerful restatement of Gilman’s own words: “Knowledge for the world.”

    What Gilman created was a research university, dedicated to advancing both students’ knowledge and the state of human knowledge through research and scholarship. Gilman believed that teaching and research are interdependent, that success in one depends on success in the other. A modern university, he believed, must do both well. The realization of Gilman’s philosophy at Johns Hopkins, and at other institutions that later attracted Johns Hopkins-trained scholars, revolutionized higher education in America, leading to the research university system as it exists today.

  • richardmitnick 12:27 pm on May 20, 2017 Permalink | Reply
    Tags: Antibody for fighting cancer emerges, , , Immunotherapy, LAP+ cells are increased in human cancer and predict a poor prognosis, , , T cells   

    From MedicalXpress: “Antibody for fighting cancer emerges” 

    Medicalxpress bloc



    Brigham and Women’s Hospital

    May 19, 2017
    No writer credit found

    Killer T cells surround a cancer cell. Credit: NIH

    While studying the underpinnings of multiple sclerosis, investigators at Brigham and Women’s Hospital came across important clues for how to treat a very different disease: cancer. In a paper published in Science Immunology, a group of researchers led by neurologist Howard Weiner, MD, describe an antibody that can precisely target regulatory T cells which in turn unleashes the immune system to kill cancer cells. The team reports that the antibody decreased tumor growth in models of melanoma, glioblastoma and colorectal carcinoma, making it an attractive candidate for cancer immunotherapy.

    “As a neurologist, I never expected I would be publishing a paper about cancer immunotherapy, but as my team studied a subpopulation of T cells that are supposed to prevent autoimmune disease, we had an idea: if cancer is the opposite of an autoimmune disease, we could turn our investigations around and think about how to restore the immune system’s ability to prevent cancer’s growth,” said Weiner, co-director the Ann Romney Center for Neurologic Diseases at BWH.v

    The Weiner lab has been studying regulatory T cells (Tregs) for many years. Tregs, which help maintain the immune system’s tolerance of “self,” can, inadvertently, promote cancer’s growth by preventing the body’s immune system from detecting and attacking cancer cells. The researchers found that they could precisely target Tregs using an antibody that locks in on a molecular complex that’s uniquely expressed on the cell surface of Tregs. The team developed these so-called anti-LAP antibodies initially to investigate the development of multiple sclerosis, but realized their work had implications for the study of cancer.

    Previous studies have shown that LAP+ cells are increased in human cancer and predict a poor prognosis. Being able to target these cells could offer a new way to treat the disease.

    In the current study, the team used preclinical models to investigate how well anti-LAP antibodies could work in blocking the essential mechanisms of Tregs and restoring the immune system’s ability to fight cancer. They found that anti-LAP acts on multiple cell populations to promote the immune system’s ability to fight cancer, including increasing the activity of certain types of T cells and enhancing immune memory.

    “In addition to studying its therapeutic effect, we wanted to characterize the mechanism by which the anti-LAP antibody can activate the immune system,” said lead author Galina Gabriely, PhD, a scientist in the Weiner laboratory. “We found that it affects multiple arms of the immune system.”

    The current study has been conducted in preclinical models of cancer. In order to move this work toward the clinic, Tilos Therapeutics will be expanding on the Weiner lab’s research to modify the antibody for use in humans, a process that usually takes several years.

    “I see this work as the perfect example of how research in all branches of immunology into the mechanistic underpinnings of disease can have a huge impact on other fields, such as oncology,” said Barbara Fox, PhD, CEO of Tilos Therapeutics.

    See the full article here .

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    Medical Xpress is a web-based medical and health news service that is part of the renowned Science X network. Medical Xpress features the most comprehensive coverage in medical research and health news in the fields of neuroscience, cardiology, cancer, HIV/AIDS, psychology, psychiatry, dentistry, genetics, diseases and conditions, medications and more.

  • richardmitnick 11:01 am on May 13, 2017 Permalink | Reply
    Tags: , , , Immunotherapy,   

    From ICL: “A lead candidate for immunotherapy may increase tumour growth in certain cancers” 

    Imperial College London
    Imperial College London

    12 May 2017
    Hayley Dunning

    Boosting a part of the immune system known to have anti-tumour properties may actually help tumours grow in cancers linked to chronic inflammation. No image credit.

    Cancer immunotherapies boost aspects of the body’s normal immune system, to help fight tumours. They are part of a fast-evolving field of research and medicine, with several types of immunotherapies currently in clinical trials.

    Now, a research team at Imperial College London has found that in a mouse model developing liver cancer, one immunoreceptor – attractive candidate for immunotherapies – promoted rather than delayed tumour growth.

    The researchers believe this could have implications for the effectiveness of immunotherapy in combating human cancers caused by inflammation, such as some liver and colon cancers. The study, funded by the Wellcome, Trust was published in Nature Communications earlier this year.

    Lead author Dr Nadia Guerra from the Department of Life Sciences at Imperial, said: “Immunotherapies have shown unprecedented successes in treating cancer patients with advanced forms of cancer, especially metastatic melanomas. These therapies are now being tested in various type of cancer and novel combination approaches are being developed at a very fast pace.

    “Nonetheless, there are still challenges ahead to optimise those therapies and reduce adverse effects. Scientists and clinicians are working at identifying cancer patients that would benefit the most from those therapies to increase success rates and hopefully achieve complete remission.”

    How immunotherapies tackle cancer

    The part of the immune system involved in the study is called NKG2D (Natural Killer Group 2 member D). NKG2D is a type of immunoreceptor – a molecule present on the surface of the body’s immune cells that recognises signals from normal cells that are distressed.

    For example, if a normal cell is infected with a virus, it will display molecules on its surface that the NKG2D immunoreceptor can detect. The immune cell then directs a lethal hit that destroys the infected cell.

    Dr Guerra first showed ten years ago that this mechanism also works against cancerous tumours – demonstrated by the fact that tumours grew faster in mice that had their NKG2D activity supressed.

    However, NKG2D contributes to inflammation and has been found to play a role in chronic inflammatory disorders, such as Crohn’s disease. In this case, the NKG2D misfires and attacks normal cells instead of damaged ones.

    The paradoxical effect of inflammation

    The team looked into whether NKG2D’s roles in chronic inflammation and cancer could help tumours to grow in these types of cancer.

