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  #11  
Old 06-18-2014, 10:12 PM
gdpawel gdpawel is offline
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Default Vaccine Targeting Dendritic Cells Produces Robust Immunity in Advanced Cancer

The ability of T cells to destroy bacteria, viruses, or tumor cells necessarily depends on recognition of the offending cell. Tumor cells hide by leveraging the immune system's own mechanisms, including immune checkpoints, such as cytotoxic T lymphocyte antigen-4 (CLTA-4) and PD-1, that serve to maintain self-tolerance and prevent the immune system from excessively damaging healthy cells when responding to pathogens (1). In general, tumors tend to express normal levels of receptors that regulate activation of T cells while overexpressing those that regulate T-cell effector functions. Using this adaptation, tumor cells evade the immune system and inhibit those T cells that do recognize them from mounting an effective immune response (1). Immunotherapy strategies to overcome this tumor cell survival strategy include CTLA-4 inhibition in melanoma (with ipilimumab) as well as research into PD-1, HSP90, and other checkpoint protein (1,2).

An innovative approach to cancer treatment stimulates tumor antigen presentation through vaccination, which in turn should provoke a robust immune response. Such an approach is now being used to treat advanced prostate cancer with sipuleucel-T, a dendritic cell (DC) vaccine that stimulates a specific T-cell response to an antigen overexpressed in prostate cancer (2).

In preclinical studies, the delivery of tumor antigen to DCs using receptor-specific monoclonal antibodies (mAbs) plus DC-activating agents has elicited robust, antigen-specific immune responses. In a study reported in the journal Science and Translational Medicine in April, researchers sought to trigger robust humoral and cellular immunity by priming the immune system with a vaccine against NY-ESO-1, an antigen expressed by several tumor types. They further hypothesized that this approach might enhance response to subsequent therapy with checkpoint inhibitors, such as ipilimumab and the Toll-like receptor (TLR) inhibitor resiquimod (3).

In this phase 1 study, 45 patients with advanced malignancies refractory to current treatment received escalating doses of CDX-1401 along with the TLR agonists resiquimod and hiltonol. The vaccine is composed of a fully human mAb-specific DEC-205, a molecule expressed on DCs, fused to a full-length NY-ESO-1 tumor antigen. Treatment-induced humoral and cellular immunity against NY-ESO-1 in patients with confirmed NY-ESO-1-expressing tumors: anti-NY-ESO-1 antibody titers developed in 79% of evaluable patients, including 33% who developed very high titers (> 1:100,000). Although NY-ESO-1–specific T-cell responses were largely absent or low at baseline, they increased postvaccination in 56% of evaluable patients, with both CD4 and CD8 T-cell responses seen.

Clinically, 13 patients experienced stable disease, with a median duration of 6.7 months (range, 2.4-13.4 months). Two patients with melanoma had tumor regression (~20% shrinkage in target lesions) and six of eight patients who received immune checkpoint inhibitors within 3 months of vaccination had objective tumor regression (3). Baseline NY-ESO-1 expression did not appear to correlate with clinical response: stable disease was seen in 26% of patients with NY-ESO-1 expression and 33% of those without NY-ESO-1 expression at baseline. However, patients who developed NY-ESO-1–specific T-cell responses after vaccination were more likely to experience stable disease than those who did not (~50% vs. 13%, respectively) (3).

Among eight patients who received subsequent treatment with ipilimumab or a TLR agonist, six had at least partial response. All six had confirmed NY-ESO-1 expression at baseline. Five developed cellular immunity to NY-ESO-1 and four developed and maintained humoral immunity to NY-ESO-1 by the end of treatment with CDX-1401. The most frequently reported adverse events were injection site reactions, fatigue, nausea, and chills, and no dose-limiting or grade 3 toxicities were reported (3).

"CDX-1401 offers a novel, well-tolerated and practical approach to generating protein-specific immunity that can be readily combined with other treatment strategies to boost immunity against pathogens and tumors," said lead author Madhav Dhodapkar, MBBS, Arthur H. and Isabel Bunker Professor of Medicine and Immunobiology, and chief of the Section of Hematology at the Department of Internal Medicine and Clinical Research Program Leader of the Hematology Program at Yale Cancer Center. "The preliminary findings in patients who received therapy with a checkpoint inhibitor following the vaccine provide further rationale for combination immunotherapy strategies, meriting further investigation."

References:

1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264.

2. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237-251.

3. Dhodapkar MV, Sznol M, Zhao B, et al. Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205. Sci Transl Med. 2014;6(232):232ra51.

