Immunotherapy Tightens the Siege of Solid Tumors.


Translational Scientists Issue an Immunological Call to Arms, Prepare to Overcome Cancer’s Defenses

Immunotherapy Tightens the Siege of Solid Tumors

This image depicts a group of killer T cells surrounding a cancer cell. [Alex Ritter, Jennifer Lippincott Schwartz, and Gillian Griffiths, National Institutes of Health]

  • In anticancer campaigns, the immune system has often shown too little fighting spirit. It can be too civilized, too restrained—unless it is specially outfitted and guided. Measures that can drive the immune system to exert itself more strenuously, more aggressively, include monoclonal antibodies, cancer vaccines, checkpoint inhibitors, and adaptive cell therapy—all the tools and techniques of immuno-oncology.

    The proliferation of immuno-oncology tools and techniques was evident at the recent Translating Science into Survival conference. This event, which was held in New York City was organized by the Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research. The organizers evidently anticipated that this event, like previous immunotherapy events, would be fairly intimate. Yet it sold out quickly and ultimately strained to accommodate 1,400 attendees.

    The event’s popularity was probably at least in partly due to recent immunotherapy successes against blood cancers. For example, adaptive cell therapy approaches have shown promise in small trials, and work along these lines continues apace, as several presentations demonstrated. Moreover, lessons derived from this work may be applied more broadly, even to the treatment of solid tumors.

    For example, in a presentation entitled “Engineered T cells for cancer therapy,” the University of Pennsylvania’s Carl June described his team’s progress in using chimeric antigen receptor (CAR)-modified T cells to treat patients with chronic lymphocytic leukemia (CLL). “We previously reported preliminary results on three patients with refractory CLL,” Dr. June noted. “Here we report the mature results for our initial trial using CAR-modified T cells to treat 14 patients with relapsed and refractory CLL.”

    The overall response rate in CLL patients was 8/14 (57%), with four complete remissions and four partial remissions. All responding patients developed B cell aplasia and experienced cytokine release syndrome, coincident with T cell proliferation. Minimal residual disease was not detectable in patients who achieved complete remission, which, Dr. June suggested, indicated that “disease eradication may be possible in some patients with advanced CLL.”

    Dr. June also summarized a separate investigation that asked whether the CAR cells used against CLL would also be effective against multiple myeloma. At first glance, this may seem odd, since the CAR cells that were effective against CLL target CD19, and CD19 expression is all but absent from myeloma cells. That is, myeloma cells don’t traditionally express CD19 on their surface because they arise from the most mature type of lymphocytes—plasma cells.

    Dr. June’s team, however, proceeded on the chance that they would be able to incorporate their anti-CD19 CAR T cells into a therapy that would target early precursors of myeloma cells. This therapy, which was administered to a patient with refractory multiple myeloma, involved an infusion of the patient’s own stem cells along with lymphodepleting chemotherapy (melphalan) as well as an infusion (two weeks later) of anti-CD19 CAR T cells.

    The patient experienced transplantation-related side effects during the time prior to receiving CTL019, including neutropenia and thrombocytopenia, nausea, fever, and an infection. After receiving the engineered cells, she experienced no fevers or other signs of cytokine release syndrome, a condition that has been observed in other patients undergoing CTL019. At last evaluation, 12 months after treatment, the patient exhibited a complete response with no evidence of progression. According to Dr. June, “This response was achieved despite absence of CD19 expression in 99.95% of this patient’s neoplastic plasma cells.”

    While the results presented by Dr. June pertain most directly to blood cancers—specifically, the inducement of favorable patient responses to treatment—they may also apply more broadly. For example, they demonstrate that a “living drug” may exert its effects indirectly. Also, they emphasize the importance of managing toxicity and ensuring the expansion of modified cells. They also raise the issue of introducing cells that may demonstrate longevity.

    More generally, uncertainties surrounding the differential expansion and persistence of distinct cell populations over time can complicate dosing. Similarly, with respect to toxicity, cytokine release and the generation of tumor-shredding products might be considered side effects or, really, evidence that a therapy is working.

    Yet engineered cells may also attack both malignant and healthy cells directly. That is, engineered cells may be sensitive to target proteins that stud both cancer cells and also, if only to a lesser degree, normal cells. In CAR T-cell therapies against leukemia and lymphoma, side effects related to direct attacks on normal cells has been manageable. Such side effects, however, may be more severe if adaptive cell therapies are directed against solid tumors.

    Leading up to the Translating Science into Survival conference, Dr. June’s group published a study that described an approach for managing target-mediated toxicity. The approach, called affinity tuning, involves generating CAR T cells that are sufficiently insensitive to ignore normal cells, which are relatively target-sparse, and yet sensitive enough to latch onto cancer cells, which are relatively target-rich.

    In a paper (“Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice”) that appeared September 1 in Cancer Research, the case was made that “affinity-tuned cells” could exhibit robust antitumor efficacy similar to high-affinity cells, but spare normal cells expressing physiologic target levels: “The use of affinity-tuned scFvs offers a strategy to empower wider use of CAR T cells against validated targets widely overexpressed on solid tumors, including those considered undruggable by this approach.”

    At the Translating Science into Survival event, the presentations concerning solid tumors emphasized that adoptive cell therapy could become more effective if obstacles in the tumor microenvironment could be overcome. For example, the University of Pennsylvania’s Ellen Puré, in a presentation entitled, “Tumor stroma: Immunomodulatory functions and a target of immunotherapy,” explained that stroma can be a barrier to T cells, including CAR T cells.

