‘On the rise:’ Immunotherapy options for head and neck cancer

Source: www.curetoday.com
Author: Kristie L. Kahl

On behalf of the Head and Neck Cancer Alliance, Dr. Michael Moore spoke with CURE® about emerging therapies that potentially offer exciting new options for the future.

Although rates of head and neck cancer have risen, in part because of the human papillomavirus (HPV), emerging therapies such as targeted agents and immunotherapies are paving the way for future treatment of the disease, according to Dr. Michael Moore.

“I would say (immunotherapy) is probably one of the more exciting parts of what we’ve learned about head and neck cancer in recent years,” he told CURE® as a part of its “Speaking Out” video series.

On behalf of the Head and Neck Cancer Alliance, CURE® spoke with Moore, associate professor of otolaryngology-head and neck surgery and chief of head and neck surgery at Indiana University School of Medicine in Indianapolis, about targeted therapies, immunotherapy and how clinical trials are leading the way for future treatments.

How have genomics and targeted therapies played a role in head and neck cancer treatment?

Well, I would say it’s an emerging role. And it’s not used as commonly in head-neck cancer as it is in some other areas. So molecular testing or targeted therapies essentially are looking at a very specific part of the tumor to see if we can develop a specific drug that will target just that; (the goal is to) weaken the cancer’s defense — that is one way to say it — and try to very specifically treat that cancer in a way that will give us the best chance of getting rid of it and potentially try to limit the side effects related to the treatments. This has become a little bit more common now that the ability to analyze these tumors has become more widely available across the country. But still, the majority of these types of treatment approaches will be in the context of a clinical trial.

Do we have any currently approved targeted therapies for head and neck cancer?

That’s a great question. I think these are kind of different and are emerging all the time. There are ones that are focused on very specific mutations, such as what’s called the BRAF mutation, which is one that can be present in melanoma or certain aggressive cancers, such as thyroid cancer. And other ones will target things like tyrosine kinase inhibitors that have a more focused route to try to combat these tumors. And then there are ones that will be discussed a little later, such as immuno-oncology drugs that focus on the program cell death ligand and the receptor to try to turn the body’s immune system back on. Another example is what’s called Erbitux (cetuximab), which is focusing on a specific receptor on cancer cells, really trying to exploit this particular difference in cancer cells compared with normal tissue to try to give the best chance of getting rid of the tumor, but minimizing the side effects of the treatment.
What role has immunotherapy had in head and neck cancer treatment?

Cancer has a way of almost turning off the local immune system. It blocks many of the local immune responses to it. Normally, the body would say, “Yeah, that’s not part of our normal tissue, we want to get rid of it.” And some cancers have a way of blocking that. These immunotherapies have a way of almost inhibiting that blockage, if you will, or turning the immune system back on and allowing your own body’s immune system to fight these tumors. These can be incredibly effective. The challenge is if they’re only effective in a small minority of cancers. And so, when they do work, they can work extremely well and can give really good and long-lasting results. But in a high percentage of patients, the responses are much more modest or (patients) may not even respond at all.

Can you discuss the currently available immunotherapies for head and neck cancer?

There are two. Opdivo (nivolumab) is one that can be used in patients who have not responded or progressed despite standard therapy, including recent treatment with chemotherapy, including cisplatin. And then Keytruda (pembrolizumab) is another similar amino therapy that can be used and has actually achieved approval for use in the primary setting. When cancer comes back in an area that can’t be treated with either definitive surgery or definitive radiation therapy, you can use that as a next avenue for treatment. These are the two (Food and Drug Administration)-approved drugs that are out there. They also have ongoing studies where they’re being combined with other standard-of- care, primary treatments for head and neck cancer. I think in the next five to 10 years, they’ll likely be integrated much more on the front end of cancer therapy, rather than just offering them to those who don’t have other treatment options.

How do clinical trials help to advance these therapies, and why should patients consider joining one?

These are really what allows us to make our cancer treatment better. We constantly are. It’s not just going out and experimenting on people but, rather, we’re comparing these treatments to see how we can improve on the current standard approach to therapy. If you were to look back 50 to 60 years ago, all we had were big, morbid surgeries that people were put through and possibly adding radiation therapy. And then we added cisplatin, which is a drug that can be effective in enhancing the effects of radiation therapy. Now, as we add these other treatments, such as immunotherapy and other targeted therapies, the only way we know if they have any advantage over what we have to offer, currently, is to compare them in a clinical trial.

And with these clinical trials, those who have designed them have been very thoughtful in trying to do so in a way that compares them and then looks to see: Does that give us a benefit in getting rid of the cancer or curing the cancer, or at a minimum, slowing it down or giving a longer life? And/or does it give better quality of life or reduce the level of side effects? That’s what many of these clinical trials are. Some are adding new agents to see if those work better than other ones. For example, in the HPV-related cancer, some of the clinical trials are saying these respond fairly well to treatment. Can we actually back off on the severity of treatment, give them just as good of a cancer cure but (with) fewer long-term side effects? I think they’re critical as the only way we’re going to figure out how best to manage these types of cancers.