Citation: Vaccine Targeting Dendritic Cells Produces Robust Immunity in Advanced Cancer. Chemotherapy Advisor. June 12, 2014.
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  #12  
Old 07-08-2014, 09:06 PM
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Default AACR & ASCO Updates

Robert A. Nagourney, M.D.

The early part of the year is always marked by the two most important meetings for physician-scientists in oncology. I'd like to use this opportunity to share some of my observations.

The American Association of Cancer Research (AACR) meeting, held in San Diego, featured many areas of active investigation. A recurring theme in both the AACR and American Society of Clinical Oncology (ASCO) meetings are the spectacular breakthroughs in immunological therapies.

Numerous presentations examined the outcomes in patients treated with what are known as "checkpoint" inhibitors. Using antibodies directed against PD-1 and PDL-1, responses are being observed in melanoma, lung, genitourinary and other malignancies. Some of the remissions are remarkably durable. More importantly, these treatment modalities carry none of the side effects associated with cytotoxic therapy. These are among the most important advances in recent decades.

Other areas of investigation include the continued pursuit of targeted agents. Our presentation at AACR focused on one class of drugs designed to inhibit the PI3K pathway. We compared and contrasted the activity profiles for the principle members of this drug class and examined disease specific profiles, as well as combination therapies.

Other areas of investigation include the continued pursuit of targeted agents. Our presentation at AACR focused on one class of drugs designed to inhibit the PI3K pathway. We compared and contrasted the activity profiles for the principle members of this drug class and examined disease specific profiles, as well as combination therapies.

Our ASCO presentation examined a different area of therapy, that which inhibits the cell cycle machinery. We reported observations with a new compound known as palbociclib. This cycle dependent kinase (CDK4/6) inhibitor has shown activity with breast cancer and is being explored in other diseases.

In addition to the clinical trials, which were reporting activities for signal transduction inhibitors, there were several studies that resonated with our work. The first was a large study that combined hormonal therapy with chemotherapy in the first line management of patients with prostate cancer. As we have been utilizing this approach for almost two decades it was gratifying to have the clinical trialists confirming activity for the combination approach in these patients.

A second area of harmonization with our work was the report of erlotinib (Tarceva) combined with bevacizumab (Avastin) in EGFR positive NCSLC. As many of you may be aware, we recognized the synergy between these classes of drugs more than one decade ago and began treating our patients with Avastin plus Tarceva at the time of diagnosis. Several of these patients are alive for more than five years using this approach.

With the luxury of a laboratory platform to examine novel drug combinations on an individual basis, we have had the good fortune to identify many highly effective treatment combinations. We are gratified that ASCO has now reported these combinations as effective treatment options. This will enable us to treat our patients with less pushback from the oncology and insurance industries. Cancer therapy moves slowly forward.
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  #13  
Old 07-18-2014, 11:21 AM
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Default A Modified Cat Parasite To Treat Cancer

A kitty poop parasite has led to a treatment that wipes out cancer in lab tests, including aggressive melanoma and ovarian cancer, preliminary studies have found.

By itself, the single-celled parasite, Toxoplasma gondii, is bad news because it can cause illness in infected people and cats. It thrives in the intestines of cats and then comes out the other end.

But scientists at Dartmouth-Hitchcock Medical Center have figured out a way to engineer a new version of the parasite that they say has remarkable cancer-fighting powers.

“We know biologically this parasite has figured out how to stimulate the exact immune responses you want to fight cancer,” explained David J. Bzik, a professor of Microbiology and Immunology at Dartmouth.

“The biology of this organism is inherently different from other microbe-based (treatments) that typically just tickle immune cells from the outside,” said senior research associate Barbara Fox. “By gaining preferential access to the inside of powerful innate immune cell types, our mutated strain of T. gondii reprograms the natural power of the immune system to clear tumor cells and cancer.”

The mutated parasite is called “cps.” Lab tests show that it’s non-replicating and safe to use. Even if the recipient has a weakened immune system, as often happens with chemotherapy, cps still retains its cancer-fighting powers in the body.

“Aggressive cancers too often seem like fast-moving train wrecks,” As Bzik said. “Cps is the microscopic, but super-strong, hero that catches the wayward trains, halts their progression, and shrinks them until they disappear.”

During the lab studies, he and his colleagues used cps to treat extremely aggressive cases of melanoma and ovarian cancer in mice. The scientists found unprecedented high rates of survival.

