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Researchers Uncover Major Clue In Predicting Response To Immunotherapy

Researchers at Memorial Sloan Kettering Cancer Center in New York have discovered that cancer cells with high numbers of faults in their DNA are more likely to respond to immune checkpoint inhibitors (ICI), a major class of immunotherapy drugs, which includes Keytruda.

The study, published today in Nature Genetics adds important pieces to the puzzle as to why some cancer patients respond to immunotherapy whereas others do not. The researchers measured ‘tumor mutation burden (TMB)’, essentially counting how many DNA faults a tumor contains by looking for errors in the DNA sequence.

“People assume that TMB is important in predicting response to immunotherapy in all cancers, but up until now, all we’ve had is data from small studies and clinical trials on mostly lung cancers and melanoma,” said Luc Morris, MD, surgical oncologist at Memorial Sloan Kettering Cancer Center and one of the lead authors of the paper.

The researchers studied the DNA of 1,662 patients with advanced cancer (classified as stage IV or metastatic disease) treated with one or more of several FDA-approved ICI drugs and DNA from 5,371 patients with advanced cancer who had not had ICI. They used a tool called MSK-IMPACT, which looks at just 3% of the coding-regions in DNA, but is correlated to the number of mutations in the genome.

“Is TMB associated with likelihood that immunotherapy has benefit? Is this true in all cancers? We wanted to find out whether TMB had broad applicability,” said Morris.

The researchers found that if they took the 20% of cancers in their data with the most mutations, these people responded better to ICI than those with lower numbers of mutations in their tumors.

However, this correlation did not hold true for all tumors, for example, in people with a type of brain cancer called glioma, those with TMB in the top 20% did no better on ICI than those with lower TMB. Also in breast cancer there was no conclusive evidence that a higher TMB predicted response to ICI, although the study included relatively few breast cancer patients as ICI is not currently widely used for the disease.

Researchers don’t exactly know why high numbers of mutations make cancers more susceptible to immunotherapy, but they do have a very plausible theory. They think that the more mutated a cell is, the more likely it is to produce incorrect, mangled proteins. These displayed on the cell surface are called neoantigens and they are so far from what would be considered normal, the immune system identifies them as foreign and attacks the cells.

This is not a unique study in concept, with previous research on a smaller number of cancers of specific types, notably lung and melanoma, indicating that TMB is likely predictive of immunotherapy response. However, it is the largest and most comprehensive study to date, providing the most persuasive evidence that this is true for a greater number of cancer types.

“Only in lung cancer is TMB being used in a clinical trial. Hopefully this data will give us permission to include it in future clinical trials on other cancer types,” said Morris.

However, some patients with high TMB don’t respond to ICI at all, so there is still work to be done to figure out why high TMB is not a universal predictor of response to ICI.

“TMB by itself is not going to give you a high confidence in predicting whether a patient is going to respond to immunotherapy or not. It is one biomarker for response, but a number of other factors are important. I would not suggest you take the data from this paper and apply it to a patient in the clinic,” said Morris.

January, 2019|Oral Cancer News|

CDC: Top HPV-Associated Cancer Is Now Oropharyngeal

Date: 08/23/18
Source: medscape.com
Author: Nick Mulcahy

Oropharyngeal squamous cell carcinoma (SCC) is now the most common HPV-associated cancer in the United States, according to a new report from the Centers for Disease Control and Prevention (CDC) that covers the years 1999 to 2015.

During that period, cervical cancer dropped from being the top HPV-associated cancer and oropharyngeal SCC took its place.

The transition happened because cervical carcinoma incidence rates decreased 1.6% per year, and oropharyngeal SCC incidence rates increased 2.7% per year among men and 0.8% per year among women.

In 2015, there were a total of 11,788 cervical cancers compared with 18,917 oropharyngeal SCCs.

The decline in cervical cancer is a “continued trend since the 1950s as a result of cancer screening,” write the report authors, led by Elizabeth Van Dyne, MD, MPH, an epidemic intelligence service officer at the CDC.

The uptick in oropharyngeal SCC could be due in part to “changing sexual behaviors,” including unprotected oral sex, especially among white men, who report having the highest number of sexual partners and performing oral sex at a younger age compared with other racial/ethnic groups, the authors say.