Henderson throat cancer patient rallies after cutting-edge treatment

Source: www.reviewjournal.com
Author: Mary Hynes, Las Vegas Review-Journal

In February, a cancerous tumor caused extreme swelling in Ruben Solis’ neck and face, blocking his airway. After an emergency tracheotomy, an incision to his windpipe that allowed him to breathe, Solis had to decide whether he wanted to enter a clinical trial to receive an experimental treatment.

The 54-year-old Henderson resident was skeptical. But with stage 4 laryngeal cancer that had spread to his lungs, he was running out of options. Three months later, after three treatments, the tumors in his throat and lungs have dramatically shrunk and the swelling subsided.

“I feel much better,” Solis said Monday.

The father and grandfather, who worked in banquets and as a food and beverage manager on the Strip before falling ill, is the first person in the world to receive a combination of two experimental drugs, Enoblituzumab and Retifanlimab, as part of a new clinical trial for head and neck cancer, according to Comprehensive Cancer Centers of Nevada, the local site participating in the global study.

Solis and his oncologist, Dr. Anthony Nguyen, spoke with reporters prior to the patient receiving his fourth infusion of the two drugs. The treatment is a new form of immunotherapy, which boosts the body’s immune system to combat the cancer.

“So his immune system is actually being manipulated, turned on, to actually fight the cancer from inside,” Nguyen said.

In this way it is different from traditional chemotherapy.

“When we think of chemotherapy and cancer medicine, we think of dropping bombs on the cancer, and the bombs will kill the cancer, but they also will hurt the surrounding tissue in the person as well,” Nguyen said. “So we’re trying to move away from traditional chemotherapy and customize it to provide something that’s a lot easier” for patients to tolerate.

The combination of drugs was customized to fit the unique molecular profile of Solis’ tumor.

The tumor in Solis’ throat grew to about an inch and a half in diameter, causing severe swelling of the neck and face, the oncologist said. A Comprehensive Cancer Centers publicist wrote to reporters that the mass grew to the size of “a football,” though Nguyen said the swelling gave the patient’s head and neck the appearance of a watermelon.

Solis, who was diagnosed with cancer in December 2019, was at first treated with more standard radiation and chemotherapy. The cancer went into remission, only to return and to spread.

The sponsor of the trial is biopharmaceutical company MacroGenics, based in Rockville, Maryland. The trial, with about 80 participants, will take place in 35 centers in the U.S., Australia and Europe.

Comprehensive Cancer Centers of Nevada is involved in about 170 clinical trials, 86 of which are in the active phase; in the remainder, the patients continue to be evaluated after the completion of the treatment phase. Medications in the trials are provided free.

Through such trials in Southern Nevada, “We’re crushing that notion that one has to travel far to get cutting edge, new medicines that are not FDA approved or not available,” Nguyen said.

Genetic changes in head and neck cancer, immunotherapy resistance identified

Source: MedicalXPress
Date: April 26th, 2021
Author: University of San Diego-California

A multi-institutional team of researchers has identified both the genetic abnormalities that drive pre-cancer cells into becoming an invasive type of head and neck cancer and patients who are least likely to respond to immunotherapy.

“Through a series of surprises, we followed clues that focused more and more tightly on specific genetic imbalances and their role in the effects of specific immune components in tumor development,” said co-principal investigator Webster Cavenee, Ph.D., Distinguished Professor Emeritus at University of California San Diego School of Medicine.

“The genetic abnormalities we identified drive changes in the immune cell composition of the tumors that, in turn, dictates responsiveness to standard of care .”

Reporting in the April 26, 2021 online issue of the Proceedings of the National Academy of Sciences, researchers describe the role of somatic copy-number alterations—abnormalities that result in the loss or gain in a copy of a gene—and the loss of chromosome 9p in the development of human papillomavirus (HPV)-negative and .

The loss of chromosome 9p and the deletion of JAK2 and PD-LI, two neighboring genes found on chromosome 9p, was associated with resistance to immune checkpoint inhibitors, a type of cancer immunotherapy that uses antibodies to make tumor cells visible to a patient’s immune system.

“Although programmed death-1 (PD-1) immune checkpoint inhibitors represent a major breakthrough in , only 15 percent of patients with HPV-negative head and neck cancer respond to treatment,” said co-principal investigator Scott M. Lippman, MD, senior associate dean, associate vice chancellor for and care and Chugai Pharmaceutical Chair in Cancer at UC San Diego School of Medicine.

“The ability to predict a patient’s response or resistance to this class of therapies, a major unmet clinical need, is a unique and novel discovery. Knowing who will not respond avoids losing several months to ineffective therapy with huge financial costs and impacts to quality of life,” said Lippman, director of UC San Diego Moores Cancer Center and medical oncologist who specializes in the treatment of patients with head and neck cancer at UC San Diego Health, San Diego’s only National Cancer Institute-designated comprehensive cancer center.