Yet another remarkable feature of this new weapon against cancer is that it could even be tailored to the individual patient.

“In translating cps therapy to the clinic, we imagine cps will be introduced into cells isolated from the patient,” Bzik said. “Then, Trojan Horse cells harboring cps will be given back to the patient as an immunotherapeutic cancer vaccine to generate the ideal immune responses necessary to eradicate their cancer cells and to also provide life-long immunity against any future recurrence of that cancer.”

More studies are needed, as the researchers are still trying to understand how cps works so well. They continue to examine its molecular targets and mechanisms.

Bzik concluded, “Cancer immunotherapy using cps holds incredible promise for creating beneficial new cancer treatments and cancer vaccines.”

If that holds true, future generations may see kitty litter in a whole new light.

Source: Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center
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  #14  
Old 10-06-2014, 04:06 PM
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Default Immunotherapy comes at the cost of a "Toxic" side effect

(Reuters) - A raft of new cancer drugs promise better, longer-lasting treatments with fewer adverse side effects -- but their high cost is a growing concern.

Drugs that help the body's own immune cells fight tumors are expected to be used in multi-drug cocktails, pushing the price of therapies costing more than $100,000 a year even higher.

At the same time, other expensive medicines are being combined to produce impressive results fighting diseases including breast and skin cancer.

Price -- just as much as safety and efficacy -- has proved a hot topic for nearly 20,000 oncology experts at the European Society for Medical Oncology (ESMO) annual congress in Madrid.

"It's going to be a real problem for society," said Solange Peters, a cancer specialist at the University Hospital of Lausanne and a member of ESMO's educational program. "We are working to make oncologists more aware of the costs."

It all spells an increased financial burden for healthcare systems already struggling to meet the demands of aging populations, and for individuals who have to pay out-of-pocket costs in markets such as the United States.

"Financial toxicity, or more generally the financial burden of disease, is a side effect just as potent as fatigue or nausea in patients," consultancy IMS Health said in a report last week, noting the average price of cancer drugs had almost doubled in the past decade to $10,000 a month.

America's Health Insurance Plans, representing U.S. insurers, says it is alarmed by a coming flood of new cancer treatments that will carry "astronomical price tags", while pricing rows have also flared in Britain, France and Italy.

TREATMENT BACKBONE

By blocking a tumor's ability to camouflage itself from attack by the immune system's cells, immunotherapy has the potential to send cancer into long-term remission.

The approach has come of age this month with the first U.S. approval of a drug blocking a protein known as Programmed Death receptor, or PD-1, from Merck and the first late-stage trial results for another PD-1 drug from Bristol-Myers Squibb presented at ESMO.

High prices are central to forecasts that sales of these new immune-boosting drugs from companies like Bristol-Myers Squibb, Merck & Co, Roche and AstraZeneca may top $30 billion a year.

But an ESMO survey showed patients in poorer parts of Europe already lack access to existing drugs such as Roche's Herceptin for breast cancer, so immunotherapies are likely to be out of reach in most of the 131 countries represented in Madrid.

Immunotherapies seem to work in more and more cancers, suggesting they could become the backbone of treatment in much the same way that chemotherapy is today.

Clinical updates in Madrid showed the efficacy of such therapies extending well beyond melanoma -- the initial focus -- to lung, kidney, bladder, head and neck, and stomach cancer.

ESMO president Rolf Stahel said they were likely to prove especially useful in diseases such as kidney and lung cancer, where slow growth favors the immunological approach.

Still, the new immunotherapies only help some patients and they do not act as quickly as other targeted drugs, suggesting the best approach will be to develop cocktails of medicines.

"Our vision is combinations," said Johann de Bono from Britain's Royal Marsden Hospital and head of ESMO's scientific committee. "We have new avenues for really changing practice globally, though there are obviously fiscal costs and concerns."

So far, doctors only have access to two types of immune system checkpoint inhibitors -- PD-1, plus the related target PD-L1, and CTLA4. But there are many other brakes and accelerators on the immune system that may be targeted. Some, like OX40, are already the subject of early trials.

BIOMARKERS

Jeffrey Weber, a cancer doctor at the Moffitt Cancer Center in Florida, who has led much of the research on Bristol-Myers' immune system drug Opdivo, is a big believer in the potential of immunotherapy but shares the concerns about costs.

"We've kind of maxed out what we're either willing or able to pay for these kinds of drugs, so it's a problem when you start combining them," he said.

"It can't just keep going exponentially, so that eventually it will be $1 million a year to get treated -- that's crazy."