    To do this, they used a mouse model of liver cancer driven by inflammation. Human and mouse NKG2D receptors are very similar, so the results are thought to be relevant to human liver cancers.

    They found that the tumours actually grew faster in mice with functional NKG2D than in mice that lacked NKG2D. Dr Guerra said: “NKG2D is a potent anti-tumour agent, but we have found that it might actually have the opposite effect in tumours that arise and/or grow from a background of chronic inflammation.”

    In these environments, the liver tissue undergoes cycles of damage and repair continuously as it is fought by NKG2D, making the cells more at risk of developing genetic mutations.

    Dr Guerra said: “The paradoxical effect of NKG2D we discovered exposes the need to selectively target the types of cancer that will benefit from NKG2D-based immunotherapy. What is beneficial in fighting one type of cancer might have the opposite effect in another.

    “We need to be more precise when administering a chosen therapy to a particular type of cancer. Our data unravels a conceptual shift that will inform which cancer these new therapies can benefit the most, and help match the best therapy to each patient.”

    See the full article here .

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    Imperial College London

    Imperial College London is a science-based university with an international reputation for excellence in teaching and research. Consistently rated amongst the world’s best universities, Imperial is committed to developing the next generation of researchers, scientists and academics through collaboration across disciplines. Located in the heart of London, Imperial is a multidisciplinary space for education, research, translation and commercialisation, harnessing science and innovation to tackle global challenges.

  • richardmitnick 2:42 pm on December 26, 2016 Permalink | Reply
    Tags: , Immunotherapy, , Nanodisc technology, ,   

    From U Michigan via phys.org: “Nanodiscs deliver personalized cancer therapy to immune system” 

    U Michigan bloc

    University of Michigan



    December 26, 2016
    Researchers at the University of Michigan have had initial success in mice using nanodiscs to deliver a customized therapeutic vaccine for the treatment of colon and melanoma cancer tumors.

    “We are basically educating the immune system with these nanodiscs so that immune cells can attack cancer cells in a personalized manner,” said James Moon, the John Gideon Searle assistant professor of pharmaceutical sciences and biomedical engineering.

    Personalized immunotherapy is a fast-growing field of research in the fight against cancer.

    The therapeutic cancer vaccine employs nanodiscs loaded with tumor neoantigens, which are unique mutations found in tumor cells. By generating T-cells that recognize these specific neoantigens, the technology targets cancer mutations and fights to eliminate cancer cells and prevent tumor growth.

    Unlike preventive vaccinations, therapeutic cancer vaccines of this type are meant to kill established cancer cells.

    “The idea is that these vaccine nanodiscs will trigger the immune system to fight the existing cancer cells in a personalized manner,” Moon said.

    The nanodisc technology was tested in mice with established melanoma and colon cancer tumors. After the vaccination, twenty-seven percent of T-cells in the blood of the mice in the study targeted the tumors.

    When combined with immune checkpoint inhibitors, an existing technology that amplifies T-cell tumor-fighting responses, the nanodisc technology killed tumors within 10 days of treatment in the majority of the mice. After waiting 70 days, researchers then injected the same mice with the same tumor cells, and the tumors were rejected by the immune system and did not grow.

    “This suggests the immune system ‘remembered’ the cancer cells for long-term immunity,” said Rui Kuai, U-M doctoral student in pharmaceutical sciences and lead author of the study.

    “The holy grail in cancer immunotherapy is to eradicate tumors and prevent future recurrence without systemic toxicity, and our studies have produced very promising results in mice,” Moon said.

    The technology is made of extremely small, synthetic high density lipoproteins measuring roughly 10 nanometers. By comparison, a human hair is 80,000 to 100,000 nanometers wide.

    “It’s a powerful vaccine technology that efficiently delivers vaccine components to the right cells in the right tissues. Better delivery translates to better T-cell responses and better efficacy,” said study co-senior author Anna Schwendeman, U-M assistant professor of pharmacy.

    The next step is to test the nanodisc technology in a larger group of larger animals, Moon said.

    EVOQ Therapeutics, a new U-M spinoff biotech company, has been founded to translate these results to the clinic. Lukasz Ochyl, a doctoral student in pharmaceutical sciences, is also a co-author.

    The study, Designer vaccine nanodiscs for personalized cancer immunotherapy, is scheduled for advance online publication Dec. 26 on the Nature Materials website.

    See the full article here .

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    U MIchigan Campus

    The University of Michigan (U-M, UM, UMich, or U of M), frequently referred to simply as Michigan, is a public research university located in Ann Arbor, Michigan, United States. Originally, founded in 1817 in Detroit as the Catholepistemiad, or University of Michigania, 20 years before the Michigan Territory officially became a state, the University of Michigan is the state’s oldest university. The university moved to Ann Arbor in 1837 onto 40 acres (16 ha) of what is now known as Central Campus. Since its establishment in Ann Arbor, the university campus has expanded to include more than 584 major buildings with a combined area of more than 34 million gross square feet (781 acres or 3.16 km²), and has two satellite campuses located in Flint and Dearborn. The University was one of the founding members of the Association of American Universities.

    Considered one of the foremost research universities in the United States,[7] the university has very high research activity and its comprehensive graduate program offers doctoral degrees in the humanities, social sciences, and STEM fields (Science, Technology, Engineering and Mathematics) as well as professional degrees in business, medicine, law, pharmacy, nursing, social work and dentistry. Michigan’s body of living alumni (as of 2012) comprises more than 500,000. Besides academic life, Michigan’s athletic teams compete in Division I of the NCAA and are collectively known as the Wolverines. They are members of the Big Ten Conference.

  • richardmitnick 9:21 pm on December 20, 2016 Permalink | Reply
    Tags: , , Immunotherapy, ,   

    From NYT: “Cancer-Free: One Recovery Inspires Another — and Could Help Thousands” 

    New York Times

    The New York Times

    DEC. 19, 2016

    Melinda Bachini, left, whose cancer treatment inspired Celine Ryan, right, with her sons Liam and Decklan, to pursue the same. Credit Left: Lynn Donaldson for The New York Times Right: Laura McDermott for The New York Times

    In this story, the science reporter Denise Grady provides human backstory about her article about a woman who, remarkably, recovered from colon cancer after treatment with cells from her own immune system.

    I’ve been meeting more and more people with cancer lately who would be desperately ill — or worse — had they not taken matters into their own hands and found their way into clinical trials in which they received experimental treatments that put the disease in remission.