For this study, co-led by New York University Langone Health’s Teresa Davoli, Ph.D., and The University of Texas MD Anderson Cancer Center’s William N. William, MD, with co-investigator Steve Dubinett, MD, of UCLA Jonsson Comprehensive Cancer Center, researchers prospectively followed 188 patients at MD Anderson Cancer Center to study genomic and immune drivers of the transition to invasive HPV-negative head and neck cancer. They reviewed comprehensive genomic and transcriptomic data of 343 HPV-negative head and neck cancer patients from The Cancer Genome Atlas and 32 HPV-negative head and neck cancer cell lines from the Cancer Cell Line Encyclopedia project, and analyzed patient survival after immunotherapy in real-world evidence cohort data from Caris Life Sciences.

In 2021, the National Cancer Institute estimates approximately 54,000 new cases of head and neck cancers will be diagnosed in the United States, with 10,850 deaths. HPV-negative head are the most common, increasing and lethal subtype of this malignancy worldwide, said Lippman.

“The data serves as a powerful predictive marker, transforming standard of care for precision immunotherapy for patients with advanced, recurrent head and ,” said Lippman. “And, while we focused in an unprecedented extensive interrogation of the most globally lethal form of head and neck squamous cancer, accounting for more than 300,000 deaths annually, the application may be useful in a wide variety of solid tumors for which immune checkpoint inhibitors comprises standard of care.”

Cancer vaccine shows early promise across tumor types

Source: www.webmd.com
Author: Walter Alexander

A personalized cancer vaccine proved possible to manufacture and was well tolerated in an early phase I clinical trial, researchers said. The vaccine, known as PGV-001, was given to 13 patients with solid tumors or multiple myeloma who had a high risk of recurrence after surgery or stem cell transplant.

At last follow-up, four patients were still alive without evidence of disease and had not received subsequent therapy, four were alive and receiving therapy, three had died, and two could not be contacted for follow-up.

Thomas Marron, MD, of Mount Sinai in New York presented these results at the American Association for Cancer Research Annual Meeting recently.

“While cancer immunotherapy has revolutionized the treatment of cancer, we know that the majority of patients fail to achieve significant clinical response,” Marron said during his presentation. Personalized vaccines may help prime an improved immune response, he said.

With this in mind, Marron and colleagues developed PGV-001, a vaccine consisting of customized peptides – a kind of amino acid — given to patients along with initial treatment.

Feasibility and safety
Vaccines were given to 13 patients. Six had head and neck cancer, three had multiple myeloma – a cancer of the white blood cells — two had lung cancer, one had breast cancer, and one had bladder cancer.

Eleven patients received all 10 intended doses, and two patients received at least eight doses.

“The vaccine was well tolerated, with only half of patients experiencing mild, grade 1 adverse events,” Marron said.

Four patients developed reactions at the injection site and one person Transient injection site reactions occurred in four patients, and one patient developed a low-grade fever.

After an exam after an average of 880 days, four patients had no evidence of cancer and had not received more therapy. This includes one patient with stage III lung cancer, one with stage IV positive breast cancer, one with stage II bladder cancer, and one with multiple myeloma.

Four patients were alive and receiving other kinds of therapy. Three patients have died, two of whom saw their cancers return.

“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” Bhardwaj said.

Deactivating cancer cell gene boosts immunotherapy for head and neck cancers

Source: newsroom.ucla.edu
Author: Brianna Aldrich

By targeting an enzyme that plays a key role in head and neck cancer cells, researchers from the UCLA School of Dentistry were able to significantly slow the growth and spread of tumors in mice and enhance the effectiveness of an immunotherapy to which these types of cancers often become resistant.

Their findings, published online in the journal Molecular Cell, could help researchers develop more refined approaches to combating highly invasive head and neck squamous cell cancers, which primarily affect the mouth, nose and throat.

Immunotherapy, which is used as a clinical treatment for various cancers, harnesses the body’s natural defenses to combat disease. Yet some cancers, including head and neck squamous cell carcinomas, don’t respond as well to the therapy as others do. The prognosis for these head and neck cancers is poor, with a high five-year mortality rate, and there is an urgent need for effective treatments.

The UCLA research team, led by distinguished professor Dr. Cun-Yu Wang, chair of oral biology at the dentistry school, demonstrated that by targeting a vulnerability in the cellular process of tumor duplication and immunity, they could affect tumor cells’ response to immunotherapy.

The enzyme they focused on, KDM4A, is what is known as an epigenetic factor — a molecule that regulates gene expression, silencing some genes in cells and activating others. In squamous cell head and neck cancers, overexpression of KDM4A promotes gene expression associated with cancer cell replication and spread.