Competition between companies may help drive down the cost, he believes, since there is no strong evidence as yet to differentiate the new PD-1 or PD-L1 drugs, which he expects to play a central in future drug combinations.

There is also debate as to whether cancer patients should be tested before treatment to see if their tumors carry biological markers that would make them more likely to respond, thereby limiting the numbers eligible for therapy.

Such biomarkers are already used for other cancer drugs that only work if there is a specific gene mutation. But the situation is not black and white with the new treatments and some oncologists worry it could exclude patients who might benefit.

Drugmakers argue they need a fair price as reward for their investment, with cancer accounting for 23 percent of the $70 billion spent by the industry on research last year, according to Thomson Reuters unit CMR International.

But they acknowledge the public purse is not bottomless.

"The willingness to pay in oncology will remain higher than in other therapeutic areas, because of the high need, but there will be a ceiling," said Joerg Barth, head of oncology at Germany's Boehringer Ingelheim.

Citation: New Cancer Therapy Comes of Age, Cost a 'Toxic' Side Effect. Medscape. Sep 30, 2014.
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Old 10-06-2014, 04:09 PM
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Default Paving the Way Forward with Biomarkers for Immunotherapy

Immune therapy drugs work by coaxing white blood cells that usually fight bacteria and viruses to kill cancer cells. For now, the drugs usually work in only about 20 to 40 percent of patients and doctors cannot yet predict which ones.

According to Ira Mellman, Ph.D., Professor of Biochemistry & Biophysics, University of California at San Francisco, developing meaningful and accurate diagnostic tests is one way to reduce uncertainty and give doctors and patients more confidence that an immunotherapy may work.

Eliminating uncertainty about who will or will not respond to an immunotherapy is exactly why we’ve committed to discovering biomarkers and developing diagnostics alongside our medicines, including the investigational immunotherapy that we’ll be presenting data on at ASCO. Our goal is to identify ahead of time who may respond to a medicine or whose disease will simply mimic a response.

Another way is to evaluate immunotherapies in combination with other targeted medicines that affect how tumors grow and spread. Smart combinations could potentially help bolster the immune response to cancer and also provide another way to combat the disease.

The science is still early, but we hold hope that immunotherapy could turn out to be a game changer for cancer treatment. We believe research into this field may help us turn advanced cancer into a chronic rather than deadly disease by enabling the immune system to continuously monitor against the re-appearance of “foreign” cancer cells. In some cases, there may be the potential to completely eliminate a tumor, which of course is the ultimate goal of cancer treatments.
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  #16  
Old 01-21-2015, 08:53 PM
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Default Some information on Bristol-Myers Opdivo and Merck's Keytruda

[url]http://www.fiercepharma.com/story/bristol-myers-scores-lung-cancer-survival-data-opdivo-merck-preps-keytruda/2015-01-12

[url]http://www.fiercepharma.com/press-releases/checkmate-017-phase-3-study-opdivo-nivolumab-compared-docetaxel-patients-se-0

[url]http://www.fiercepharma.com/press-releases/merck-provides-update-strategic-actions-transform-company-and-build-platfor-0

Other case studies:

[url]http://www.opp.net/don-case-study.pdf

Nivolumab is on average $28.78 per mg and Ipilimumab is $157.46 per mg or roughly 4 times the current price of gold as stated by Dr. Saltz from Sloan Kettering at the ASCO. Below is a link to the whole article as well information on the current checkmate 067 trial.

[url]https://am.asco.org/asco-plenary-nivolumab-ipilimumab-combination-effective-advanced-melanoma
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  #17  
Old 11-29-2015, 06:35 PM
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Default Biomarkers in Oncology

Robert A. Nagourney, M.D.

The treatment of advanced human malignancies has progressed slowly since the first introduction of systemic chemotherapy in the 1950’s. Our capacity to harness adaptive immunity using T-cell checkpoint inhibitors has added a new modality for treatment. It has long been recognized that the selection of candidates for treatment using biological markers could enhance outcomes, facilitate drug discovery, reduce costs and curtail futile care. These predictive/prognostic biological markers are known as “biomarkers”.

Biomarkers are defined as “objectively measured indicators of biological processes or response to a therapeutic intervention.[1] The FDA uses four subgroups I) exploration, 2) demonstration, 3) characterization and 4) surrogacy, with only surrogacy accepted for drug approval. Recognized surrogates include serum cholesterol, HIV viral load and blood pressure. Biomarker validation including calibration, precision, specificity and sensitivity remains the principal developmental hurdle. In this expanding era of immunotherapy, the need for validated predictive biomarkers has rapidly grown.