    There were no guarantees. New treatments don’t always work, and experiments have risks. [My own wife died after, first, immunotherapy that did not work and then clinical trial which at best did not work and at worst possibly killed her.] The patients I met are here to tell their stories because they’re among the lucky few, the successes. Still, the cancer landscape does seem to be brightening, if only just a bit, in large part thanks to immunotherapy, which includes various treatments that help the patient’s own immune system to fight cancer.

    The latest good news from the cancer front came last week, from Celine Ryan, a 51-year-old woman from Rochester Hills, Mich., a suburb of Detroit. She homeschools her five children, the youngest of whom is seven years old. Ms. Ryan has colon cancer, and two years ago, doctors found that despite surgery, radiation and chemotherapy, the cancer had spread and invaded her lungs, where scans detected 10 tumors.

    Ms. Ryan is an engineer and database programmer, and to her scientific mind, it seemed highly unlikely that more chemo would control the disease. Chemo made her sick the first time around, and she had every reason to belief it would do so again. She and her husband, who is also an engineer, agreed that she should forgo chemo and instead try to tap into a major research center for help.

    “I remembered that I had read about another cancer patient, Melinda Bachini. It stuck in my brain,” Ms. Ryan said. “I found out about this trial she did, and I said, ‘That’s what I want to do.’”

    A front-page article I wrote in May 2014 about Ms. Bachini, a paramedic in Billings, Mont., might have been the article that Ms. Ryan remembered. Ms. Bachini had a deadly cancer, cholangiocarcinoma, that had started in her bile duct; Ms. Bachini underwent surgery and several grueling rounds of chemo, but the cancer nontheless spread to her liver and lungs. In April 2012, her life expectancy was a matter of months. Ms. Bachini, 43 at the time, had six children and, like, Ms. Ryan, did not think further chemotherapy would help.

    Instead, she combed the internet looking for clinical trials and came upon one, run by Dr. Steven A. Rosenberg, at the National Cancer Institute, that made sense to her.

    She was accepted into the study, and got very lucky. Dr. Rosenberg’s team found that she had a type of cancer-killing immune cell that could destroy her tumors without harming normal cells. The researchers multiplied those cells in the lab and dripped more than 100 billion of them back into her. Ms. Bachini’s tumors melted away.

    Inspired by Ms. Bachini’s story, Ms. Ryan called the cancer institute. She was deferred twice because her tumors were not big enough to yield enough immune cells. But she persisted, and even sent the researchers screen shots from her scans, with measurements of tumors that she and her husband thought met the trial criteria. Eventually, she was accepted into the study and, like Ms. Bachini, was one of the fortunate ones: Now, thanks to the cell treatment and surgery, she is cancer-free.

    Ms. Ryan’s case made medical history, because it was the first time researchers found cells that could attack a common cancer causing mutation — a finding that may help thousands of other patients with the same mutation.

    In November 2015, after the first scan showed that her tumors had shrunk markedly, Ms. Ryan tracked down Ms. Bachini and emailed her. “Call me!” Ms. Bachini replied. Ms. Bachini and Ms. Ryan have been friends ever since and stay in touch by phone and on Facebook.

    “When Celine and I connected, I was so unbelievably happy for her,” Ms. Bachini said.

    They hope to meet in person, maybe by coordinating their checkups at the cancer institute. Both try to help other patients who are looking for help and considering clinical trials.

    Ms. Bachini needed more treatment recently, because tumors in her lungs began to grow again. She had surgery and was given an immunotherapy drug, a type called a checkpoint inhibitor, which has begun shrinking the tumors.

    “I spend a lot of time talking to patients, doing cancer advocacy stuff,” Ms. Bachini said. “It’s how I can pay it forward.”

    See the full article here .

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  • richardmitnick 7:25 am on July 31, 2016 Permalink | Reply
    Tags: , , Immunotherapy, ,   

    From NYT: “Harnessing the Immune System to Fight Cancer” 

    New York Times

    The New York Times

    Steve Cara in an examination room at Memorial Sloan Kettering Cancer Center. Mr. Cara learned two years ago that he had advanced lung cancer, but immunotherapy drugs called checkpoint inhibitors have helped wipe out the disease. Credit Sam Hodgson for The New York Times

    Steve Cara expected to sail through the routine medical tests required to increase his life insurance in October 2014. But the results were devastating. He had lung cancer, at age 53. It had begun to spread, and doctors told him it was inoperable.

    A few years ago, they would have suggested chemotherapy. Instead, his oncologist, Dr. Matthew D. Hellmann of Memorial Sloan Kettering Cancer Center in New York, recommended an experimental treatment: immunotherapy. Rather than attacking the cancer directly, as chemo does, immunotherapy tries to rally the patient’s own immune system to fight the disease.

    Uncertain, Mr. Cara sought a second opinion. A doctor at another major hospital read his scans and pathology report, then asked what Dr. Hellmann had advised. When the doctor heard the answer, Mr. Cara recalled, “he closed up the folder, handed it back to me and said, ‘Run back there as fast as you can.’”

    Many others are racing down the same path. Harnessing the immune system to fight cancer, long a medical dream, is becoming a reality. Remarkable stories of tumors melting away and terminal illnesses going into remissions that last years — backed by solid data — have led to an explosion of interest and billions of dollars of investments in the rapidly growing field of immunotherapy. Pharmaceutical companies, philanthropists and the federal government’s “cancer moonshot” program are pouring money into developing treatments. Medical conferences on the topic are packed.

    All this has brought new optimism to cancer doctors — a sense that they have begun tapping into a force of nature, the medical equivalent of splitting the atom.

    “This is a fundamental change in the way that we think about cancer therapy,” said Dr. Jedd Wolchok, chief of melanoma and immunotherapeutics services at Memorial Sloan Kettering.

    Hundreds of clinical trials involving immunotherapy, alone or combined with other treatments, are underway for nearly every type of cancer. “People are asking, waiting, pleading to get into these trials,” said Dr. Arlene Siefker-Radtke, an oncologist at the University of Texas M.D. Anderson Cancer Center in Houston, who specializes in bladder cancer.

    The immune system — a network of cells, tissues and biochemicals that they secrete — defends the body against viruses, bacteria and other invaders. But cancer often finds ways to hide from the immune system or block its ability to fight. Immunotherapy tries to help the immune system recognize cancer as a threat, and attack it.