It is well known that tumor cells can spread undetected by the immune system and, without surveillance, can metastasize to lymph nodes or other parts of the body. In this instance, tumor cells that develop in the epithelial layer that lines the structures of the head and neck can turn into head and neck squamous cell carcinoma when unchecked.

Cancer cell replication occurs through the abnormal spread and activation of signaling pathways for cancer cells, and the researchers asked the question: If we can disrupt these processes and identify a vulnerability, can we change the body’s response to fighting cancer cells and its response to outside immunotherapy?

“We know that the KDM4A gene plays a critical role in cancer cell replication and spread, so we focused our study on removing this gene to see if we would get an opposite response,” said Wang, the study’s corresponding author and a member of the UCLA Jonsson Comprehensive Cancer Center.

By removing the KDM4A gene in their mouse models, the researchers witnessed a notable decrease in squamous cell carcinomas and far less metastasis of cancer to the lymph nodes — a precursor to the spread of the disease throughout the body. Surprisingly, they also discovered that the KDM4A’s removal also led to the recruitment and activation of the body’s infection-fighting T cells, which killed cancer cells and stimulated inherent tumor immunity.

They then sought to uncover why the squamous carcinoma cells had such a poor response to immunotherapy treatment. In another set of mouse models, they again removed KDM4A and introduced a PD-1 blockade, which signals immunotherapy drugs to attack cancer cells. The combination of immunotherapy and KDM4A removal further decreased squamous cell cancer growth and lymph node metastasis.

Next, the researchers tested whether a small-molecule inhibitor of KDM4A could improve the efficacy of the original PD-1 blockade–based immunotherapy. They found that the inhibitor also significantly helped remove cancer stem cells, which are associated with cancer relapse.

The findings hold promise for the development of more specific inhibitors for KDM4A and more effective cancer immunotherapies.

“I am continuously impressed by Dr. Cun-Yu Wang and his team for breaking through barriers in our understanding of cancer-causing cellular processes,” said Dr. Paul Krebsbach, dean and professor at the UCLA School of Dentistry. “The results of this study have major implications for the development of more effective, life-saving cancer therapies.”

The work was supported by grants from the National Institute of Dental and Craniofacial Research, which is part of the National Institutes of Health.

Dr. Wang is the Dr. No-Hee Park Professor of Dentistry at UCLA, a professor at the UCLA Samueli School of Engineering and a member of Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Additional authors include Wuchang Zhang, Wei Liu, Lingfei Jia, Demeng Chen and Dr. Insoon Chang, all of the Laboratory of Molecular Signaling at the UCLA School of Dentistry and members of the Jonsson Comprehensive Cancer Center, and Dr. Michael Lake and Laurent Bentolila, both of the California NanoSystems Institute at UCLA.

On treating advanced head and neck cancer without cisplatin – an oncology grand rounds discussion

Source: www.medpagetoday.com
Author: Mark L. Fuerst

An oncology grand rounds discussion with Sachin Jhawar, MD.

Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous set of diseases with different features and treatment recommendations. Physicians face challenges in initial treatment decision-making and response assessments, including the changing role of surgery, the incorporation of human papilloma and Epstein Barr virus status, as well as the potential for treatment de-escalation using patient-related and tumor-related factors.

A recent “Oncology Grand Rounds” article in the Journal of Clinical Oncology provides an overview of treating advanced HNSCC when cisplatin is not an option, including concurrent chemotherapy, cetuximab, targeted therapy, and immunotherapy.

In the following interview, the paper’s lead author, Sachin Jhawar, MD, of Ohio State University Comprehensive Cancer Center in Columbus, reviews the main issues.

What is the focus of the article?
Jhawar:
We focused on patients with locally advanced disease who would be receiving definitive non-surgical treatment when possible treatment with concurrent cisplatin, delivered either every 3 weeks or weekly, is always the preferred treatment.

We specifically wanted to delve into the subset of patients who we would not recommend to receive cisplatin because of age or comorbidities. This could be concurrent chemotherapy (carboplatin/paclitaxel), concurrent cetuximab, and altered or standard fractionation radiation schedules without systemic therapy, as well as when to consider immunotherapy and palliative radiation for those with recurrent or metastatic disease.

There is also a great deal of institutional preference involved. At our institution, we prefer concurrent carboplatin/paclitaxel in patients who cannot receive cisplatin. Generally, we reserve definitive radiation alone options for patients who are completely ineligible for any systemic therapy.

If definitive therapy would be considered too difficult, or for those who have metastatic disease, still other palliative regimens are available.

When should clinicians consider nivolumab or pembrolizumab?
Jhawar:
At this time, immuno-oncology agents such as nivolumab or pembrolizumab are approved and used regularly only in the recurrent or metastatic setting. Even in the recurrent setting, they are generally considered only if surgery or re-irradiation therapy is not an option.

These novel agents should only be considered earlier in a patient’s treatment course in place of more traditional systemic options via a clinical trial.