Checkpoint inhibitors targeting PD1, PDL1and CTLA4 offer fertile ground for discovery. PDL1 (CD279) is highly expressed in T, B, NK-cells and macrophages and serves as a receptor for PDL1, PDL2, B7H3, and B7H4. PDL1 expression in tumor cells, immune cells or both has been proposed as a predictive biomarker yet technical variability, differing cutoffs (1%, 5%, 10%, 50%), frozen vs FFPE and varying clinical circumstances continue to complicate treatment-candidate selection. Recently, BIM expression was reported as a new PD1 response biomarker.[2] Additional markers, including CD8+/CD20+ ratios, circulating cytokines and the use of tumor exomes are under investigation.[3] Anti-CTLA4 (ipilumab) has also been the subject of biomarker analyses with response shown to correlate with T-cell count, T-cell activation, inflammatory micro-environment and T-cell clonotypes. Whole exome sequencing has been used to screen candidate neo-antigens with immune signatures then shown to correlate with outcome (p=0.01).[4] However, these investigators noted, “no gene was universally mutated”.

The complexity of human immunity continues to challenge those seeking to identify specific mutations, splice variants or amplifications that can segregate responders from non-responders The NEJM study used phenotypic autologous T-cell response to identify relevant neo-antigens while the Mayo investigators defined a “response phenotype” using BIM expression Thus genotypic interrogation can be enhanced through the study of the human phenotype. Closing the gap between genotype and phenotype offers unique opportunities to advance cancer therapy and drug development.

To date, genomic prediction of clinical response to “molecularly targeted agents” has met with limited success. One study provided a 1.5% (1/68) objective response rate in colon cancer patients who received molecularly targeted therapy,[5] similar to the 4% (1/27) response rate observed in BRAF mutation (+) colon cancer patients selected for Vemurafenib.[6] A recent trial that randomized patients to “molecular selection” vs. “physician choice” showed no difference in time to progression (2.3 vs 2.0 months) with the authors concluding that “Off label use of molecularly targeted agents should be discouraged”.[7]

The decades-long focus upon altered cell proliferation over more modern concepts of altered cell survival (apoptosis), a focus upon the cancer cell and not its micro-environment and the promotion of genomics over functional platforms have contributed to slow progress in cancer research. Nonetheless, the application of laboratory models capable of interrogating the biologic basis of clinical response at the phenotypic level has the potential to inform and accelerate future developments.

We have explored functional analyses that examine human tumor biology phenotypically. The Ex Vivo Analysis of Programmed Cell Death (EVA-PCD) incorporates the modern tenets of drug induced programmed cell death in the context of human tumor primary culture microspheroids that recapitulate native state human tumors replete with stroma, vasculature, inflammatory cells, cytokines, and cell-cell interactions. Results have been shown to correlate with response, time to progression and survival and have been the subject of prior meta-analyses.[8],[9] Preliminary work supports their capacity to examine biologic response modifiers like VEGF inhibitors.[10] More recently this platform has been applied to the study of human ovarian carcinoma using cell death measures as correlates with metabolomic endpoints.[11]

We are witness to a growing appreciation of human tumor phenotypic analyses as important adjuncts to genomic, transcriptomic and proteomic platforms. Phenotypic analyses have the capacity to interrogate the complexities, redundancies and promiscuities of human tumor biology. The intelligent combination of phenotypic (functional) and analyte-based (molecular) platforms will facilitate patient selection and drug discovery.

[1] Firestein GS. A biomarker by any other name. Nature Clinical Practice Rheum Vol 2:12; 635, 2006

[2] Dronca RS, et al. BIM as a predictive T cell biomarker for response to anti-PD-1 therapy in metastatic melanoma Proc Int’l Canc Immunotherapy Conf, Ab A007, 2015

[3] Whiteside Theresa. Immune responses to cancer: are they potential biomarkers of prognosis? Frontiers in Oncology 3:107;1-8, May 2013

[4] Snyder A, et al. Genetic Basis for Clinical Response to CTLA4 blockade in melanoma. NEJM 371:2189-2199, 2014

[5] Dienstmann R, et al. Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials.Molecular Cancer Therapeutics, 11(9)2062-2071, 2012

[6] Hyman David M., Puzanov Igor, Subbiah Vivek, et al. (2015) Vemurafenib in multiple nonmelanoma cancers with BRAF V600 Mutations. NEJM 373;8:726-736