    Doctors tried a primitive version of immunotherapy against cancer more than 100 years ago. It sometimes worked remarkably well, but often did not, and they did not understand why. Eventually, radiation and chemotherapy eclipsed it.

    Researchers are now focused on two promising types of immunotherapy. One creates a new, individualized treatment for each patient by removing some of the person’s immune cells, altering them genetically to kill cancer and then infusing them back into the bloodstream. This treatment has produced long remissions in a few hundred children and adults with deadly forms of leukemia or lymphoma for whom standard treatments had failed.

    The second approach, far more widely used and the one Mr. Cara tried, involves mass-produced drugs that do not have to be tailored to each patient. The drugs free immune cells to fight cancer by blocking a mechanism — called a checkpoint — that cancer uses to shut down the immune system.

    These drugs, called checkpoint inhibitors, have been approved by the Food and Drug Administration to treat advanced melanoma, Hodgkin’s lymphoma and cancers of the lung, kidney and bladder. More drugs in this class are in the pipeline. Patients are clamoring for checkpoint drugs, including one, Keytruda, known to many as “that Jimmy Carter drug” which, combined with surgery and radiation, has left the former president with no sign of recurrence even though melanoma had spread to his liver and brain.

    Checkpoint inhibitors have become an important option for people like Mr. Cara, with advanced lung cancer.

    “We can say in all honesty to patients, that while we can’t tell them we can cure metastatic lung cancer right now, we can tell them there’s real hope that they can live for years, and for a lot of patients many years, which really is a complete game-changer,” said Dr. John V. Heymach, a lung cancer specialist and chairman of thoracic/head and neck medical oncology at M.D. Anderson.

    Yet for all the promise and excitement, the fact is that so far, immunotherapy has worked in only a minority of patients, and researchers are struggling to find out why. They know they have their hands on an extraordinarily powerful tool, but they cannot fully understand or control it yet.

    One Patient’s Story

    Mr. Cara, an apparel industry executive from Bridgewater, N.J., had non-small-cell lung cancer, the most common form of the disease. The diagnosis shattered what had been an idyllic life: a happy marriage, sons in college, a successful career, a beautiful home, regular vacations, plenty of golf.

    In December 2014, he began treatment with two checkpoint inhibitors. They cost about $150,000 a year, but as a study subject he did not have to pay.

    These medicines work on killer T-cells, white blood cells that are often described as the soldiers of the immune system. T-cells are so fierce that they have built-in brakes — the so-called checkpoints — to shut them down and keep them from attacking normal tissue, which could result in autoimmune disorders like Crohn’s disease, lupus or rheumatoid arthritis. One checkpoint stops T-cells from multiplying; another weakens them and shortens their life span.

    As the name suggests, checkpoint inhibitors block the checkpoints, so cancer cannot use them to turn off the immune system.

    Mr. Cara took drugs to inhibit both types of checkpoints. Every two weeks, he had intravenous infusions of Yervoy and Opdivo, both made by Bristol-Myers Squibb. He had no problems at first, just a bit of fatigue the day after the infusion. He rarely missed work.

    But turning the wrath of the immune system against cancer can be a risky endeavor: Sometimes the patient’s own body gets caught in the crossfire. About two months into the treatment, Mr. Cara broke out in a rash all over his arms, back and chest. It became so severe that he had to go off the drugs. A steroid cream cleared it up and he was able to resume treatment — but with only one drug, Opdivo. Doctors stopped the other in hopes of minimizing the side effects.

    Checkpoint inhibitors can take months to begin working, and sometimes cause inflammation that, on scans early in treatment, can make it look like the tumor is growing. But Mr. Cara’s first scans, in March 2015, were stunning.

    His tumor had shrunk by a third.

    By August, more than half of the tumor had vanished. The rash came back, however, and worsened. Steroids worked again, but in October a far more alarming side effect set in: breathing trouble.

    Doctors diagnosed pneumonitis, a lung inflammation caused by an attack from the immune system — a known risk of checkpoint drugs. Continuing the treatment posed too great a danger.

    Mr. Cara stopped the infusions, but the months of treatment seemed to have transformed his cancer to stage 2 from stage 4, meaning that it was now operable. This spring surgeons removed about a third of his right lung, and discovered that the cancer was actually gone.

    “No cancer was seen in any of the tissue they took out,” Dr. Hellmann said. “‘One hundred percent treatment effect,’” he read from the pathology report. “It was pretty cool.”

    Immunotherapy had apparently wiped out the disease. “It’s amazing. Unbelievable,” Mr. Cara said.

    As of now, he needs no further treatment, but he will be monitored regularly. He is back to work, and golf.

    “He’s had the best possible response,” Dr. Hellmann said. “I hope that remains permanent. Only time will tell, and I think he’s conscious of that.”

    Mr. Cara acknowledged, “Is there something in the back of me that says this thing never goes away, it could come back any time? Sure. But it’s not the main thing I think. I’m young, I’m strong, I’m healthy, my pathology report came back clean.”

    He considered framing that pathology report.

    But, he said, “I don’t want to jinx myself.”

    Drugs Help Some, but Not Others

    When checkpoint inhibitors work, they can really work, producing long remissions that start to look like cures and that persist even after treatment stops. Twenty percent to 40 percent of patients, sometimes more, have good responses. But for many patients, the drugs do not work at all. For others, they work for a while and then stop.

    The vexing question, and the focus of research, is, why?

    One theory is that additional checkpoints, not yet discovered, may play a role. The hunt is on to find them, and then make new drugs to act on them.

    Despite the gaps in knowledge, checkpoint inhibitors are coming into widespread use and are being tried in advanced types of cancer for which standard chemotherapy offers little hope.

    NYT Immunotherapy

    One example is anal cancer, a painful disease that carries a stigma because it is often linked to the sexually transmitted human papillomavirus or HPV, which also causes cervical cancer.

    Lee, 59, who asked that her last name be withheld to protect her privacy, found out in 2014 that she had the disease, and that it had spread to her liver.

    “I was told I’d be dead in 12 to 18 months with treatment, six months with no treatment,” she said.

    Chemotherapy and radiation at a hospital near Dallas brought a remission that lasted only a few months. The cancer spread to her lungs.