Oropharyngeal SCCs include those at the base of tongue, pharyngeal tonsils, anterior and posterior tonsillar pillars, glos­sotonsillar sulci, anterior surface of soft palate and uvula, and lateral and posterior pharyngeal walls.

The new report was published August 24 in the Morbidity and Mortality Weekly Report.

The study authors defined HPV-associated cancer as “an invasive malignancy in which HPV DNA was frequently found in special studies.” In other words, the new study data reveal the total number of certain cancers that are associated with — but not necessarily caused by — HPV.

A total of 30,115 new cases of HPV-associated cancers were reported in 1999 and 43,371 in 2015.

Overall, the rate of HPV-associated cancers dropped among women (change, –0.4%) during the study period and rose among men (change, 2.4%).

The CDC analyzed data from their National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program for all years from 1999 to 2015. “These data cover approximately 97.8% of the US population,” say the authors.

However, these two population-based cancer registries have a limitation: They tally invasive cancers but not the HPV status of cancers.

The authors point out HPV causes cervical cancer and “some oropharyngeal, vulvar, vaginal, penile, and anal cancers.”

Table. Annual Change in Type of Cancer From 1999 to 2015

Cancer Type Average Annual Change (%)
Cervical –1.6
Vaginal –0.6
Oropharyngeal in men 2.7
Oropharyngeal in women 0.8
Anal in men 2.1
Anal in women 2.9
Vulvar 1.3

Penile cancer rates remained stable during the study period.

The study authors say that the public health implication of the study is that HPV vaccination “can prevent infection with the HPV types most strongly associated with cancer.”

January, 2019|Oral Cancer News|

Five Things To Look Out For In Cancer Research In 2019

Date: 12/28/18
Source: Forbes.com
Author: Victoria Forster

2018 was a remarkable year for cancer research, with great strides made in diagnosing and treating various types of cancer as well as important breakthroughs looking at the health of cancer survivors. What can we expect to see from cancer research in 2019? As a cancer research scientist, here are the top five topics that I’ll be looking out for.

1. Immunotherapy. Who will respond, who won’t respond and why?

Immunotherapy is now seemingly everywhere, with several therapies approved for various cancer types, including CAR T-cells and immune checkpoint inhibitors and several more in development such as tumor infiltrating lymphocyte (TIL) therapy. TILs successfully cleared all tumors from a woman with metastatic breast cancer, in a research breakthrough which was one of the most reported in 2018.

Over 2,500 trials are now registered worldwide, but as the use of immunotherapy grows, there are still major questions to be answered. One particularly important to the use of immune-checkpoint blocking drugs such as those which target PD-1 or CTLA-4 is ‘why do some patients respond whereas others do not?’ Several research teams worldwide are currently grappling with this question, which is unlikely to have a single, clear answer, but I expect to see much more research published on this in 2019, which will hopefully start to benefit patients by identifying who will and won’t respond to these expensive drugs.

2. Liquid biopsy tests. More clarity on precisely what they do and more evidence that they do it accurately.

The liquid biopsy industry has exploded in 2018, perhaps unsurprising given the market is expected to be worth over $2 billion annually by 2022. The promise is that eventually, we should be able to diagnose cancer with a simple blood test, earlier, more cheaply and even more accurately than we currently do and even use these tests to monitor response to cancer treatment and when and if a tumor returns.  As a cancer research scientist, the number of research papers, presentations at top conferences and news releases by the dozens of companies currently developing these technologies can make it a little overwhelming to figure out what is going on.

In 2018, two of the top liquid biopsy tests on the market had their efficacy called into question with researchers from Johns Hopkins suggesting that the two competing tests gave different results with the same patient samples. A claim which was then challenged by representatives from both companies.

Liquid biopsy tests undoubtedly have huge potential and may indeed live up to their hype, but currently, the field is a little messy and difficult to understand for scientists, patients and oncologists who are not specialists. The American Society for Clinical Oncology (ASCO) issued a statement in March of this year essentially concluding that for most liquid biopsy tests there is currently not enough evidence to recommend their use in either the diagnosis or monitoring of cancer. Hopefully, 2019 brings greater clarity about how these tests can fit into the diagnosis and care of people with cancer and ASCO will be able to review their stance accordingly.