    Stromal components such as fibroblasts and the extracellular matrix can play myriad functions in cancer. For example, Puré noted, reactive stroma enriched in growth and angiogenic factors presents chemoattractants that promote the recruitment of bone marrow-derived cells and can modulate inflammatory and immune cell function, all of which can contribute to its tumor-permissive nature relative to normal stroma.

    “A significant portion of cancer-associated fibroblasts in virtually all human carcinomas express the cell surface protease fibroblast activation protein (FAP),” Puré continued. “Our studies indicate that FAP+ cells are required for the generation and maintenance of desmoplastic stroma and that depletion of FAP+ cells can inhibit tumor growth through both immune-dependent and immune-independent mechanisms.”

    Another take on the tumor microenvironment was presented by Wolf H. Fridman, Cordeliers Research Centre, Paris. In a talk entitled, “Cancer subtypes and their immune microenvironments,” Dr. Fridman described how his group was elaborating on the Immunoscore concept, which goes back at least as far as 2006. Basically, Immunoscore builds on the insight that in many patients, the density of T cells near tumor cells could be a better predictor of survival than traditional staging based on a cancer’s size and spread.

    In general, for a patient’s prognosis to be favorable, immune cells need to infiltrate a solid tumor. But recent work also suggests that more immune cells may not always be better. Apparently some immune cells are less helpful than others. Some may even be deleterious, depending on the interactions that occur between a tumor’s microenvironment and the immune system.

    “Our team studied the immune infiltrates of pulmonary metastases from colorectal cancer (CRC) and renal cell carcinoma (RCC),” reported Dr. Fridman. “As in primary tumors, a high density of CD8+ T cells correlated with good prognosis for CRC metastases, while it correlated with a bad prognosis for RCC metastases.”

    “In addition, in both cancer types, we identified subgroups of poor-prognosis patients with high tumoral lymphocyte infiltration, in the context of high expression of genes related to inflammation, immunosuppression, and angiogenesis,” he continued. “These results suggested that the identity of the tumor cells, rather than the organ where they grow, is critical for shaping the immune contexture of a given tumor.”

    A particular cancer, then, may have an ecology of its own, one in which the overall disposition of elements—tumor cells, immune cells, extracellular matrix elements, and so on—matters, much as the overall disposition of chess pieces matters in a game of chess. Even though it might be advantageous to occupy a particular space on the board, apparently not any chess piece will do. Frustratingly, one’s own pieces may be poorly positioned, so as to get in each other’s way.

    Nonetheless, as Dr. Fridman concluded, the integration of molecular and immune tumor phenotypes could guide the selection of immunotherapies “appropriate to specific, potentially responding groups of patients.”

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Latest advances in oncology


 The findings support a new treatment based on immunotherapy

Drugs that “release the brakes” on the body’s immune system have been shown in clinical trials to boost the survival of patients with fatal forms of cancer – further evidence to support a new form of tumour treatment based on immunotherapy.

Two separate clinical trials on different cancers have shown that drugs that block the natural “checkpoints” of the immune system can trigger the destruction of tumour cells by the body’s own immune defences and extend the lives of patients with fatal forms of cancer.

In a clinical trial involving 260 lung-cancer patients, doctors found that those who were given the immune checkpoint inhibitor nivolumab lived on average 3.2 months longer than patients who received conventional chemotherapy.

However, the apparently small increase in survival may actually mask much better longer-term outcomes as patients who respond to immunotherapy tend to continue with a response, said Julie Brahmer of Johns Hopkins University in Baltimore, who led the study.

“This solidifies immunotherapy as a treatment option in lung cancer. In the 20 years that I’ve been in practice, I consider this a major milestone,” Dr Brahmer said.

“Patients who respond to immunotherapy tend to continue their responses for long durations, and these lengthier responses are cut off in calculations of median overall survival,” she said.

In a separate trial on 945 patients with advanced melanoma skin cancer, scientists found that combining two checkpoint inhibitors – nivolumab and ipilimumab – resulted in a significant extension in progression-free survival of patients compared to patients taking either drug on its own.

“All the early preclinical and clinical work supported the idea that combining these two immunotherapy drugs could result in better outcomes for patients,” said Jedd Wolchok of the Memorial Sloan Kettering Cancer Centre in Chicago, who led the melanoma trial.

“We’re encouraged by the progression-free survival data we’re currently reporting. It is a testament to how drastically immunotherapy has altered the prognostic landscape for advanced melanoma patients,” Dr Wolchok said.

“Just five years ago, many of these patients would have been expected to live for only seven months following diagnosis, but it’s important to remember that overall survival data for this group is not yet available,” he said.

Advanced melanoma patients who received a combination of nivolumab and ipilimumab experienced a median period of progression-free survival of 11.5 months compared to 6.9 months for patients on nivolumab alone and 2.9 months for ipilimumab alone.

The results of both sets of trials were presented on Sunday to the American Society of Clinical Oncology meeting in Philadelphia, and published in the New England Journal of Medicine.

Check-point inhibitors such as nivolumab and ipilimumab block a chemical “handshake” between cells of the immune system that limit its activity as a natural safety mechanism. Cancer cells exploit this handshake to evade detection, but the drugs counteract this, which is why they are described as being able to release the brakes on the immune defences to accelerate the destruction of tumour cells.

The immune system has several checkpoints designed to stop a dangerous overreaction. Ipilimumab works by blocking the CTLA-4 checkpoint, a molecular brake that stops the killer T-cells of the immune system from becoming fully and persistently activated. Nivolumab works on another checkpoint by blocking the ability to tumour cells to deactivate T-cells

Tests can show which patients will respond better to each of the drugs which will help doctors to work out whether someone should be given each drug on its own or in combination, Dr Wolchok said.