    Bedridden and in severe pain, she entered an immunotherapy trial at M.D. Anderson. In May 2015 she began receiving Opdivo every two weeks. The tumors in her liver and lungs have shrunk by about 70 percent. She is back at work.

    While the drugs initially were given only to people with advanced disease, especially those who had little to lose because chemotherapy had stopped working, Dr. Heymach of M.D. Anderson predicted that soon some patients — including some with earlier stages of lung cancer — will receive checkpoint inhibitors as their first treatment.

    Immunotherapy is also enabling doctors to help patients in unexpected ways.

    Until recently, surgeons were reluctant to operate on people with advanced cancer because they knew from experience that it would not lengthen the patient’s life. But checkpoint inhibitors are changing that. For instance, some patients have taken checkpoint inhibitors for an advanced cancer that had spread around the body, and wound up with only one stubborn tumor left. They then have had it surgically removed and have gone years without a relapse.

    “Time has slowed down to the point where you can pay attention to individual tumors, since you’re not running to put out the fire of wholesale systemic progression,” Dr. Wolchok said.

    If there is a potential downside to the advances, Dr. Hellmann said, it is that the buzz about immunotherapy has led some patients to think chemotherapy is passé.

    “Immunotherapy represents a hugely important new tool, but chemotherapy can work too and has been the backbone of the way we’ve treated patients with lung cancer,” he said. “Immunotherapy is not a replacement for that. It’s a new weapon.”

    One of his patients, a 60-year-old man with lung cancer that had spread to his brain, was eager to try immunotherapy instead of chemotherapy. After having radiation treatment for one brain tumor, he began treatment with two checkpoint inhibitors.

    But they did not work. So his doctors switched to chemotherapy. “He’s had a tremendous response,” Dr. Hellmann said.

    He said it was impossible to tell whether the immunotherapy could have had some delayed effect and worked synergistically with the chemotherapy. Clinical trials are now trying to resolve that question.

    But the potential for dangerous side effects cannot be overemphasized, doctors say. A 2010 article in a medical journal reported that a few melanoma patients had died from adverse effects of Yervoy.

    In addition to causing lung inflammation, checkpoint inhibitors can lead to rheumatoid arthritis and colitis, a severe inflammation of the intestine — the result of an attack by the revved-up immune system that over-the-counter remedies cannot treat. Patients need steroids like prednisone to quell these attacks. Fortunately — and mysteriously, Dr. Wolchok said — the steroids can halt the gut trouble without stopping the immune fight against the cancer. But if patients delay telling doctors about diarrhea, Dr. Wolchok warned, “they could die” from colitis.

    Checkpoint inhibitors can also slow down vital glands — pituitary, adrenal or thyroid — creating a permanent need for hormone treatment. Mr. Cara, for instance, now needs thyroid medication, almost certainly as a result of his treatment. Doctors have reported that a patient with a kidney transplant rejected it after taking a checkpoint inhibitor to treat cancer, apparently because the drug spurred his immune system to attack the organ.

    Another of Dr. Hellmann’s lung-cancer patients, Joanne Sabol, 65, had to quit a checkpoint inhibitor because of severe colitis. But she had taken it for about two years, and it shrank a large abdominal tumor by 78 percent. Patients like her are in uncharted territory, and doctors are trying to decide whether to operate to remove what is left of her tumor.

    “I have aggressive cancer, but I’m not giving in to it,” Ms. Sabol said. “It’s going to be a big battle with me.”

    Coley’s Toxins

    Dr. William B. Coley, an American surgeon born in 1862, is widely considered the father of cancer immunotherapy. But he practiced a crude form of it, without understanding how it worked.

    Distressed by the painful death of a young woman he had treated for a sarcoma, a bone cancer, in 1891, Dr. Coley began to study the records of other sarcoma patients in New York, according to Dr. David. B. Levine, a medical historian and orthopedic surgeon.

    One case leapt out at him: a patient who had several unsuccessful operations to remove a huge sarcoma from his face, and wound up with a severe infection, then called erysipelas, caused by Streptococcal bacteria. The patient was not expected to survive, but he did — and the cancer disappeared.

    Dr. Coley found other cases in which cancer went away after erysipelas. Not much was known about the immune system, and he suspected, mistakenly, that the bacteria were somehow destroying the tumors. Researchers today think the infection set off an intense immune response that killed both the germs and the cancer.

    Dr. Coley was not alone in believing that bacteria could fight cancer. In a letter to a colleague in 1890, the Russian physician and playwright Anton Chekhov wrote of erysipelas: “It has long been noted that the growth of malignant tumors halts for a time when this disease is present.”

    Dr. Coley began to inject terminally ill cancer patients with Streptococcal bacteria in the 1890s. His first patient, a drug addict with an advanced sarcoma, was expected to die within weeks, but the disease went into remission and he lived eight years.

    Dr. Coley treated other patients, with mixed results. Some tumors regressed, but sometimes the bacteria caused infections that went out of control. Dr. Coley developed an extract of heat-killed bacteria that came to be called Coley’s mixed toxins, and he treated hundreds of patients over several decades. Many became quite ill, with shaking chills and raging fevers. But some were cured.

    Parke-Davis and Company began producing Coley’s toxins in 1899, and continued for 30 years. Various hospitals in Europe and the United States, including the Mayo Clinic, used the toxins, but the results were not consistent.

    Early in the 20th century, radiation treatment came into use. Its results were more predictable, and the cancer establishment began turning away from Coley’s toxins. Dr. Coley’s own institution, Memorial Hospital (now Memorial Sloan Kettering Cancer Center) instituted a policy in 1915 stating that inpatients had to be given radiation, not the toxins. Some other hospitals continued using them, but interest gradually waned. Dr. Coley died in 1936.

    Chemotherapy, developed after World War II, was another blow to his methods. And in 1965, the American Cancer Society added Coley’s toxins to its list of “unproven” treatments. (The toxins were later taken off the list.)

    After Dr. Coley’s death, his daughter, Helen Coley Nauts, studied some 800 case records that he had left behind, and became convinced that he was onto something important. She tried to rekindle interest in his work, but she was thwarted by doctors who opposed it, including some with high rank at Sloan Kettering. However, in 1953 she founded the Cancer Research Institute in New York, a nonprofit that has become a significant supporter of research on the interplay between cancer and the immune system. The group awarded more than $29.4 million in scientific grants in 2015, and its advisory board includes Dr. Wolchok and the scientist credited with developing the first checkpoint inhibitor, James P. Allison.