3. More focus on the side-effects of cancer treatment.

As a cancer survivor myself and an advocate for more research into what happens to cancer survivors past the ‘all clear,’ 2018 has been a remarkable year for research into the numerous and often disabling side-effects cancer survivors experience. For decades, cancer research has understandably been mainly focused on making sure as many people survive the disease as possible, but now with millions of cancer survivors in the world, a new research field looking at what actually happens to cancer survivors as a result of their treatments is growing at considerable speed.

From a study which hopes to have found a solution to male infertility after childhood cancer treatment to work showing that some women with early-stage breast cancer can have less radiotherapy without compromising their chance of survival, 2018 was a good year for cancer survivorship research. The highlight, in my opinion, was work from Stanford University scientists that may have figured out why ‘chemo brain’ happens, one of the most commonly-reported side-effects that cancer survivors experience. Even better, the scientists suggest that it may be treatable.

4. Cancer and the microbiome.

The microbiome has been one of the most talked about topics in medicine in 2018 and shows no sign of slowing down. Amidst the predictable flurry of supplements, fad-diets and blog posts giving scientifically-questionable advice telling you how to cherish and nurture your own gut flora, plenty of solid, evidence-backed research has been published showing that the microbiome is potentially involved in multiple sclerosis, inflammatory bowel disease and even Alzheimer’s disease. But what about cancer?

There are already several studies published showing that the microbiome can influence the response to chemotherapy drugs and even in some cases cause the production of toxic breakdown products of the drug. Earlier this month, work published in Nature Communications showed how a particular bacterial strain common in the human microbiome could influence the immune system to drive the progression of a currently incurable type of blood cancer called multiple myeloma. The study raised the possibility that targeting these bacteria with drugs could halt or slow the disease.

5. Organoids, the new secret weapon in personalized cancer medicine.

Back in November 2017, I wrote about how organoids, tiny lab-grown organs made from patient tissue samples would revolutionize the treatment of cancer by allowing researchers to test drugs on patient tumors before deciding which to give the patient. Several pharmaceutical and biotechnology companies have large-scale programs to commercially develop these technologies for using organoids in drug screening for patients and the increasing accessibility of organoid growing kits from companies which supply academic and hospital research laboratories mean research papers are coming out thick and fast.

But, organoids are by no means a perfect way to test new drugs yet. For example, it is easy and quick to make organoids from certain tumor types-such as colorectal, but very difficult from others such as brain tumors. Organoids grown in the lab also don’t have a blood supply, nor are they connected to other body systems which may influence the response of a patient to anti-cancer drugs. But researchers are making progress in organoid development all of the time, figuring out better ways to make and culture them so they more accurately reflect the tumor they were originally made from.  Expect to see them playing an increasing role in designing personalized medicine approaches for cancer patients as well as being involved in more lab-based cancer breakthroughs.

January, 2019|Oral Cancer News|

Hospitals required to post all prices online beginning January 1

Date: 12/26/18
Source: KATV
Author: Associated Press

 

Medicare will require hospitals to post their standard prices online and make electronic medical records more readily available to patients, officials said Tuesday.

The program is also starting a comprehensive review of how it will pay for costly new forms of immunotherapy to battle cancer.

Seema Verma, head of the Centers for Medicare and Medicaid Services, said the new requirement for online prices reflects the Trump administration’s ongoing efforts to encourage patients to become better-educated decision makers in their own care.

“We are just beginning on price transparency,” said Verma. “We know that hospitals have this information and we’re asking them to post what they have online.”

Hospitals are required to disclose prices publicly, but the latest change would put that information online in machine-readable format that can be easily processed by computers. It may still prove to be confusing to consumers, since standard rates are like list prices and don’t reflect what insurers and government programs pay.

Patients concerned about their potential out-of-pocket costs from a hospitalization would still be advised to consult with their insurer. Most insurance plans nowadays have an annual limit on how much patients must pay in copays and deductibles — although traditional Medicare does not.

Likewise, many health care providers already make computerized records available to patients, but starting in 2021 Medicare would base part of a hospital’s payments on how good a job they do.

Using electronic medical records remains a cumbersome task, and the Trump administration has invited technology companies to design secure apps that would let patients access their records from all their providers instead of having to go to different portals.