“One of the biggest questions in the field of immunotherapy has been how to determine which patients will respond to immune-modulating drugs. Now we have another piece of data,” he said.

‘Cure for terminal cancer’ found in game-changing drugs – Telegraph


Immunotherapy, which harnesses the body’s own immune system to destroy deadly tumours, has been hailed as one of the biggest breakthroughs in the treatment of cancer for decades

X-rays showing a patient's tumor, circled, before, leftm and after immunotherapy

X-rays showing a patient’s tumor, circled, before, leftm and after immunotherapy

Terminally ill cancer patients have been “effectively cured” by a game-changing new class of drugs.

In one trial, more than half of patients who had just months to live saw deadly tumours shrink or completely disappear.

In recent days, the results of trials of a number of treatments which harness the body’s immune system have been announced at the American Society of Clinical Oncology’s annual conference in Chicago. They show promise in the fight against skin cancer and lung disease.

But results from a slew of trials released last night at the conference showed “spectacular” effects against a multitude of cancers.

Experts said the advances suggest terminally ill patients with common cancers – including lung, bowel, ovarian and womb – could in future be cured by the therapies.

The evidence in favour of the radical drugs is so overwhelming that they could save tens of thousands of lives in the UK within a decade, it is claimed.

 

Senior cancer doctors said the treatment, known as immunotherapy, could radically change the standard treatment for cancer, sparing some sufferers from some of the toxic effects of chemotherapy.

Roy Herbst , chief of medical oncology at Yale Cancer Centre, described the string of results as “spectacular”.

“I think it’s huge,” he said. “I think we are seeing a paradigm shift in the way oncology is being treated.”

“I’m seeing this work in almost every cancer,” added Prof Herbst, who said the results suggested the therapy worked best on the cancers that were hardest to treat.

“The potential for long-term survival, effective cure, is definitely there,” he said.

Peter Johnson, Professor of Medical Oncology, from Cancer Research UK, said the therapies – which work by “re-educating” the immune system – are one of the greatest breakthroughs in cancer treatment in four decades.

“The evidence emerging from clinical trials suggests that we are at the beginning of a whole new era for cancer treatments,” he said.

“Some of the most common types of cancer seem to be treatable with immunotherapy. Overall, cancers of the lung, kidney, bladder, head and neck, and melanoma cause about 50,000 deaths a year, or around one third of cancer deaths.”

In one British-led study, 58 per cent of patients with advanced skin cancer saw their tumours reduce significantly when given a new combination of immunotherapy drugs.

In more than one in 10 cases, those given the drugs, called nivolumab and ipilimumab , the growths were entirely destroyed.

Such patients could expect to live just nine months if given standard treatment. The two-year study of 950 patients has yet to publish survival data but researchers said they were hopeful that half of the patients would end up “living disease-free”.

Lead author Dr James Larkin, consultant medical oncologist at the Royal Marsden Hospital, said he was excited about the prospects of the new treatments.

“We’ve seen these drugs working in a wide range of cancers and I think we are at the beginning of a new era of treating cancer,” he said.

Iplimumab, the only immunotherapy in use by the NHS, costs around £100,000 for four treatments.

The second drug, nivolumab, is expected to be licensed for use in Europe this summer.

The study found their results, when combined, were three times as good as when iplimumab was given alone. Trials involving a treatment for the most common type of lung cancer doubled the chances of survival for some patients.

Meanwhile trials examining the use of the drugs in womb, liver, head and neck, and bowel cancer showed “remarkable” results, specialists said.

Experts said the new treatments, which use the body’s immune system to stall the spread of disease, could soon become the mainstream treatment for a wide range of cancers.

“Cancers develop because they manage to hide from the immune system and disguise the danger they pose. Immunotherapy works by making the cancer visible again and alerting the body’s immune system to the danger,” Prof Johnston said. Patients who began some of the earliest trials 10 years ago appeared to have been cured, he added.

Last week, scientists announced that a genetically modifed herpes virus could spark the immune system into action, in another breakthrough in skin-cancer treatment.

Half of cancer sufferers will be ‘cured’

NSCLC immunotherapy coming of age.


Following the success of immune checkpoint inhibitors such as programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors in advanced melanoma, these agents are now emerging as effective treatments for non-small-cell lung cancer (NSCLC).

“This year, nivolumab became the first PD-1 inhibitor to receive US FDA approval for advanced NSCLC that has progressed on platinum-based chemotherapy,” said Dr. Solange Peters of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, at the European Lung Cancer Conference (ELCC) 2015 held recently in Geneva, Switzerland.

“In a phase III trial of 272 patients, nivolumab reduced mortality by 41 percent and prolonged survival by 3.2 months vs docetaxel,” She continued. [US FDA press release, 4 March 2015] “In an earlier phase II trial, single-agent nivolumab achieved a 15 percent response rate in heavily pretreated squamous cell NSCLC.”

Next in line is likely to be pembrolizumab, having shown an overall response rate of 45.2 percent in patients with ≥50 percent of tumour cells positive for PD-L1 expression. [N Engl J Med 2015, doi: 10.1056/NEJMoa1501824]

“These drugs as well as a number of other agents, such as ipilimumab and tremelimumab, and the PD-L1 inhibitors MPDL3280A, MEDI4736 and BMS936559, are also being evaluated in phase II/III trials with very encouraging results. Given the huge lung cancer market, the pharmaceutical companies are in a tight race,” she added.