[7] LeTournea Christophe, Delord Jean-Pierre, Goncalves Anthony, et al. (2015) Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicenter, open-label, proof-of-concept, randomized, controlled phase 2 trial. Lancet, 16-13;1324-1334

[8] Bosanquet Andrew G, Kasper Gertjan J, Larsson Rolf, et al. (2007) Individualized Tumor Response (ITR) Profiling for Drug Selection in Tailored Therapy: Meta-analysis of 1929 Cases of Leukemia and Lymphoma. Blood 110; abs 3471

[9] Apfel Christian, Souza Kimberly, Cyrill Hornuss, et al. (2013) Accuracy and clinical utility of in vitro cytometric profiling to personalize chemotherapy: Preliminary findings of a systematic review and meta-analysis. J Clin Oncol 31, 2013 (suppl; abs e22188)

[10] Weisenthal LM et al Cell Culture detection of microvascular cell death in clinical specimens of human neopalsms and peripheral blood. J Intern Med. 264 (3) 275-287, 2008

[11] D’Amora Paulo, Dale Ismael, Salzgeber Marcia, et al. A Phase II study in epithelial ovarian cancer (EOC) to correlate drug sensitivity and metabolomic signatures with objective response (OR), time to progression (TTP) and overall survival (OS). 19 Congresso Brasileiro de Oncologia Clinica, Oct 2015.
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Old 01-09-2016, 10:42 PM
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Default Training The Immune System To Fight Cancer Has 19th-Century Roots

A novel immunotherapy drug is credited for successfully treating former President Jimmy Carter's advanced melanoma. Instead of killing cancer cells, these drugs boost the patient's immune system, which does the job instead.

Immunotherapy is cutting-edge cancer treatment, but the idea dates back more than 100 years, to a young surgeon who was willing to think outside the box.

His name was William Coley, and in the late summer of 1890 he was getting ready to examine a new patient at his practice in New York City. What he didn't know was that the young woman waiting to see him would change his life and the future of cancer research.

Her name was Elizabeth Dashiell, also known as Bessie, says Dr. David Levine, director of archives at the Hospital for Special Surgery in New York. Bessie was 17 and showed up complaining of a problem with her hand. It seemed like a minor injury, just a small bump where she'd hurt it, but it wasn't getting better, and she was in a lot of pain. She'd seen other doctors but nobody could diagnose the problem.

At first Coley thought Bessie must have an infection. But when he took a biopsy, it turned out to be a malignant, very advanced cancer called a sarcoma.

In those days there wasn't very much anyone could do for Bessie. This was before radiation and chemotherapy, so Coley did the only thing he could — he amputated Bessie's right arm just below the elbow in an attempt to stop the disease from spreading. Sadly, it didn't work, and within a month, according to David Levine, the cancer had spread "to her lungs, to her liver and all over her body."

Bessie's final days were wrenching and painful. Coley was with her when she died on Jan. 23, 1891. Bessie's death made a huge impression on the young surgeon. "It really shocked him," says Stephen Hall, who wrote about Coley in his book A Commotion in the Blood: Life, Death and the Immune System.

Bessie's death also spurred Coley into action. There wasn't a lot known about cancer at the time, so Coley started digging through dozens upon dozens of old records at New York Hospital. He was looking for something that would help him understand this cruel and aggressive disease.

As a student, Coley had read Charles Darwin, and one of the lessons he took away from Darwin, Hall says, was to always pay attention when there's a biological exception to the rule. "To ask yourself: Why this has happened?"

Coley discovered one of these biological exceptions. It was the case of a German immigrant named Fred Stein. Stein had been a patient in New York Hospital eight years earlier. He had a tumor on his neck that doctors tried to remove several times. Unfortunately for Stein, the tumor kept coming back and doctors expected him to die from the disease.

Then Stein contracted a serious infection of the skin caused by the strep bacteria. "It looked like Stein's days were numbered," Levine says. But Stein didn't die. In fact, his tumor disappeared, and he was discharged. Coley wondered if all these years later, Stein could still be alive.

So in the winter of 1891, William Coley the surgeon became William Coley the detective. He headed for the tenements of the Lower East Side of Manhattan where the German immigrant community lived. He knocked on door after door asking for a man named Fred Stein who had a distinctive scar across his neck. After several weeks of searching, Coley found him alive and cancer-free.