Verma also announced Medicare is starting a comprehensive review of how it will pay for a costly new form of immunotherapy called CAR-T. It’s gene therapy that turbocharges a patient’s own immune system cells to attack cancer.

Immune system T cells are filtered from the patient’s own blood and reprogrammed to target and kill cancer cells that had managed to evade them. Hundreds of millions of copies of the revved-up cells are then returned to the patient’s blood to take on the cancer.

Though only a couple of such treatments have been approved for blood cancers, the cost can exceed $370,000 per patient.

“It’s a new area for the agency,” said Verma. “We haven’t seen drugs priced at this level and we’re having to think about our strategy.”

January, 2019|Oral Cancer News|

Immunotherapy extends the life of head and neck cancer patients

Source: Pharmatimes.com
Date: 12/3/18
Author: Anna Smith

A new immunotherapy can greatly extend the lives of a proportion of people with advanced head and neck cancer, with some living for three years or more, reports a major new clinical trial.

The study, by The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, found that the drug – MSD’s Keytruda (pembrolizumab) – has been shown to have significant benefits for patients, with 37% of those who received it surviving for a year or more, compared with only 26.5% of those on standard care.

The drug was evaluated in a trial of nearly 500 patients with very advanced head and neck cancer that had spread around the body and already become resistant to platinum chemotherapy, the first-line treatment for the disease.

Some 247 patients were randomised to receive Keytruda and 248 to standard of care – chemotherapy or the targeted agent Erbitux (cetuximab).

When chemotherapy or targeted therapies stop working, treatment options for people with advanced head and neck cancer are limited, and they are normally expected to survive for less than six months.

Patients in the Keytruda arm survived for a median of 8.4 months, compared to 6.9 months with standard treatment. However, a minority of patients responded extremely well to Keytruda – 36 patients saw their cancer partially or completely disappear, and some are still cancer free three years after first receiving the drug.

“Our findings show that the immunotherapy pembrolizumab extends the life of people with advanced head and neck cancer overall, and in a group of patients has really dramatic benefits. It is also a much kinder treatment than those currently approved,” said Professor Kevin Harrington, professor of Biological Cancer Therapies at The Institute of Cancer Research, London, and consultant at The Royal Marsden NHS Foundation Trust.

“I would like to see pembrolizumab approved for use in the clinic, so that people with advanced head and neck cancer can be offered the chance of a longer life and improved quality of life.

“There is also an urgent need to work out how we can identify in advance which patients are likely to benefit, given that some of these people may do much better than they do on standard treatment.”

The trial was sponsored and funded by MSD, and the results are published in The Lancet.

December, 2018|Oral Cancer News|

Study: Immunotherapy better than chemotherapy for subtype of head and neck cancer

Date: November 30th, 2018
Source: Scienmag

A randomized clinical trial involving 97 medical centers in 20 countries, including Moores Cancer Center at UC San Diego Health, found that treating patients who have chemotherapy-resistant head and neck cancer with the immunotherapy drug pembrolizumab is more effective and less toxic than standard chemotherapy, reports an international team of researchers in the November 30 online issue of The Lancet.

Previous research had shown that pembrolizumab (Keytruda) was safe and effective for treating patients with recurrent or metastatic head and neck squamous cell carcinoma whose disease had progressed while on or after receiving standard chemotherapy. Data from this clinical trial called KEYNOTE-040, a phase III study sponsored by Merck & Co., the manufacturer of the drug, takes the research a step further by comparing the immunotherapy drug head-to-head to three go-to chemotherapy drugs currently used as standard treatment: methotrexate, docetaxel and cetuximab.

“We compared pembrolizumab against standard of care to see if it fulfilled the promise of early data for patients who are unlikely to do well on standard therapy,” said Ezra Cohen, MD, professor of medicine at University of California San Diego School of Medicine and corresponding author on the study.

“In this trial, patients who received pembrolizumab alone had a higher response rate compared to those receiving standard chemotherapy while those responses lasted, on average, one-and-a-half years. Furthermore, the median survival at one year was markedly better. I feel it is safe to say that these types of therapies should be the new standard therapy for people with cancer that recurs and is resistant to therapy.”