Despite the early stage, some experts are now advocating immunotherapy as first-line treatment. “PD-1/PD-L1 inhibitors have demonstrated better clinical outcomes than chemotherapy, with a 15 percent increase in response rate and 2-month longer progression-free survival. Importantly, immunotherapy elicits a fast and durable response and is less toxic,” argued Dr. Jean-Charles Soria of the Institut Gustav Roussy, Villejuif, France, at a debate session. “For these reasons, it’s a good first-line alternative for advanced nononcogene-addicted NSCLC.”

The opponent, Dr. Kenneth O’Byrne of Queensland University of Technology in Brisbane, Australia, claimed, however, that the enthusiasm is premature and phase III data are needed to establish immunotherapy’s role in the first-line setting.

Despite the excitement, many challenges remain with immunotherapy, including side effects (diarrhoea, colitis, fatigue and pneumonitis) and pseudo progression, which should be considered when assessing patient response. Another drawback is the lack of a suitable biomarker. “PD -L1 expression in tumour cells is of limited value in predicting activity, as some patients with weak expression also respond, and could benefit from immunotherapy,” noted Peters. “The criteria for patient selection should be refined, as patient and tumour characteristics, including smoking status, previous therapy, histology and mutations, have been associated with responses to immunotherapy.”

The combination of immunotherapy with other treatment modalities such as chemotherapy, targeted therapy, radiotherapy or another immunotherapy is also being explored in many trials, according to Dr. Martin Reck of the Lung Clinic Grosshansdorf, Germany. “There are promising data but also conflicting results. Clinical development has somewhat overtaken the science behind. Proper translational research will be crucial and we should never forget safety when dealing with the powerful immune system,” he said.

A Promising New Immunotherapy for Advanced Melanoma


A small, early-phase trial of a new immunotherapy yielded “durable responses” for patients with advanced melanoma and ocular melanoma.

Each year some 2,000 to 2,500 people in the United States are diagnosed with ocular melanoma, a serious cancer of the eye.

In about half of those diagnosed with this form of cancer, also called uveal melanoma or intraocular melanoma, the disease spreads, often to the liver. The prognosis for patients with metastatic ocular melanoma is poor, with median survival of just two to eight months.

So the report at the American Association for Cancer Research (AACR) Annual Meeting 2015 in April, of results from a phase I/IIa clinical trial of a new type of immunotherapy – albeit in a small group of 17 patients with advancedmelanoma and ocular melanoma – is promising.

The trial was of a first-in-class immunotherapy called IMCgp100. This therapeutic has “two functional ends,” explained Mark R. Middleton, PhD, professor of experimental cancer medicine at the University of Oxford in the United Kingdom. “The targeting end attaches to melanoma cells and the effector end locks on to any neighboring killer T cell [a type of immune cell], resulting in directed destruction of the tumor.”

In essence, IMCgp100 connects the immune cells to the melanoma cells, encouraging them to destroy the cancer.

“Among these patients, we observed lasting tumor responses for both cutaneous and ocular melanoma,” said Dr. Middleton. “Importantly, responses were even observed in patients with advanced melanoma that was resistant to the immune checkpoint inhibitors that have recently become standard of care in many locations.”

Among the 17 patients, three partial responses and one complete response were observed; two of the partial responses are still ongoing and have lasted more than 18 months, Dr. Middleton and his colleagues reported. The complete response in one patient with advanced ocular melanoma lasted over four months.

“It is too early to say if IMCgp100 is particularly effective in ocular melanoma, although the results are encouraging. These observations will be investigated further, both clinically and experimentally,” said Dr. Middleton. “We look forward to continuing to follow all the patients who remain on the trial and to enrolling more patients to firmly establish the utility of IMCgp100 as a treatment for advanced melanoma.”

Anti-PDL1 Agent Promising in Advanced Breast Cancer


Immunotherapy with monoclonal antibody proves safe in phase Ia trial..

In patients with metastatic triple-negative breast cancer, immunotherapy with the monoclonal antibody MPDL3280A appeared to be safe, tolerable, and capable of durable clinical activity, according to results from an ongoing multicenter phase Ia study.

“The latest analysis of our data revealed a 24-week progression-free survival rate of 27% with an objective response rate of 19%, and three of four responses are ongoing,” reported Leisha A. Emens, MD, PhD, of Johns Hopkins University, and colleagues in a press release at the American Association for Cancer Research annual meeting.

“MPDL3280A was generally well tolerated and demonstrated promising efficacy in pretreated metastatic PD-L1 IHC 2 or 3 TNBC patients,” she added. “Furthermore, circulating biomarker analyses revealed pharmacodynamic responses to MPDL3280A.”

The triple-negative breast cancer cohort is part of an ongoing trial into the efficacy and safety of MPDL3280A in a number of advanced solid tumors.

Triple-negative breast cancer has higher programmed death-ligand 1 (PD-L1) expression levels than other breast cancers and this can inhibit T-cell antitumor responses, Emens noted. MPDL3280A is an engineered anti-PDL1 antibody that inhibits the binding of PD-L1 to PD-1 and B7.1.

“Inhibiting PD-L1/PD-1 and PD-L1/B7.1 interactions can restore antitumor T-cell activity and enhance T-cell priming,” Emens said. “MPDL3280A leaves the PD-L2/PD-1 interaction intact, maintaining immune homeostasis and potentially preventing autoimmunity.”

The high mutation rate of triple-negative breast cancer, which can produce neoantigens that induce an immune response, makes it a candidate for cancer immunotherapy, in particular PD-L1-targeted therapies. In addition, patients with triple-negative breast cancer with high levels of tumor-infiltrating lymphocytes (TILs), have improved outcomes, Emens said.