    Dr. James P. Allison and Dr. Padmanee Sharma have been research collaborators since 2005, and spouses since 2014. Dr. Allison developed Yervoy, the first of the checkpoint inhibitors. Credit Ilana Panich-Linsman for The New York Times

    The Scientist and the Doctor

    “Are you Dr. Allison?”

    James Allison and his wife, Dr. Padmanee Sharma, had just settled into their airplane seats when another passenger approached with tears in her eyes and thanked him for creating the drug that was keeping her husband alive. Dr. Sharma described the encounter during a joint interview with her and Dr. Allison in his office at M.D. Anderson in Houston, where both work.

    “Every time Jim meets a patient, he cries,” Dr. Sharma said.

    “Well, not every time,” Dr. Allison said.

    Dr. Allison, 67, and Dr. Sharma, 45, have been research collaborators since 2005, and spouses since 2014, when he proposed by saying that nobody else could stand either of them — they talk about their work all the time — so they might as well get married.

    The drug the woman on the plane thanked him for was Yervoy, the first of the checkpoint inhibitors. It was approved for advanced melanoma in 2011. Dr. Allison — a scientist, not a physician — has won numerous research awards and is expected by many to win a Nobel Prize. He drives a Porsche convertible with a license plate bearing the name of the checkpoint he deciphered: CTLA-4.

    A bearded, slightly rumpled figure, Dr. Allison plays harmonica with research colleagues in a blues-rock band called the Checkpoints. He is good enough to have accompanied Willie Nelson onstage at the Redneck Country Club in Stafford, Tex., this spring, playing, “Roll Me Up and Smoke Me When I Die.”

    Immunology, particularly the study of T-cells, has been his life’s work. Cancer came later. “I became interested in cancer because I’ve lost a number of family members to cancer,” said Dr. Allison, chairman of the immunology department and executive director of the immunotherapy platform at M.D. Anderson. “My mother and two of her brothers, and my own brother, died of cancer.”

    Around the time of his brother’s death from prostate cancer, Dr. Allison learned that he had the same disease himself. He was treated successfully, he said, adding with a laugh that he was more likely to die from inactivity than from cancer.

    In the 1990s, Dr. Allison, then at the University of California, Berkeley, and Dr. Jeffrey Bluestone of the University of California, San Francisco, independently made a landmark discovery: They proved that a molecule widely believed to activate the immune system actually shut it down. The molecule was a protein on the surface of T-cells — a crucial checkpoint — and it was nature’s way of subduing the T-cells, apparently to dial back their ferocious activity and prevent them from attacking a person’s own tissue. Cancer cells can sometimes lock onto checkpoints, disabling the T-cells.

    Dr. Allison wondered if it might be possible to block the checkpoint and launch the T-cells against cancer. He and a postdoctoral fellow, Dana Leach, developed an antibody — a molecule made by certain cells of the immune system — that would stick to the checkpoint and block it. When the researchers gave the antibody to mice with cancer, tumors vanished.

    Recalling those first tests in mice, Dr. Allison said it was astounding to see the cancers shrink and disappear. Veterinarians thought the mice had contracted an infection or a skin disease. But the sores that worried the vets were actually tumors that were ulcerating and rotting away under assault by T-cells.

    Many drug companies were skeptical about the findings, but one, Medarex, created a human version of the antibody. Medarex was later acquired by Bristol-Myers Squibb, and the antibody, given the trade name Yervoy, was approved in 2011 to treat advanced melanoma.

    It became the first drug to prolong survival in people with this deadly form of cancer. Major studies that started before it was approved found that among 1,861 patients treated for advanced disease, about 22 percent were still alive three years later, with no signs of recurrence — an astounding result for a disease that was almost always fatal. Some have survived 10 years or longer.

    The discoveries that led to the drug, Dr. Allison said, came entirely from years of basic research in immunology — experiments in test tubes and mice — and not from the clinical or “translational” science, aimed at moving rapidly into humans, that is so heavily favored now by institutions that pay for studies.

    “None of this came from cancer research, none,” Dr. Allison said, adding that without support for basic research, “progress, if any, will be incremental, not a big leap.”

    His own work is well funded, he said, but he worries about an overall trend to shortchange basic science.

    The focus of much of his and Dr. Sharma’s research now is to understand how and why checkpoint inhibitors work in some patients and not others.

    Dr. Sharma, a professor of genitourinary medical oncology, is a physician and researcher who treats patients and oversees clinical trials, and she brings stories home to Dr. Allison about patients whose lives may be extended by his discoveries.

    In general, checkpoint inhibitors seem to work best for tumors with many mutations, like most melanomas and cancers of the lung and bladder.

    “It’s like buying a lottery ticket,” Dr. Sharma said. “The more genetic abnormalities, the more lottery tickets you’ve bought — and you have a much higher chance of a T-cell recognizing something to start the immune response.”

    One area of particular interest is the tissue immediately in and around a tumor, what researchers call the microenvironment. By examining that zone, scientists can tell whether T-cells are fighting the cancer. Sometimes T-cells mob the margins of a tumor, but cannot get in. Other times, they get in but cannot kill it.

    “How do we understand what drives the immune response in one patient to give a good clinical outcome, and how do we then drive that same immune response in all the other patients?” Dr. Sharma asked. “Did the T-cells get in? If not, is there another drug that can drive the T-cells in?”

    Researchers also suspect that checkpoint inhibitors might work better if combined with treatments that kill tumor cells, because debris from dead cancer cells may help the immune system recognize its target. Studies are underway to test checkpoint drugs in combination with cell-killing treatments like chemotherapy and radiation. But it is a delicate balance to adjust the timing and doses, because in addition to killing cancer cells, those other treatments can knock out the immune system just when it is needed most.

    Flying 3,300 Miles for Treatment

    As word spreads about immunotherapy, a troubling fact remains: Patients do not have equal access to the new treatments, which can be prohibitively expensive. Insurers cover F.D.A.-approved treatments, but co-payments can be high for costly drugs. Some people get costs covered by volunteering for clinical trials that are testing new drugs or novel combinations. But not everyone can, or wants to, enter a study. Participants tend to have the education, determination and means required to get second and third opinions, rearrange their lives, and buy plane tickets to get to cutting-edge medical centers. And they are willing to take risks for a chance to survive. Minorities have been underrepresented in studies, for reasons that are not clear.