Pembrolizumab is an antibody that inhibits the abnormal interaction between the molecule PD-1 on immune cells and the molecule PD-L1 on tumor cells, allowing the immune cells to activate and attack tumors. Similar results were recently published for another anti-PD-1 drug, nivolumab (Opdivo). Both drugs should be considered by treating physicians for patients with this disease, said Cohen.

The study also pointed to potential biomarkers that can guide oncologists to determine which patients are most likely to respond to these anti-PD-1 drugs.

“It’s fairly clear that patients whose tumors express PD-L1 are most likely to benefit from this type of immunotherapy drug,” said Cohen, associate director for translational science at Moores Cancer Center and an internationally recognized physician-scientist who specializes in novel cancer therapies. “In this trial, overall survival was driven by PD-L1 expression. Only patients whose tumors expressed PD-L1 had a response to pembrolizumab and those responses tended to be durable.”

Over a 17-month period, 247 patients were randomized to receive pembrolizumab and 248 patients were randomly selected by their physicians to receive one of the three standard therapies. The median overall survival for patients receiving immunotherapy was 8.4 months and 6.9 months for patients treated with standard care. Patients received treatment until their cancer progressed, they developed unacceptable toxicity, they withdrew or their physician removed them.

The median duration of response was 18.4 months in the pembrolizumab group, compared with five months in the standard therapy group.

Twelve months after initiating the trial, 37 percent of patients receiving pembrolizumab were alive compared to 26.5 percent of patients on standard therapy.

###

Co-authors include: Denis Soulières, Centre Hospitalier de l’Université de Montréal; Christophe Le Tourneau, Institut Curie, INSERM U900 Research Unit, Versailles-Saint-Quentinen-Yvelines University; José Dinis, Instituto Português de Oncologia do Porto Francisco Gentil; Lisa Licitra, Fondazione IRCCS Istituto Nazionale dei Tumori; Myung-Ju Ahn, Samsung Medical Centre; Ainara Soria, Hospital Universitario Ramón y Cajal; Jean-Pascal Machiels, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain; Nicolas Mach, Hôpitaux Universitaires de Genève; Ranee Mehra, Fox Chase Cancer Center; Barbara Burtness, Yale University School of Medicine and Yale Cancer Center; Pingye Zhang, Jonathan Cheng, Ramona F Swaby, Merck & Co; and Kevin J Harrington, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, National Institute of Health Research Biomedical Research Centre.

This research was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. The funder contributed to study design, data collection, data analysis, data interpretation, and the writing of The Lancet paper. The funder maintained the study database. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Disclosure: Cohen reports grant support to the institution from Merck Sharp & Dohme for clinical research related to the submitted work and serving an advisory role for AstraZeneca, Bristol-Myers Squibb, Eisai, Merck, Human Longevity and Pfizer, all outside the submitted work.

December, 2018|Oral Cancer News|

Scientists Confirm There’s Nothing But Misinformation On Anti-Vax Sites

Source: Huffington Post, LIFE
Author: Agata Blaszczak-Boxe
Date: 11/04/18

Many websites that promote unscientific views about vaccinations use pseudoscience and misinformation to spread the idea that vaccines are dangerous, according to a new study.

For example, of the nearly 500 anti-vaccination websites examined in the study, nearly two-thirds claimed that vaccines cause autism, the researchers found. However, multiple studies have shown that there is no link between vaccines and autism.

About two-thirds of the websites used information that they represented as scientific evidence, but in fact was not, to support their claims that vaccines are dangerous, and about one-third used people’s anecdotes to reinforce those claims, the scientists found.

Some websites also cited actual peer-reviewed studies as their sources of information, but they misinterpreted and misrepresented the findings of these studies.

“So the science itself was strong, but the way it was being interpreted was not very accurate,” said study author Meghan Moran, an associate professor in Johns Hopkins University Bloomberg School’s Department of Health, Behavior and Society. “It was being distorted to support an anti-vaccine agenda.”

In the study, the researchers looked at websites with content about childhood vaccines. They used four search engines to find the sites — Google, Bing, Yahoo and Ask Jeeves — and searched for terms including “immunization dangers” and “vaccine danger” as well as other phrases. Their final sample of 480 anti-vaccination websites included a mix of personal websites, blogs, Facebook pages and health websites. The researchers examined the content of the websites, looking for vaccine misinformation, the sources of the misinformation and the types of persuasive tactics that the sites used to convince people that vaccines are dangerous.