The TNBC cohort enrolled 54 patients (median age 48), both PD-L1-negative and PD-L1-positive. The key eligibility criteria were measurable disease per RECIST v1.1 and ECOG PS 0 or 1; 52% had ECOG PS 0 and 44% had ECOG PS 1.

At baseline, visceral metastases were present in 59% of patients and bone metastases in 11%. In addition, 85% received four or more prior systemic regimens, neoadjuvant, adjuvant, or metastatic.

Patients received MPDL3280A at 15 mg/kg, 20 mg/kg or 1,200 mg flat dose IV q3w.

Treatment-related adverse events, summarized for the safety follow-up from the first dose to 30 days after the last dose, were seen in 63% of patients. The most common included fatigue (22%), pyrexia (15%), neutropenia (15%) and nausea (15%).

Some 11% of patients experienced grade 3 to 5 treatment-related adverse events. The grade 3 adverse events included adrenal insufficiency, neutropenia, nausea, vomiting, and decreased white blood cell count. There were two deaths, which are currently under investigation, the authors stated.

 The median duration of response has not yet been reached (range: 18 to 56-plus weeks). Patients with evidence of durable nonclassical responses suggestive of pseudoprogression were also observed. The median duration of survival follow-up is 40 weeks.

Emens pointed out that while bevacizumab (Avastin) is approved in more than 80 countries worldwide for the treatment of metastatic triple-negative breast cancer, there are no targeted therapies in the U.S. for metastatic triple-negative breast cancer, which has a worse prognosis than other breast cancer subtypes.

Clinical evaluation of MPDL3280A in metastatic PD-L1 IHC 0 or 1 triple-negative breast cancer is ongoing.

Immunotherapy used to reduce memory problems with Alzheimer’s disease .


Neurofibrillary tangles in the hippocampus of an elderly person with Alzheimer-related pathology.

A new study from the University of Texas Medical Branch (UTMB) at Galveston has revealed that a single dose of an immunotherapy reverses memory problems in an animal model of Alzheimer’s disease. The article appears in the Journal of Neuroscience.

Researchers have been working for decades to map out how Alzheimer’s disease wields its devastating effects. Although it’s known that two molecules – tau and amyloid beta – are considered responsible for the disease’s progression, the relationship between these two proteins and resulting memory problems has remained unclear.

Brain cells depend on tau protein to form highways for the cell to get nutrients and get rid of waste. In some neurodegenerative diseases such as Alzheimer’s disease, the tau protein changes into a more toxic oligomer form. When this happens, molecular nutrients can no longer move to where they are needed and the brain cells eventually die.

Scientists from UTMB have previously shown their anti-tau oligomer immunotherapy reduced levels of tau oligomers and reversed memory deficits in an animal model of Alzheimer’s. In the current study, it came as a surprise that the immunotherapy also reduced amyloid beta oligomer levels, suggesting that the detrimental effects of amyloid beta are dependent on the presence of toxic forms of tau.

“Our findings with this immunotherapy study indicate a link between tau oligomers and amyloid beta,” said lead author and associate professor of neurology, Rakez Kayed. “Because of this relationship, removing tau oligomers with our immunotherapy may also decrease the harmful effects amyloid beta and mitigate memory deficits.”

What sets Kayed’s therapy apart from other tau immunotherapy drugs is that his targets only the toxic oligomer form of tau and leaves the normal tau alone and able to carry out its typical functions.

These findings provide strong evidence of the benefits of targeting tau oligomers with immunotherapeutic approaches as an Alzheimer’s disease treatment.

– See more at: http://www.neuroscientistnews.com/research-news/immunotherapy-used-reduce-memory-problems-alzheimer-s-disease#sthash.Jx2AzHri.dpuf

Immunotherapy, Ovarian Cancer Treatment Top List of 2014 Cancer Developments .


Immunotherapy, treatments for ovarian cancer, and investigating game-changing drug therapies topped the list of the most important cancer research and clinical developments at Dana-Farber Cancer Institute in 2014.

Here are some highlights from the last year in research:

Hodgkin lymphoma
Some of the most dramatic evidence of potential of immunotherapies was in the treatment of Hodgkin lymphoma.

In an early-phase clinical trial, research showed nivolumab, a drug that unleashes the immune system to attack cancer cells, achieved complete or partial remissions in Hodgkin lymphoma patients with resistant forms of the disease.

The success of nivolumab in this study prompted the U.S. Food and Drug Administration (FDA) to designate it a “breakthrough therapy” for treating relapsed Hodgkin lymphoma, and a large, multinational phase 2 trial is now under way.

“What makes these results especially encouraging is that they were achieved in patients who had exhausted other treatment options,” said the study’s co-senior author, Margaret Shipp, MD, chief, Division of Hematologic Neoplasia at Dana-Farber. “We’re also excited by the duration of responses to the drug: the majority of patients who had a response are still doing well more than a year after their treatment.”

Joyce Liu, MD, in her lab

Ovarian cancer
Research reported in Octobershowed a combination drug therapy may be highly effectivein recurrent ovarian cancer. This is the first ovarian cancer study to test a combination of drugs that could be taken orally.

A clinical trial compared the activity of the combination of the drug olaparib, which blocks DNA repair, and the blood vessel inhibitor drug cediranib, against olaparib by itself. Trial results showed a near doubling of progression-free survival benefit for the combination therapy over use of the single drug alone.

“The findings of this study are exciting because they support the idea that combining these two targeted oral therapies results in significant activity in ovarian cancer, more so than olaparib alone,” said Joyce Liu, MD, MPH, the lead investigator and medical oncologist at the Susan F. Smith Center for Women’s Cancers at Dana-Farber. “We are looking forward to further exploring this combination in ovarian cancer and potentially increasing effective treatment options for our patients with this cancer.”