So why did Stein's cancer go away and stay away after he got a bacterial infection? Coley speculated that the strep infection had reversed the cancer. and wondered what would happen if he tried to reproduce the effect by deliberately injecting cancer patients with bacteria.

He decided to test his idea on people who were the most seriously ill. His first subject was an Italian immigrant named Zola who, just like Bessie Dashiell, was suffering from sarcoma. Zola had tumors riddling his throat. He was so sick he could barely eat or speak or even breathe. For months Coley would try to make Zola sick from infection by creating little cuts and rubbing the strep bacteria into them, Hall says. There would be "a slight response but not too much."

Then Coley got his hands on a much stronger strain of the bacteria. This time, Zola became violently ill with an infection that could easily have killed him. But within 24 hours, Zola's orange-sized tumor began to liquefy and disintegrate. "This was a phenomenon that occurred rarely, but when you saw it you were utterly astonished," Hall says.

Zola completely recovered. Coley knew he was on to something. He kept experimenting and refining his use of bacteria. Eventually, he named the treatment Coley's toxins.

It was an exciting time. Coley was having tremendous success and his efforts were celebrated in America and abroad. But Bradley Coley Jr., William Coley's grandson, says the American medical establishment at the time was skeptical. Nobody knew how Coley's toxins worked, or why they worked sometimes and not others. Not even Coley could explain it.

That's largely because the immune system was still a mystery and would remain so for decades to come.

When radiation therapy came along in the early 1900s, interest in Coley's toxins was completely overshadowed by this new therapy. When his grandfather died, Bradley Coley says, "All interest in [Coley's toxins] stopped."

And quite possibly, that's where Coley's legacy would have ended except for this: After Coley's death in 1936, his daughter, Helen Coley Nauts, started looking through her father's papers while doing research for his biography. She found about 1,000 files of patients her father had treated with Coley's toxins.

She spent years carefully analyzing these cases and could see that he had extraordinary rates of success in regressing some cancerous tumors. She couldn't get anyone interested in studying her father's work, so she decided to do it herself. With a small grant, in 1953 Helen Coley Nauts started the Cancer Research Institute, dedicated to understanding the immune system and its relationship to cancer.

In the more than 60 years since, researchers have expanded their understanding of the immune system dramatically and today, that understanding is paying off. Treatments that harness the power of the immune system are now available for a range of cancers such as stomach, lung, leukemia, melanoma and kidney.

Jedd Wolchok, chief of the melanoma and immunotherapeutics service at Memorial Sloan Kettering Cancer Center, says any treatment currently in use that exploits the power of the immune system to fight cancer has to "tip its hat" to the work William Coley began more than 100 years ago.

Source: NPR

Listen to the story:

[url]http://www.npr.org/player/v2/mediaPlayer.html?action=1&t=1&islist=false&id=4592 18765&m=461247423
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Old 09-06-2017, 07:03 AM
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Default Progress of Cancer Immunotherapy: The Tip of the Iceberg

Cancer Care, and Research News
By Dana-Farber Cancer Institute

If the human immune system was a powerful racing car, you could say that scientists in the past few years have gained unprecedented control over how to make it accelerate, and what causes it to slow or stop. This knowledge has spawned new immunotherapy drugs that are delivering dramatic benefits to some patients with advanced cancers.

“Checkpoint blockers are transformational,” asserts Laurie H. Glimcher, MD, president and CEO of Dana-Farber and a prominent immunologist, referring to drugs that disable the brakes that cancer cells use to fend off an attack on them by immune system T cells.

“The idea that you can take someone who has stage IV metastatic cancer and halt the cancer – and manage it more like a chronic disease…it’s remarkable,” Glimcher says.

“However,” she adds, “it’s just the tip of the iceberg.” Beyond the impressive but limited successes of recent immunotherapy advances lies the potential to bring the strategy to more patients and more kinds of cancer.

The iceberg’s tip also represents current knowledge of the powerful immune system’s intricate and complex set of controls. Much of what will be needed to shape and steer the immune attack against cancers remains to be discovered.

“There’s so much we don’t understand,” Glimcher says. “Our task is to figure out the answer to at least two questions. First, why do only some patients with tumors that can respond to immunotherapy – like melanoma, lung, bladder and kidney – not respond to immunotherapy? Why is it only 20 or 30 or 40 percent? Why don’t all of them respond?

“And second, why do some cancers not respond at all, like pancreatic, prostate, ovarian, and breast cancer, glioblastoma, and colon cancer other than patients with Lynch syndrome?”