In examining the websites, the researchers also observed a lot of misunderstanding and misinterpretation of epidemiological principles, Moran told Live Science.

For example, epidemiologists know that correlation does not imply causation. “Just because two things happen at the same time, that doesn’t mean that one is causing the other,” Moran said. But some of the websites presented timelines that showed that, as rates of immunization went up over a certain period of time, so did autism diagnoses, Moran said.

Although it is true that both have increased over the same period, the anti-vaccine websites frequently implied that “it must be that the immunizations were causing autism, which we know is not true,” Moran said.

Another tactic commonly employed by the websites in the study was the use of anecdotes and stories of parents of children with autism, the researchers said. Because such stories are easy for other parents to connect to, they help to make the anti-vaccine agenda that these sites are promoting appear “a lot more vivid and powerful,” Moran said.

Some of the sites also included information promoting positive health behaviors, the researchers said. For example, 18.5 percent of them promoted eating healthy, about 5 percent promoted eating organic food and 5.5 percent recommended breast-feeding.

The biggest takeaway from the findings is that researchers and health officials “need to communicate to the vaccine-hesitant parent in a way that resonates with them and is sensitive to their concerns,” Moran said in a statement. “In our review, we saw communication for things we consider healthy, such as breast-feeding, eating organic, the types of behavior public health officials want to encourage. I think we can leverage these good things and reframe our communication in a way that makes sense to those parents resisting vaccines for their children.”

The new findings were presented today (Nov. 3) at the American Public Health Association’s Annual Meeting in Chicago.

 

November, 2018|Oral Cancer News|

Research Update: Vaccine Plus Checkpoint Inhibitor Combos for HPV-related Cancers

Source: MedPage Today
Author: Mark L. Feurst

Two new studies show the profound impact of a combined vaccine and anti-programmed death-1 (PD-1) antibody approach in the treatment of human papilloma virus (HPV)-related cancers.

HPV causes nearly all cervical cancers, as well as most oropharyngeal, anal, penile, vulvar, and vaginal cancers. HPV16 and HPV18 are the leading viral genotypes that increase cancer risk. Given the viral cause of these cancers, immunotherapy has been considered a strong potential approach.

Many patients with the HPV16 and HPV18 subtypes of head and neck squamous cell carcinoma have good outcomes from treatment that includes surgery or chemotherapy and radiation. Although anti-PD-1 therapy is approved for patients who do not respond to treatment or who develop metastatic disease, it benefits only about 15% of patients. The theory, therefore, is that a vaccine could potentially boost the immune systems of patients with HPV-related head and neck cancer, opening the door for better responses to other existing therapies.

Vaccine + Nivolumab in Phase II Study

In the first study, a phase II trial, a tumor-specific vaccine combined with the immune checkpoint inhibitor nivolumab was found to shrink tumors in patients with incurable HPV-related cancers.

“Ours are the first results with this particular approach,” Bonnie Glisson, MD, of the Department of Thoracic Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, told the Reading Room. “The rates of response and survival are approximately double what have been observed with nivolumab given alone to similar patients. These results will lead to larger, randomized clinical trials of this combination.”

Vaccines specific to HPV antigens found on tumors had previously sparked a strong immune response, but had not by themselves been active against established cancers, she noted.

“Vaccines are revving up the immune system, but the immunosuppressive tumor microenvironment probably prevents them from working. Our thinking was that inhibition of programmed death-1 (PD-1) would address one mechanism of immunosuppression, empowering the vaccine-activated T lymphocytes to attack the cancer.”

Glisson and colleagues combined the vaccine ISA101, which targets peptides produced by the strongly cancer-promoting HPV16 genotype of the virus, along with nivolumab, a checkpoint inhibitor that blocks activation of PD-1 on T cells.

The single-arm, single-center clinical trial included 24 patients with incurable HPV-16–positive cancer who were followed for 12.2 months. The vaccine was given subcutaneously on days 1, 22, and 50. A nivolumab dose of 3 mg/kg was given intravenously every 2 weeks beginning on day 8 for up to 1 year. Of the 24 patients with recurrent HPV16-related cancers, 22 had oropharyngeal cancer, one had cervical cancer, and one had anal cancer. The overall response rate was 33% (eight patients), and the median duration of response was 10.3 months. Five of eight patients remain in response, the team reported.