In December, the FDA also approved olaparib as a new treatment for advanced and recurrent ovarian cancer.

Stomach cancer
Based on results of a clinical trial led by Dana-Farber scientists, in 2014 the FDA approved a molecularly targeted drug as second-line treatment in advanced stomach cancer that has progressed after standard chemotherapy has failed.       

“For years we have looked for new and really effective drugs for stomach cancer,” saidCharles Fuchs, MD, MPH, director of the Gastrointestinal Cancer Center at Dana-Farber.“We have relied on standard chemotherapies for a long time, and we’ve needed targeted agents based on the fundamental biology of stomach cancer.”

The drug, Ramucirumab, is a monoclonal antibody compound that attacks the cancer by preventing it from developing new blood vessels to nourish its growth.

Prostate Cancer
Dramatic results in a phase 3 trial reported this year should change the way physicians have routinely treated prostate cancer patients.

The study showed men with newly diagnosed metastatic, hormone-sensitive prostate cancer lived more than a year longer when they received a chemotherapy drug as initial treatment instead of waiting to for the disease to become resistant to hormone blockers.

“The benefit is substantial and warrants this being a new standard treatment for men who have high-extent disease and are fit for chemotherapy,” said Christopher J. Sweeney, MBBS, of Dana-Farber’s Lank Center for Genitourinary Oncology and principal investigator for the study.

Melanoma
In September, the FDA approved a new type of immunotherapy drug for melanoma. The drug, pembrolizumab, was designated as a “breakthrough therapy” by the FDA and placed on a fast-tracked approval process. Marketed as Keytruda, the new drug was the first in the U.S. that blocked the PD-1 protein, which is used by melanoma and other cancer cells to avoid detection and attack by the body’s immune system.

A few months later, the FDA also approved Opdivo, another immunotherapy drug for skin cancer that blocks the PD-1 protein.

Jim Allison confronts cancer, critics with immunotherapy.


Decked out in black tie, Jim Allison stood on the red carpet in Silicon Valley. It was unfamiliar territory for the small-town boy from South Texas who had become a scientist and spent his research career on what many considered a lost cause, the study of the immune system’s cancer-fighting potential.

But he always believed that’s where the action would be, and now here was Facebook CEO Mark Zuckerberg saying Allison’s breakthrough “will change lives for generations to come.” For that, late-night television host Conan O’Brien handed him the 2014 Breakthrough Prize in Life Sciences, which includes a $3 million check.

Allison had become a rock star.

There had been something fiercely independent in him since high school, where he battled teachers over creationism.

There had been an extraordinary run of cancer deaths in his family, not least his 45-year-old mom, which convinced him that there had to be better treatment than radiation and chemotherapy.

And there had been that wild, creative streak that once led to him blowing a harmonica with country music legend Willie Nelson.

Whatever the source of his genius, Allison, chairman of immunology at the University of Texas M.D. Anderson Cancer Center, is credited with one of the most important breakthroughs in cancer history, the discovery that finally frees the immune system to attack tumors – a dramatic departure from the existing models of treating the disease.

Allison did it – made the discovery, then translated it into a drug – in a climate that wasn’t exactly welcoming.

The achievement has recently won Allison a raft of awards that M.D. Anderson President Dr. Ron DePinho thinks will culminate in the Nobel Prize. “By creating this brilliant approach that treats the immune system rather than the tumor, Jim Allison opened a completely new avenue for treating cancers that’s the most exciting and promising area of cancer research today,” DePinho says.

Bearded and scraggly haired, the 65-year-old Allison insists he never set out to cure cancer. Rather, he describes his motivation as “the selfish desire to be the first person on the planet to know something.”

“It can be hard to go against the system,” Allison says, “but sometimes you have to do it for progress to be made.”

Six months before his red carpet moment in Mountain View, Allison found himself arriving late to Chicago’s famed Arie Crown Theater, site of an immunotherapy session at the American Society of Clinical Oncology’s 49th annual meeting.

For years, he’d been going to such gatherings. Historically, they’d been sparsely attended, the result of a series of flops that changed the idea of enlisting the immune system to fight cancer from the field’s Holy Grail to a forgotten stepchild.

But here were 4,000 doctors who’d come from around the world to hear how the immune system was saving the lives of patients whose cancers historically meant a death sentence. They had come because of a flash of brilliance by Allison that deciphered which molecules on the surface of T cells function as catalysts – and which one functions as the brake.

Jim Allison's work with immunotherapy is considered a breakthrough against cancer. Photo: Craig Hartley, For The Chronicle

Family cancers
Allison was 11 years old when his mother died.

She’d been seriously sick with lymphoma for some time, but he had no idea how seriously when his father called him to her bedside, stopping him from heading to the local swimming pool with some buddies. She died as he held her hand.

Allison remembers walking out of the house and wandering aimlessly, trying to comprehend things. No one ever told him much about his mother’s illness, certainly not that she had cancer. That only came later.

The family cancers would keep coming. He lost an uncle to melanoma, another to lung cancer. Years later, his brother would die of prostate cancer.

It was all a motivating force, he says, but emphasizes he never considered curing cancer his purpose.

“If I had, I’d never have found the immune system’s brake,” says Allison, who was diagnosed with prostate cancer and successfully treated by prostatectomy in 2005.

“Because of my family history, I always had in the back of my mind that if my research uncovered something that might help, I’d make the leap,” he says. “But I always knew the key was figuring out how things work, finding the right button to push.”