Despite those unanswered questions, the science behind immunotherapy is far more advanced than it was even a decade ago. For nearly 100 years, since the idea first emerged, efforts to harness the immune defenses as a cancer treatment met with many failures and limited success – even though the immune system, which evolved mainly to combat infectious viruses and bacteria, is capable of eliminating body cells that have become cancerous. Many strategies focused on stimulating the immune response with vaccines or removing T cells from a patient, “educating” them in the laboratory, and returning them to the body to seek out and destroy cancer cells. But except in a few instances, these measures didn’t spark an effective immune reaction.

It took what Glimcher calls an “Aha!” insight to jump-start the field of cancer immunotherapy.

That realization was that the best way to activate the immune system was not by stepping on the gas pedal – but by removing the brakes. Scientists learned that cancer cells evade the immune forces by activating molecular “checkpoints” that both conceal the identity of the cancer cells and switch off the immune response. These natural checkpoints are crucial to health – without them, people would be much more vulnerable to misguided attacks on normal tissue, as in autoimmune diseases like lupus. The role of one of those checkpoints on cancer cells, PDL-1, was identified by Dana-Farber’s Gordon Freeman, PhD, who in 2000 discovered that it partnered with another molecule on T cells, PD-1, to stave off attack by immune T cells. Another checkpoint, CTLA-4, also switches off the immune response.

“The T cells can get exhausted, and go into a state where the tumor is masked from the immune system, or the tumor secretes substances that create a highly immunosuppressive microenvironment” around the tumor, like a moat around a castle, says Glimcher.

The “moat,” a microenvironmental barrier that prevents killer T cells from invading the tumor, is composed of many kinds of suppressor cells including macrophages, dendritic cells, endothelial cells, and others. Glimcher’s own research has identified key molecular signaling pathways in the tumor microenvironment that are hijacked by cancer cells as protection; she and others are exploring strategies for “reprogramming” the environment to boost the immune response against tumors.

The discoveries of checkpoints that allow cancer to escape immune attack rapidly led to the development of “checkpoint blockade” antibody drugs that free T cells to attack and kill cancer cells. Dana-Farber’s F. Stephen Hodi, MD, director of the Center for Immuno-Oncology, led a groundbreaking clinical trial showing that ipilimumab (Yervoy), which blocks CTLA-4, could slow advanced melanoma in a significant number of patients and prolong their survival. Several other antibody drugs that block the PD-1/PD-L1 interaction have been approved, including pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq). These drugs have found a place in treating non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin lymphoma, and are being tested in other forms of cancer.

While many other checkpoint blockers are in company pipelines or clinical trials, researchers are exploiting the power of the immune system in other ways.

One approach that has gotten a lot of attention because of some early dramatic successes is CAR T cells. The patient’s T cells are removed and genetically modified in the laboratory to produce special receptors on their surface that recognize a specific protein on tumor cells. Then billions of the CAR T cells are infused into the patient to seek out and destroy the cancer. In some patients with very advanced blood cancers this strategy has had remarkable success, but it also can produce severe side effects that need to be closely managed.

Cancer vaccines continue to intrigue immunologists. Even though there are effective vaccines against the human papilloma virus (HPV), which causes cervical cancer, and some head and neck and anal cancers, only a minority of people at risk have undergone vaccination, Glimcher says. “It’s really a crime,” she says. “No women should die of cervical cancer.” She says she believes effective vaccines for non-viral cancers are possible, but the field is still in its infancy. Such vaccines would provoke the immune system to react against proteins displayed on the surface of cancer cells.

“Ultimately,” says Glimcher, “I think the answer is going to be combination therapy, just as it was for HIV/AIDS. The key to turning HIV from a lethal disease to a chronic disease was realizing you have to attack it with several drugs at the same time. It’s going to be trying to figure out which drugs work in which patients, precision immuno-oncology both for the tumor and the immune system.”

The potential of immuno-oncology is just beginning to be realized. Uncovering more of the iceberg will take both a much more detailed understanding of how the immune response is controlled and the tools or treatments to manipulate it for clinical benefit.

“I can’t think of a place that’s better equipped than Dana-Farber to take this on,” Glimcher reflects. “We have fantastic researchers who work closely with clinicians. And we can actually generate drugs here – we can take a basic discovery in the lab, do a proof of principle assay in animals, identify tool compounds, and then our chemists can turn that into a drug that could go into humans. Very few institutions have this capability.”

Source: Dana-Farber’s 2017 issue of Paths of Progress
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