The overall median survival was 17.5 months, progression-free survival was 2.7 months, and 70% of patients survived to 12 months.

Grades 3 to 4 toxicity occurred in two patients (asymptomatic grade 3 transaminase level elevation in one patient and grade 4 lipase elevation in one patient), requiring discontinuation of nivolumab therapy. The researchers observed side effects expected from the two treatments separately, but said they were encouraged to see no sign of synergistic side effects caused by the combination.

“The combination was very well tolerated as opposed to other immunotherapy combinations such as combined blockade of PD-1 and CTLA-4,” Glisson said. “The vaccine did stimulate a strong HPV-specific immune response in peripheral blood T cells, although this was not correlated with response or survival. This suggests that other immune-suppressive factors in the tumor environment are contributing to immune evasion.”

Randomized clinical trials of the vaccine and anti-PD1 combinations for cervical and oropharyngeal cancer are ongoing, she added. “These are promising data that will be confirmed in a randomized trial. Positive results could lead to marketing of the first therapeutic HPV vaccine.”

Vaccine Helps T cells Infiltrate HPV-related Head and Neck Cancer

In the second study, another vaccine was shown to boost antibodies and T cells to help them infiltrate tumors and fight off HPV-related head and neck cancer. This approach might complement PD-1 or programmed death-ligand 1 inhibition in HPV-associated head and neck cancers to improve therapeutic outcomes, explained the study’s lead author, Charu Aggarwal, MD, MPH, of the Perelman School of Medicine at the University of Pennsylvania.

“We wanted to know if this vaccine can boost the immune systems of patients with HPV-related head and neck cancer, potentially opening the door for better response rates to other existing therapies. Our findings show that we can.”

Aggarwal and colleagues conducted a Phase Ib/II safety, tolerability, and immunogenicity study of immunotherapy with MEDI0457, a DNA immunotherapy targeting HPV16/18 E6/E7 with interleukin-12 encoding plasmids. The vaccine was delivered via electroporation to 21 patients. One group of patients received one dose before surgery, followed by three doses after surgery. The second group received four doses following chemotherapy and radiation.

Eighteen of the 21 patients (86%) showed elevated T cell activity that lasted at least 3 months after the final vaccine dose, the team reported. Five tumors were biopsied both before and after one dose of the vaccine, and there was evidence of T cells reacting with antigens contained in the vaccine in all five of these samples. One patient who developed metastatic disease and was treated with anti-PD-1 therapy developed a rapid and durable complete response that has lasted more than 2 years.

“We have not seen that kind of infiltration with just one dose of a vaccine before. These findings open the door for utilizing targeted immunotherapy approaches against specific cancer-causing targets like HPV,” said Aggarwal, adding that the vaccine was well tolerated, with no serious side effects reported.

“This response suggests that the vaccine may, in some manner, prime the immune system, potentially boosting the effects of subsequent anti-PD-1 therapy,” she explained, noting that a multi-site clinical trial is now open to patients with metastatic HPV-associated head and neck cancer, who will receive a combination of the vaccine with anti-PD-1 therapy.

Previously, the CheckMate-141 trial tested nivolumab in 361 patients with recurrent or metastatic, chemotherapy-refractory squamous cell head and neck cancer, and the results led to FDA approval in that setting. Sixty three of these patients were HPV16-positive, and the overall response rate among this group was 15.9%, with a median overall survival of 9.1 months.

 

November, 2018|Oral Cancer News|

No De-escalation of Therapy for HPV+ Throat Cancer

Source: www.medscape.com
Author: Alexander M. Castellino, PhD

Another trial has shown that de-escalating therapy does not work in patients with good prognosis human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma or throat cancers.

Results from the De-ESCALaTE HPV study show that using the targeted drug cetuximab with radiotherapy does not improve side effects and, more importantly, has worse survival compared with the standard of care — chemotherapy with cisplatin and radiotherapy.

The finding echoes the results from the US National Cancer Institute’s Radiation Therapy Oncology Group (RTOG) 1016 trial, the top-line results of which were released earlier this year, and details of which were presented this week at the American Society of Radiation Oncology (ASTRO) 2018 meeting.