The hardest thing to accept was that his breakthrough didn’t come soon enough to save his brother, who had ignored joint pain, only to learn it was advanced prostate cancer.

Allison was at his brother’s side, too, when he died in 2005, holding his hand.

Important revelation

At 16, Allison graduated from high school and went to University of Texas-Austin, where he quickly lost interest in going on to medical school, soured, first, by all the memorization it would require, then by the realization that doctors have an inordinate amount of responsibility.

“As a scientist you make mistakes all the time – that’s how you learn,” Allison says. “But a physician has to be right all the time. I prefer the scientist’s life – get an idea, devise an experiment, learn if it checks out. You only have to be right sometimes.”

After completing his undergraduate studies and doctorate, Allison went to Scripps Clinic and Research Foundation near San Diego for his postdoctoral fellowship.

Some of his most lasting memories there didn’t involve science.

Allison describes himself as “always kind of doodling on the harmonica,” but it was during those postdoc nights that he became more serious. For a couple of years he played regularly with Clay Blaker and the Texas Honky Tonk Band.

He’d wangled an invitation to a party Willie Nelson’s label threw to celebrate the “Red Headed Stranger” album going platinum, and when Nelson asked Allison if he knew anywhere he could pick some music the next night, Allison didn’t hesitate to volunteer it was talent night at the Stingaree bar where he played.

Allison would join Nelson onstage there for “Blue Eyes Crying in the Rain.”

Music or science?

For all his love of music, Allison had no illusions. Asked by Blaker to accompany the band when it left Southern California to play Texas clubs, he opted to keep his day job.

He returned to Texas a year after completing his Scripps Clinic fellowship. He showed up at M.D. Anderson’s new science campus and procured a biochemist job.

By then, the mid-’70s, Allison already was keenly aware of cancer immunotherapy’s checkered history.

It was all the rage for a time, but when early mice experiments didn’t show benefits, immunotherapy fell out of favor.

“It had such a bad rap,” Allison says. “People would say to me, ‘Don’t do tumor immunology, it’ll ruin your reputation.’ “

In the ensuing years, cancer immunotherapy made some strides, but they were frequently undermined by hype, sometimes by the scientists themselves. Allison believed none of them really knew what they were doing. He set out to be the one who did.

He’d become fascinated following an undergraduate experiment he conducted that showed mice cured of leukemia had acquired an immune response that rejected his attempts to inject new tumors. He’d become even more interested as he learned of the immune system’s complexity, the communication and coordination it calls upon to recognize and eliminate any pathogen, all without causing damage to healthy tissue.

Fascinated by T cells

Allison was most interested in T cells, the immune system’s little-understood soldiers that “do all the killing.”

He wondered what about cancer disarms them. Why do they so efficiently attack virus-infected cells but not get the necessary signals to attack tumors?

In the next decade, Allison’s work laid important basic science groundwork. He identified, first, the T cells’ ignition switch, a receptor that has to recognize proteins on tumor cells, then the gas pedal, a co-stimulatory molecule necessary to activate the T cells. They would provide key insights that helped facilitate the big discovery still to come.

In that time, UC Berkeley came recruiting. He dithered for two years, but finally decided it was time to make the move. It took a former adviser telling him if he passed the job up, he’d put up his feet 10 years later thinking he could have been a contender.

By the ’90s, the race was on.

Numerous immunology labs were looking for molecular signals to rally T cells into action, and nothing looked so promising as CTLA-4. A newly discovered protein that protrudes from T cells’ surface, CTLA-4 turned out to resemble the structure of the “gas pedal” Allison described, so it seemed logical that it was an activation signal.

But when he tried binding molecules with CTLA-4 as he had done with the “gas pedal” protein, he got an opposite effect: It inhibited T-cell proliferation. Could it be a brake, not a gas pedal?

So while most everyone else was looking for evidence that CTLA-4 turned on the immune system, Allison designed a study based on the novel hypothesis that CTLA-4 turned it off: He implanted mice with cancer cells and treated some with an antibody that blocked CTLA-4 – in essence, taking the brake off the immune system.

Allison was astounded by the initial data his research fellow showed him at the end of November 1995: While all the untreated mice had died, 90 percent of the cancers of the treated mice had disappeared. Allison wanted to reproduce the results immediately, but there was a problem: His fellow was headed off to a European vacation, and Berkeley would soon be closing for Christmas.

Impatient, Allison instructed the fellow to inject tumors into a new bunch of mice, including a control group that didn’t get the antibody. He’d come in during the break and monitor the mice himself, unaware which was the control group and which got the treatment, a truly blinded study.

Gradual progress
Allison took the measurements every other day during December and, for a short while, the results were the source of despair. All the tumors were continuing to grow. But at about the third week, things began to change. In half of the mice, the cancers first stopped growing, then started shrinking, then disappeared.

In March 1996, the journal Science published Allison’s research: Blocking CTLA-4 enhances antitumor responses.

“Everyone thought I was crazy,” Allison says.

He took the finding and determined to apply it to cancer. He developed an antibody that worked great in mice, but for two years couldn’t find a company to fashion a human version. Most were still gun-shy about cancer immunotherapy because of the field’s past failures, and most were still convinced that the future of cancer treatment involved molecular targets on tumors, not the immune system itself.

Finally, a small New Jersey company named Medarex took the plunge, sublicensing the patent and manufacturing a drug called ipilimumab (ippy for short), the first of a new class of drugs called immune checkpoint inhibitors. The company would ultimately be acquired by Bristol-Myers Squibb for $2.4 billion.