What are the potential benefits of the combined use of immunotherapy, chemotherapy, and vaccines?
Jhawar:
The potential benefits of combination strategies using checkpoint inhibitors and other immuno-oncology treatments, including vaccines, in combination with more traditional therapies including surgery, radiation, and chemotherapy are still being worked out. It is likely that we will first see applications of these newer therapies in the recurrent and metastatic setting, but they may be incorporated earlier into patient care as more data about safety and efficacy emerges.

We have seen regular use of immuno-oncology treatments in other disease sites, and these therapies are being introduced earlier in the treatment course for patients. I would expect a similar pattern to emerge for HNSCC, although we will need to wait for phase III randomized controlled trial data for these immunotherapies to be ready for prime time.

It should be noted, however, that given the heterogeneity of HNSCC, there are certain scenarios in which we are working towards de-escalation of therapy, and addition of more therapies may not be needed.

In the patients with HPV-positive oropharyngeal squamous cell carcinoma and less than 10 pack-year smoking histories, the cure rates are more than 90% with current standard-of-care treatment. We are now working towards de-escalating therapy. It is not clear what role, if any, immuno-oncology will play in these already favorable situations.

What about the potential synergy of molecular targeted agents with radiation?
Jhawar:
There are multiple potential targets that could lead to synergy with radiation. Cetuximab actually acts on one of these targets, the epidermal growth factor receptor. Other potential targets that are being studied for combinations with radiation include cell signaling pathways (mTOR, AKT), cancer metabolism, tumor hypoxia, and DNA repair pathways (PARP, ATR).

There are other studies that have been completed or are ongoing that use agents to improve radioprotection of normal tissues. To date, none of these targeted agents are being regularly used on their own or in combination in the care of patients outside of clinical trials.

What improvements with new targeted therapies and immunotherapies do you foresee?
Jhawar:
As our understanding of the molecular mechanisms of carcinogenesis, aberrant cancer signaling pathways, and the tumor microenvironment improves, I expect that the number of targets and, therefore, the number of molecular targeted agents will grow. This will lead to a large increase in the number of clinical trials and expansion of our armamentarium against HNSCC.

Similarly, as our understanding of the interplay between cancer and the immune system and mechanism of immune escape improves, I suspect we will be able to improve response rates from immuno-oncology drugs. Currently, only 10% to 20% of patients respond to immuno-oncology treatments, leaving a great deal of room for improvement.

Taken together, this will allow for more individualized, patient-specific care and afford the ability to test novel combinations to improve cure rates. Simultaneously, this will decrease toxicity by choosing the right treatment for the right patient, rather than having a one-size-fits-all approach to therapy.

What’s the take-home message for practicing oncologists?
Jhawar:
There is a great deal of change forthcoming in the treatment of HNSCC, but at this time standard-of-care therapy still consists of some combination of traditional cancer therapies, including radiation, surgery, and chemotherapy.

Read the study here and expert commentary about the clinical implications here.

Personalized vaccines: the new frontier in cancer treatment

Source: www.wildcat.arizona.edu
Author: Udbhav Venkataraman

Exciting results from a new clinical study showed that a personalized vaccine combined with an immunotherapy drug had a promising response rate in patients with advanced incurable head and neck cancer.

Dr. Julie Bauman, chief of Hematology and Oncology at the University of Arizona College of Medicine — Tucson, led a phase one clinical trial with the pharmaceutical company, Moderna, to test the combined use of personalized vaccines created from tumor DNA with the immunotherapy drug pembrolizumab.

Of the 10 patients involved in the study, five of the them responded to the treatment, meaning 30% of the cancer mass had decreased. Furthermore, two of the patients completely responded, meaning that cancer could not be detected.

Molly Cassidy is one of those two patients. What was initially determined to be a stress-related ear-ache turned out to be an aggressive case of squamous cell carcinoma, a form of head and neck cancer.

Head and neck cancers impact the linings of the mouth and throat. Risk factors for this disease include alcohol consumption, smoking and other environmental carcinogens that we are all exposed to. It can also be caused by human papillomavirus (HPV).

Cassidy did not fit this profile at all.

“I’m HPV-negative. I didn’t drink. I didn’t smoke. I’m a woman. I was the first person in my family to have cancer. I was 35 when I got my diagnosis,” Cassidy said. “I was also in really good health … To hear that I had cancer was really surprising.”

With an initial prognosis that the cancer was curable, Cassidy underwent a standard but invasive surgery followed by a grueling series of radiation and chemotherapy sessions over the next few months.

Just a week after completing Cassidy’s initial treatment plan, the cancer returned aggressively. She had several tumors in her neck and they were spreading to her lungs. Her prognosis became bleaker.

“Having such a quick recurrence was not a good sign … they put me on a palliative plan and I was told I need to get my affairs in order,” Cassidy said. “I wasn’t expected to live for more than a year.”