    David Wight, a retired oil engineer in Anchorage, is a study participant who has been able to take every possible step to save his life. When bladder cancer began to spread in his abdomen, he was given three to 12 months to live. That was four and a half years ago.

    On a recent Saturday, Mr. Wight, who is 75 but looks younger, refereed a boys’ soccer game, racing up and down the field with the players. The following Wednesday he rose at 3 a.m. to fly 3,300 miles to Houston, where he would arrive at about 5 p.m. He has been making that trip every other week for over two years to receive immunotherapy at M.D. Anderson. For about a year and a half, his disease has been in complete remission.

    Until recently, he paid his own airfare. But a few months ago, Bristol-Myers Squibb, the maker of the drug being studied, began picking up the tab, even reimbursing him retroactively — about $50,000 so far.

    He has five children: three in their 40s, a son, 16, and a daughter, 10. The younger two were only 10 and 5 when he learned he was ill, and the thought that he might not have survived to raise them still brings tears to his eyes. Describing the time he has gained to be with his family, he said, “I won a lottery that’s bigger than anybody could imagine.”

    His cancer was diagnosed in summer 2010, after a test during a routine physical found cancer cells in his urine. A small tumor had invaded the wall of his bladder. Mr. Wight had his bladder removed at a hospital in Anchorage, and was told he needed no further treatment.

    A year after the surgery, he and his doctors were horrified to find that a large tumor had wrapped itself around his colon. Only then did the doctors discover that he had a rare, aggressive type of bladder cancer, called plasmacytoid. His doctors consulted with a hospital in Seattle, which devised a treatment plan.

    “They said one word that told me I was not where I wanted to be: ‘palliative,’” Mr. Wight said. He knew palliative treatment was meant to ease symptoms, but not cure the disease. “I said, ‘No thank you. We can do better than that,’” he recalled.

    His next stop was M.D. Anderson. Months of chemotherapy shrank the tumor enough to allow colon surgery in May 2012. But the disease kept coming back: spots in one lung, then the other, then a tumor under his kidney.

    “I was getting a new tumor every six to eight months,” he said.

    Chemotherapy and an experimental gene therapy cleared his lungs and shrank the tumor near his kidney but could not get rid of it.

    In June 2014, Mr. Wight became one of the first patients with bladder cancer at M.D. Anderson to enter a study of two checkpoint inhibitors. For three months he received Yervoy and Opdivo every two weeks, and then continued with only Opdivo.

    The tumor under his kidney shrank, then disappeared. It has been gone for a year and a half, and he has had no other signs of cancer. He is still receiving Opdivo — the reason for his regular trips to Houston.

    “I’m very fortunate,” Mr. Wight said. “It has for me a single irritating side effect. It makes me itch like you wouldn’t believe. I itch all the time but it’s a small price to pay to stay alive and be feeling pretty well.”

    An antihistamine helps. Regarding how long he will keep being treated, he said: “It’s experimental. You don’t know the answer. As long as I have positive results I’m eligible for the treatment.”

    His oncologist, Dr. Siefker-Radtke, called his response to immunotherapy “fantastic” and said other patients, also in complete or partial remission, were flying or driving to Houston for treatments every two or three weeks. Many do not want to stop taking the drugs.

    But doctors do not know how long the treatments should continue. They wonder how long the remissions will last, and whether some will even turn out to be cures, Dr. Siefker-Radtke said. Some studies were planned to last just a year or two, longer than the life expectancy of most patients with advanced disease. Researchers did not think they would have to decide whether to keep treating people for years.

    “We were not expecting to see patients going this long,” Dr. Siefker-Radtke said.

    Correction: July 30, 2016

    An earlier version of this article overstated the initial effect of a new treatment against cancer for the patient, Steve Cara. His tumor had shrunk by a third, not half, at the time of his first scanning in March 2015. By August, more than half, not 90 percent, of the tumor had vanished.

    See the full article here .

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  • richardmitnick 6:55 am on July 31, 2016 Permalink | Reply
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    From NYT: “What Is Immunotherapy? The Basics on These Cancer Treatments” 

    New York Times

    The New York Times

    JULY 30, 2016

    A nurse prepared an immunotherapy drug at the University of Texas M.D. Anderson Cancer Center in Houston. Credit Ilana Panich-Linsman for The New York Times

    Some of the most promising advances in cancer research in recent years involve treatments known as immunotherapy. These advances are spurring billions of dollars in investment by drug companies, and are leading to hundreds of clinical trials. Here are answers to some basic questions about this complex and rapidly evolving field.

    What is immunotherapy?

    Immunotherapy refers to any treatment that uses the immune system to fight diseases, including cancer. Unlike chemotherapy, which kills cancer cells, immunotherapy acts on the cells of the immune system, to help them attack the cancer.

    What are the types of immunotherapy?

    Drugs called checkpoint inhibitors are the most widely used form of immunotherapy for cancer. They block a mechanism that cancer cells use to shut down the immune system. This frees killer T-cells — a critically important part of the immune system — to attack the tumor. Four checkpoint inhibitors have been approved by the Food and Drug Administration and are on the market. They are given intravenously.

    Another form of immunotherapy, called cell therapy, involves removing immune cells from the patient, altering them genetically to help them fight cancer, then multiplying them in the laboratory and dripping them, like a transfusion, back into the patient. This type of treatment is manufactured individually for each patient, and is still experimental.

    Bispecific antibodies are an alternative to cell therapy, one that does not require individualizing treatment for each patient. These antibodies are proteins that can attach to both a cancer cell and a T-cell, that way bringing them close together so the T-cell can attack the cancer. One such drug, called Blincyto, has been approved to treat a rare type of leukemia.

    Vaccines, another form of immunotherapy, have had considerably less success than the others. Unlike childhood vaccines, which are aimed at preventing diseases like measles and mumps, cancer vaccines are aimed at treating the disease once the person has it. The idea is to prompt the immune system to attack the cancer by presenting it with some piece of the cancer.

    The only vaccine approved specifically to treat cancer in the United States is Provenge, for prostate cancer. Another vaccine, BCG, which was developed to prevent tuberculosis, has long been used to treat bladder cancer. As a weakened TB bacterium, BCG appears to provoke a general immune system reaction that then works against the cancer. Researchers hope that other vaccines may yet be made to work by combining them with checkpoint inhibitors.