Ippy was tested, successfully, in human patients for the first time in 2001, but results from its first large-scale trial weren’t good. There was little impact at 12 weeks, the point at which chemotherapy is assessed, so it was declared a failure. It took a second large trial for ippy’s prospects to gain momentum, after clinicians noticed some tumors that were unaffected at 12 weeks had shrunk; years later, some patients were thriving.

It turns out that the immune system sometimes took time to rev up, but once it did, its effects last, unlike other cancer therapies.

Patient’s turnaround

Sharon Belvin burst into tears in September 2006 when she was introduced to Allison.

Now employed at New York City’s Memorial Sloan Kettering Cancer Center – he’d left Berkeley in 2004 so he could work closely with doctors and make sure his discovery wasn’t mishandled – Allison had stopped by the office of Dr. Jedd Wolchok, his clinical partner. There was Belvin, the first patient he’d ever met who had received his drug.

She’d been diagnosed, at 22, with stage four melanoma, words she says are “impossible to hear and not think ‘death.’ ” In the next year, when nothing stopped the spread of Belvin’s cancer from her chest and lungs to her brain, Wolchok offered her ippy. Desperate, she jumped at the chance.

Infused through a vein every three weeks over three months, ippy quickly shrank Belvin’s tumors and had her walking again. A year later, the day Wolchok summoned Allison, she’d just gotten the news that she was in remission.

“That’s the reason you do this work,” says Allison, still moved by the memory. “It’s not about the awards, it’s about the difference made in people’s lives.”

Finally, FDA approval

It would take 10 years of trials involving 6,500 patients, but in 2011 the Food and Drug Administration finally approved ippy – brand name Yervoy – for melanoma. No previous treatment ever made a meaningful dent in the advanced disease’s five-year death rate of more than 95 percent, but the latest statistics show almost a quarter of all melanoma patients treated with ippy live at least three years, after which point none dies of the disease.

For a time, Allison loved living on Manhattan’s Upper East Side, enjoying Central Park and the Metropolitan Museum of Art. But the charm eventually wore off.

Dr. John Mendelsohn, then president of M.D. Anderson, began wooing him to Houston, promising that the famed cancer hospital could provide an even larger platform for Allison’s work. Mendelsohn retired in 2011 without making a formal offer, but DePinho, his successor, pushed hard to pick up the recruitment.

Allison accepted in late 2012, a year after the Cancer Prevention and Research Institute of Texas approved a $10 million grant for his recruitment. M.D. Anderson invested $30 million more to bolster its immunotherapy research capabilities, which enables Allison to design trials across a variety of tumor types, using ippy by itself or combining it – with other checkpoint inhibitors and with chemotherapy or targeted therapy.

It also provides Allison access to freshly removed tumors, which he can analyze to gauge ippy’s effect and understand how it works, as he did with mice.

On demand

These days Allison never finds himself bored. When not in his lab, he is wildly in demand on the lecture circuit, traveling constantly to evangelize about cancer immunotherapy’s promise.

The speaking engagements come not just because of Allison’s drug but because his discovery blasted open the door for cancer immunotherapy.

Scientists have since discovered eight other immune system brakes and developed a few corresponding pharmaceuticals now in clinical trials, one of which combined with Yervoy in the trial presented at the American Society of Clinical Oncology meeting in Chicago to bring advanced melanoma patients’ 1 1/2-year survival rate to 80 percent.

The National Institutes of Health began funding a network of 27 centers’ immunotherapy trials in 2011. Every major pharmaceutical company is investing heavily.

Because the target is the immune system rather than the tumor, immune checkpoint drugs are expected to work on all sorts of cancers. Besides melanoma, Allison’s drug and the others in clinical trials already have had success against cancers of the lungs, colon, kidney, breasts, ovaries, pancreas and prostate.

“There’s a sense of paradigms shifting,” Science magazine wrote in an article that declared cancer immunotherapy the Breakthrough of the Year for 2013. “Immunotherapy marks an entirely different way of treating cancer – by targeting the immune system, not the tumor itself. Oncologists, a grounded-in-reality bunch, say a corner has been turned and we won’t be going back.”

For all the excitement, there are still questions about ippy. Researchers have no idea why it benefits some people but not others. Because releasing the brake facilitates an all-out attack by the immune system, it can cause serious side effects – colitis, skin rashes, impaired pituitary function – that must be managed.

And the drug’s price is $130,000, an amount Allison calls obscene.

Still, years of skepticism about immunotherapy have finally faded. Allison notes that even James Watson, Nobel Prize-winning co-discoverer of DNA’s structure and onetime immunotherapy skeptic, recently told him, “This is going to do it.”

Oral Immunotherapy Shows Promise for Children with Egg Allergy .


Oral immunotherapy with egg-white powder can lead to sustained unresponsiveness to the allergen in nearly a third of children with egg allergy, according to a New England Journal of Medicine study.

Researchers randomized 55 children (aged 5 to 11 years) with egg allergy to oral immunotherapy with egg-white powder or placebo. Immunotherapy lasted 22 months and involved dose-escalation on day one, a build-up phase, and a maintenance phase in which children consumed up to 2 g/day of egg-white powder (roughly equivalent to a third of an egg).

At 22 months, three quarters of immunotherapy recipients passed a 10-g egg-white powder challenge (no placebo recipient did). And 2 months after immunotherapy ended, 28% of treated children successfully ate a whole egg; these children were consuming eggs a year later.

In Journal Watch Pediatrics and Adolescent Medicine, David Amrol writes: “Although oral immunotherapy is our best chance for a food allergy cure, it is not ready for mainstream use until protocols are further refined. Patients who are not enrolled in clinical trials must continue to rely on allergen avoidance, patient education, and self-injectable epinephrine.”

Source: NEJM