“Do not change your clinical practice of using cisplatin with radiotherapy in these patients,” cautioned Hisham Mehanna, MBChB, PhD, chair of head and neck surgery at the University of Birmingham, United Kingdom, and lead investigator of the De-ESCALaTe study. He presented the results during a presidential session here at the European Society for Medical Oncology (ESMO) 2018 Congress (abstract LBA9).

“Cetuximab did not cause less toxicity and resulted in worse overall survival and more cancer recurrence than cisplatin. This was a surprise — we thought it would lead to the same survival rates but better toxicity. Patients with throat cancer who are HPV+ should be given cisplatin, and not cetuximab, where possible,” Mehanna said in a statement.

Hope for Fewer Side Effects
Cetuximab with radiation is already approved by the US Food and Drug Administration for use in head and neck cancer, including oropharyngeal cancer, and is an accepted standard of care, especially for patients who cannot tolerate cisplatin.

The hope behind de-escalation of therapy was that this regimen would offer similar efficacy but have fewer side effects than the standard regimen of cisplatin plus radiation.

“The side effects of treatment for patients with head and neck cancers are devastating. They experience loss of speech, loss of taste, and have trouble swallowing,” explained ESMO expert Jean-Pascal Machiels, MD, PhD, head of the department of medical oncology at the Cliniques Universitaires Saint-Luc, Brussels, Belgium.

“With HPV increasing rapidly in the Western world, HPV+ head and neck cancers are typically seen in younger patients who respond well to treatment and live for three to four decades. These patients would like to live without the toxicities associated with treatment,” he added.

“Based on a large study in 2006, many patients have been receiving cetuximab with radiotherapy on the assumption that it was as effective as chemotherapy with radiotherapy and caused fewer side effects,” Mehanna commented. That study showed that for patients with squamous cell carcinoma of the head and neck, treatment with cetuximab and high-dose radiotherapy improved locoregional control and reduced mortality. At the same time, side effects were no worse (N Engl J Med. 2006;354:567-578).

 

OCF NOTE: The foundation’s donors were funders of the RTOG 1016 clinical trial over several years.

HPV vaccine gains support of ADA

Source: Multi Briefs
Date: October 24th, 2018
Author: Tammy Adams

The American Cancer Society estimates there will be more than 50,000 new cases of oral cancer in 2018. And between 70 to 80 percent of these cases will be attributed to the human papillomavirus virus (HPV), a virus that has types associated with oropharyngeal cancer.

These staggering numbers call for action; action the American Dental Society is willing to take. Why? Because the HPV vaccine could prevent the vast majority of these new cases, but compared to other vaccines in the U.S., it is underutilized.

According to a resolution passed recently by the ADA House of Delegates, the ADA urges dentists to support the use and administration of the human papillomavirus virus vaccine, recognizing it as a way to help prevent infection of the types of HPV associated with oropharyngeal cancer.

Resolution 53H-2018 cites recommendations from the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. It states that the vaccination is a “safe and effective intervention to decrease the burden of oral and oropharyngeal HPV infection.”

The policy is the result of a multifaceted ADA council proposal that includes input from the Council on Scientific Affairs, the Council on Advocacy for Access and Prevention and the Council on Dental Practice. A workgroup committed to the HPV issue and led by ADA volunteer members developed an evidence-based background report to help write the policy.

Dr. Paul Eleazer, past chair of the ADA Council on Scientific Affairs, said that he is encouraged to see the ADA “get behind” this growing crisis, referring to the rising number of HPV-associated cancers being reported. “There is incontrovertible evidence that this virus is responsible for the sharp uptick in oropharyngeal cancers, especially in younger patients and young adults,” said Dr. Eleazer.

In 2017, the ADA Council on Scientific Affairs and Center for Evidence-Based Dentistry published “Evidence-based Clinical Practice Guideline for the Evaluation of Potentially Malignant Disorders in the Oral Cavity” to inform dental professionals about the potential use of adjuncts as triage tools for the evaluation of lesions, including potentially malignant disorders, in the oral cavity. To view this guideline, visit ADA.org/OralCancer.

To read the full resolution related to the HPV vaccine, members can log in to the Member Center on ADA.org and click on “Committee C—Dental Education, Science and Related Matters” under Reports and Resolutions. It is Resolution 53.

October, 2018|Oral Cancer News|