    Which types of cancer are treated with immunotherapy?

    Checkpoint inhibitors have been approved to treat advanced melanoma, Hodgkin’s lymphoma and cancers of the lung, kidney and bladder. The drugs are being tested in many other types of cancer.

    So far, cell therapy has been used mostly for blood cancers like leukemia and lymphoma.

    Which cancer drugs are checkpoint inhibitors?

    The four on the market are: Yervoy (ipilimumab) and Opdivo (nivolumab), made by Bristol-Myers Squibb; Keytruda (pembrolizumab), by Merck; and Tecentriq (atezolizumab), by Genentech.

    How well does immunotherapy work?

    Though immunotherapy has been stunningly successful in some cases, it still works in only a minority of patients. Generally, 20 percent to 40 percent of patients are helped by checkpoint inhibitors — although the rate can be higher among those with melanoma. Some patients with advanced disease have had remissions that have lasted for years. In some cases, combining two checkpoint inhibitors increases the effectiveness. But for some people the drugs do not work at all, or they help just temporarily.

    Cell therapy can produce complete remissions in 25 percent to 90 percent of patients with lymphoma or leukemia, depending on the type of cancer. In some cases the remissions can last for years, but in others relapses occur within a year.

    What are the side effects?

    Checkpoint inhibitors can cause severe problems that are, essentially, autoimmune illnesses, in which the immune system attacks healthy tissue as well as cancer. One result is inflammation. In the lungs it can cause breathing trouble; in the intestine it can cause diarrhea. Joint and muscle pain, and rheumatoid arthritis can also occur, and the immune system can also attack vital glands like the thyroid and pituitary. These reactions are dangerous, but can often be controlled with steroid medicines like prednisone.

    Cell therapy can also lead to severe and potentially fatal reactions resulting from the overstimulation of the immune system. The reactions can usually be controlled, but patients may need to be treated in an intensive care unit.

    What does immunotherapy cost? Does insurance cover it?

    Checkpoint inhibitors can cost $150,000 a year. Many insurers will pay if the drug has been approved for the type of cancer the patient has. But sometimes there are high co-payments. Patients in clinical trials may get the drugs free.

    Manufacturers have not said yet how much they will charge for cell therapies, assuming they win approval and reach the market. But experts expect the price to be as high as a few hundred thousand dollars.

    Where can I get immunotherapy?

    Any oncologist can prescribe the checkpoint inhibitors that are on the market. Patients with cancers for which the drugs have not been approved may find insurers reluctant to pay, but may be able to get the drugs for free by volunteering for clinical trials.

    Cell therapies are available only through clinical trials now. Most of the study sites are major medical centers.

    How can I find out about clinical trials in immunotherapy?

    Information is available on the Cancer Research Institute website, or by calling 1-855-216-0127 (Monday through Friday, 8:30 a.m. to 6 p.m. E.T.). Another source is ClinicalTrials.gov.

    See the full article here .

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  • richardmitnick 5:46 am on July 15, 2016 Permalink | Reply
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    From UCLA: “Cancer-fighting gene immunotherapy shows promise as treatment for HIV” 

    UCLA bloc


    July 14, 2016
    Enrique Rivero

    Researchers find that potent antibodies can be used to generate a specific type of cell that can be used to kill cells infected with HIV-1. An HIV-infected T cell is shown here. NIAID/Flickr

    A type of immunotherapy that has shown promising results against cancer could also be used against HIV, the virus that causes AIDS.

    In a study published July 11 in the peer-reviewed Journal of Virology, researchers from the UCLA AIDS Institute and Center for AIDS Research found that recently discovered potent antibodies can be used to generate a specific type of cell called chimeric antigen receptors, or CARs, that can be used to kill cells infected with HIV-1.

    CARs are artificially created immune T cells that have been engineered to produce receptors on their surface that are designed to target and kill specific cells containing viruses or tumor proteins. Chimeric receptors are the focus of ongoing research into how gene immunotherapy can be used to fight cancer. But they could also be used to create a strong immune response against HIV, said Dr. Otto Yang, professor of medicine in the division of infectious diseases at the David Geffen School of Medicine at UCLA and the study’s corresponding author.

    Although the human body’s immune system does initially respond to and attack HIV, the sheer onslaught of the virus — its ability to hide in different T cells and to rapidly replicate — eventually wears out and destroys the immune system, leaving the body vulnerable to a host of infections and diseases. Researchers have been looking for ways to strengthen the immune system against HIV, and it now appears CARs could be a weapon in that fight.

    “We took new generation antibodies and engineered them as artificial T-cell receptors, to reprogram killer T cells to kill HIV-infected cells,” said Yang, who is also director of vaccine and pathogenesis research at the AIDS Institute and Center for AIDS Research. “Others have used antibodies against cancer antigens to make artificial T-cell receptors against cancer and shown this to be helpful in cancer treatment.” UCLA is the first to design this strategy for HIV.

    While the receptors approach has been in use for almost 10 years to fight cancer, this is the first attempt to use the technique to treat HIV since 15 years ago, when experiments proved unsuccessful. The new research differs because it takes advantage of new antibodies that have been discovered in the past few years. In the previous trials, researchers had used an early type that was not antibody-based. That approach, however, was abandoned because it was clinically ineffective.

    Here the researchers used seven recently discovered “broadly neutralizing antibodies” that have the ability to bind multiple strains of invading viruses, unlike earlier isolated antibodies that tend to bind few strains. These antibodies were re-engineered as artificial CAR-T cell receptors to have activity against broad strains of HIV. In lab tests, the researchers found that all seven had varying degrees of ability to direct killer T cells to proliferate, kill and suppress viral replication in response to HIV-infected cells.

    Yang notes that “what works in a test tube doesn’t necessarily work in a person,” so the next step is to find strategies to put these receptors into humans. But this therapy shows enough promise to move forward with further research.

    Grants funding this study are the California Institute for Regenerative Medicine (#TR4-06845), the AIDS Healthcare Foundation, and the UCLA AIDS Institute and Center for AIDS.

    Study co-authors, all of UCLA, are Ayub Ali, who was the lead author, Scott Kitchen, Irvin Chen, Hwee Ng and Jerome Zack.

    See the full article here .

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