Cassidy now had advanced incurable head and neck cancer which occurs when an initial cancer treatment fails and the cancer returns. This combined with the fact that she was HPV negative made her eligible for Bauman’s clinical study.

One of the recent frontiers of cancer research has been immunotherapy — harnessing our immune systems to fight cancer. Our immune system is able to detect and attack foreign invaders in our bodies, including cancer cells. However, these cells develop ways to hide from the immune system.

Immunotherapy can involve using medication to activate and train the immune system to recognize and eliminate these cancer cells. When this treatment is effective, the response can be long-lived.

“I can give you chemo and drive you to a complete response, but as soon as chemo is not there, the cells that are left become resistant and grow back,” Bauman said. “Immunotherapy leaves behind an army of T-cells that if the cancer rears its ugly head again, will presumably kill it.”

According to Bauman, the current U.S. Food and Drug Administration-approved therapies are non-specific. These therapies generally activate the T-cells of the immune system which recognize foreign invaders. This method means that T-cells that recognize cancer cells would be activated. This method of therapy however has a low effectiveness rate.

“In head and neck cancer, this class of therapy is successful 10-15%of the time … We want that to be more often,” Bauman added.

Furthermore, there can be auto-immune side effects because T-cells that recognize our own healthy tissues may start attacking those very tissues.

This is where new and fascinating technology comes into the picture: personalized vaccines. This approach is a specific approach, where T-cells are activated based on the mutations of the patient’s cancer.

After taking a sample of cancer cells from the patient, those cells’ DNA is sequenced. Using a computational algorithm, the cancer DNA is compared to the patient’s healthy DNA to find the specific mutations present in that patient’s cancer. From all those mutations, Moderna is able to synthesize a messenger RNA vaccine, which can be used to train the appropriate T-cells to recognize abnormal proteins from these cancer cells.

A helpful video about the process can be found at the UA Health Sciences website. The clinical trial consisted of using both this personalized vaccine approach with the FDA approved T-cell activator pembrolizumab.

“The trial is the combination of using those mutations almost like a trojan horse … educating the immune system to see those mutated proteins at the same time as we give the unbridled T-cell activator,” Bauman said. “We’re awakening T-cells, but we’re saying this is the particular class of T-cells that we are calling.”

For the trial, each patient was given two doses of pembrolizumab over six weeks. During this time, the vaccine was developed by Moderna. After the vaccines were created, the patients received one dose of their vaccine every three weeks for nine weeks along with the pembrolizumab, and the cancer was monitored using a CAT scan.

And the results show that the vaccines are safe. This seems really promising and exciting to pursue.

“Although it is only 10 patients, and we have to not only overpromise … it is a really strong signal to expand the study and to see if we continue to see what we saw with these 10 patients,” Bauman said.

“When I was going into treatment, I was really ill and the treatments themselves were pretty hard on me. Cancer treatment is no walk in the park,” Cassidy said. “But once I got through the treatment’s initial side effects, I started to notice an increase in my energy and I wasn’t in as much pain.”

Having completely responded to her treatment, Cassidy is now able to live a normal life. She has spoken with various dentists and used her platform to help educate people about the prevalence and signs of oral cancers and the importance of understanding what the inside of our mouths are supposed to look like.

“It also brought forth what are the most important things for me — my son and husband and the importance of slowing down and enjoying my time with my family,” Cassidy said.

There are many new things that Bauman is looking into researching further. As they expand the trial to 40 participants for the next phase of trials, she is exploring how to optimize the vaccine.

“If we can selectively educate the immune system … we can have a therapy that is active, could drive a permanent response and not be toxic or harsh on the rest of the body,” Bauman said.

Bauman also mentioned that this optimization might mean potentially experimenting with a different drug than pembrolizumab for treatment, although this is a great start. They have also taken samples of the T-cells from the patients to see which types of mutations the T-cells respond best to.

“People who have advanced in cancer … have extraordinary suffering because cancer is uncontrolled in this area where things are critical to our humanity, like talking and breathing and eating and kissing and smiling. To be able to reverse that suffering and offer that hope is uniquely gratifying,” Bauman said.

2020-12-09T06:51:37-07:00December, 2020|Oral Cancer News|

Why immunotherapy only works for some with head and neck cancer

Source: medicalxpress.com
Author: Katie Pence, University of Cincinnati

Image of a healthy T cell on left compared to a cancer T cell on right. Credit: Ameet Chimote

University of Cincinnati researchers have discovered new clues into why some people with head and neck cancer respond to immunotherapy, while others don’t.

Findings published in the Journal for ImmunoTherapy of Cancer show that it could all come down to “channeling” the power and function within one particular type of immune cell.

Laura Conforti, Ph.D., professor in the Department of Internal Medicine at the UC College of Medicine and corresponding author on the study, says understanding these mechanisms could help in creating combination treatments to more effectively treat some patients with cancer.

She points out that head and neck cancers are the sixth most common cancers in the world, affecting about 53,000 Americans every year. To combat the deadly disease, doctors often turn to immunotherapy, which boosts the body’s own immune system in an effort to identify and kill cancer cells.

“Our immune cells are naturally programmed to distinguish between our body’s ‘normal’ cells and what they see as ‘foreign’ cells and attack only the foreign cells,” explains Conforti.

She says the immune cells—called T cells— lead the body’s attack against cancers but the impact of that attack can be proven futile if a molecule in cancer cells is able to bind to an immune checkpoint in the T cells and effectively “turn them off like a light switch.” As a result, the T cells leave the cancer cells alone, which Conforti says is “a major problem,” especially for head and neck cancers.

A known immunotherapy treatment (pembrolizumab) targets the checkpoint molecule and blocks the “off switch” of the T cells, but scientists are trying to determine why this method works in some people and not in others. Conforti further explains that the ability of these T cells to attack and destroy cancer cells relies on molecules called potassium ion channels, which are present in T cells and are responsible for a variety of functions, including killing cancer cells.

Conforti’s team includes co-lead authors Hannah Newton, Ph.D., a recent UC doctoral graduate; Vaibhavkumar Gawali, Ph.D., postdoctoral fellow; and Ameet Chimote, Ph.D., research scientist in Conforti’s lab. The team found that when patients with head and neck cancer were given immunotherapy at UC Medical Center, T cells in these patients showed increased activity in these channels, allowing them to more effectively reach the cancer cells and kill them.

The team also found that after the treatment was delivered to patients, these channels in the T cells circulating in their blood were more active, meaning they were more equipped to continue fighting off the cancerous cells.

“We also saw that head and neck cancer patients who were responding to this immunotherapy, meaning their tumors were shrinking, had greater channel activity in their T cells soon after treatment, and the T cells had more ability to enter into the tumors to continue killing cancer cells,” Conforti adds. “However, patients who did not respond lacked this increased activity.

“Immunotherapy is not one-size-fits all, since some patients respond to immunotherapy, while others don’t, but our research shows that ion channels within T cells of these patients play a crucial role in the response of immunotherapy. Now that we know the benefits of these channels, more research is needed to look at ways we can activate them or create combination therapies to help patients increase their chance of survival.”

Team member Newton, who recently completed her doctorate at UC and is now working at the National Institutes of Health-sponsored Frederick National Laboratory for Cancer Research, says that working on this study at UC was invaluable.

“This research allowed me to collaborate with diverse professional individuals including medical oncologists, clinical coordinators and other researchers and gave me the opportunity to better understand the bench-to-bedside procedure for drug development,” Newton says. “Most importantly, it could help clinicians determine more personalized and effective treatment combinations for patients with head and neck cancer.”

2020-11-25T13:38:19-07:00November, 2020|Oral Cancer News|

Engineered killer immune cells target tumours and their immunosuppressive allies

Source: medicalxpress.com
Author: eLife staff

Scientists have engineered natural killer immune cells that not only kill head and neck tumor cells in mice but also reduce the immune-suppressing myeloid cells that allow tumors to evade the immune response, according to a new study in eLife.

The engineered cell therapy could be used as an alternative approach for treating cancer in patients for whom previous immunotherapy based on the activation of T cells has failed. These findings are reported by researchers at the U.S. National Institutes of Health (NIH) in Bethesda, Maryland.

In recent years, treatments called T-cell therapy or CAR-T cell therapy have been approved to treat blood cancers, and many others are now in development for other forms of cancer. However, these T-cell therapies rely on the ability to reprogram a patient’s own T cells to express a chimeric antigen receptor (CAR) that targets tumor cells. This process of reprogramming a patient’s own T cells is expensive and laborious.

High affinity natural killer cells (haNKs) represent potential ‘off-the-shelf’ cell therapies that do not rely on reprogramming a patient’s own immune cells. The same cells could be produced in mass and potentially given to anyone. But the presence of immune-suppressing myeloid cells in the tumor microenvironment remains a barrier to effective immunotherapy, including haNK cell-based treatment.

To address this barrier, researchers from the NIH’s National Institute on Deafness and Other Communication Disorders (NIDCD) and National Cancer Institute have utilized haNKs expressing a CAR that targets a molecule called programmed death ligand 1 (PD-L1). PD-L1 is a well-known culprit that cancer and immunosuppressive myeloid cells produce in high amounts to dampen down the immune system.

Led by senior author Clint Allen, Principal Investigator, Section on Translational Tumor Immunology, NIDCD, the team tested the engineered PD-L1 haNKs versus ordinary haNKs against human and mouse head and neck cancer cells. They found that the haNKs expressing the PD-L1 CAR kill mouse and human tumor cells to a greater degree than haNKs without the CAR, and that this ability was retained even if they had already been exposed to cells carrying PD-L1 before. This is important because natural killer cells are known to become ‘exhausted’ after killing target cells.

In mice with head and neck tumors, the haNK cell-based therapy cured the mice in 30% of cases and slowed the growth of tumors in the rest of the mice, without causing toxicity. Treatment with haNKs also reduced the numbers of immunosuppressive myeloid cells that carry PD-L1 within the tumor, while having no effect on other immune-boosting white blood cells.

To investigate whether this effect on the immune cells also occurred in patients, the team incubated white blood cells from people with advanced head and neck cancer with the PD-L1 haNK cells. As they saw in the mice, the immunosuppressive myeloid cells that carry PD-L1 were significantly reduced after treatment with the PD-L1 haNK cells. This suggests that this treatment can both directly kill tumor cells and remove the immunosuppressive myeloid cells that prevent conventional immunotherapies from working.

These findings suggest that haNK cells expressing a PD-L1 CAR may overcome some of the limitations of conventional immunotherapy that relies on T-cell activation, and could be used in patients who are predicted to be insensitive to or have failed existing immunotherapy treatments. The researchers say the next steps would be to take this treatment into the clinic to explore the safety of PD-L1 haNKs in people with advanced or recurring cancer, and to see whether combining haNK cell therapy with other immunotherapies that activate T cells can enhance treatment response.

Palbociclib plus cetuximab shows antitumor activity among head and neck cancer subset

Source: www.healio.com
Author: Adkins D, et al.

A combination of palbociclib and cetuximab demonstrated substantial antitumor activity among patients with platinum- or cetuximab-resistant HPV-unrelated head and neck squamous cell carcinoma, according to results of a multigroup phase 2 trial published in The Lancet Oncology.

“Currently, effective therapeutic options for patients with cetuximab-resistant HNSCC are few. Traditional chemotherapy has marginal activity, with 6% of patients or fewer achieving a tumor response,” Douglas R. Adkins, MD, professor in the oncology division of the department of medicine at Washington University School of Medicine in St. Louis, and colleagues wrote. “The most effective therapy for these patients might be pembrolizumab [Keytruda, Merck] or nivolumab [Opdivo, Bristol-Myers Squibb], which have resulted in responses in 11% to 16% of patients and median OS of 6.9 months to 8 months. Novel treatment strategies are needed for patients with recurrent or metastatic HNSCC.”

The combination of the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib (Ibrance, Pfizer) and epidermal growth factor receptor inhibitor cetuximab (Erbitux, Eli Lilly) appeared safe and tolerable in the phase 1 portion of the multicenter trial, conducted across eight U.S. university sites.

For phase 2, Adkins and colleagues divided 62 patients with HPV-unrelated HNSCC (median age, 66 years; interquartile range [IQR], 58-70; 71% men) into two groups: those who were platinum-resistant (group 1; n = 30) and those who were resistant to cetuximab (group 2; n = 32). Primary tumor sites included the oral cavity (42%) and larynx (29%), and 81% of patients had received one or two prior lines of treatment for metastatic or recurrent disease.

All participants received oral palbociclib (125 mg daily on days 1-21) and IV cetuximab (400 mg/m2 on day 1 of cycle one, followed by 250 mg/m2 once weekly) in 28-day cycles. Objective response, defined as complete and partial responses per RECIST 1.1 criteria, served as the primary endpoint.

Researchers followed patients in group 1 for a median 5.4 months (IQR, 4.4-12.1) and those in group 2 for a median 5.5 months (IQR, 4.3-8.3).

Among 28 evaluable group 1 patients, 11 (39%; 95% CI, 22-59) attained an objective response, including three complete responses. Repeat scans confirmed all but one of the responses. Half of the group 1 patients (n = 14) had stable disease and three (11%) demonstrated progressive disease. Median duration of response was 4 months (IQR, 1.8-5.6), median PFS was 5.4 months (95% CI, 3.4-7) and median OS was 9.5 months (95% CI, 5.3-16.5).

Palbociclib plus cetuximab shows antitumor activity among head and neck cancer subsetAmong 27 evaluable group 2 patients, five (19%; 95% CI, 6-38) achieved an objective response, including one complete response. Four of the responses were later confirmed. Thirteen of the group 2 patients (48%) had stable disease and nine (33%) demonstrated progressive disease. Median duration of response was 6 months (IQR, 2-15.5), median PFS was 3.7 months (95% CI, 2.9-4.3) and median OS was 6.3 months (95% CI, 4.9-10).

In each group, only one patient with a tumor response previously had received immunotherapy.

The most prevalent grade 3 to grade 4 adverse event associated with palbociclib was neutropenia, which occurred in 34% (n = 21) of all patients. The researchers did not document any treatment-related deaths.

The researchers cited various limitations to their study, including its single-group design, and noted that the results will need to be confirmed in a controlled trial with a larger sample size. They acknowledged that immunotherapy might have affected OS outcomes, and that the study design did not permit the evaluation of whether palbocilib’s antitumor activity occurred directly or by reversal of primary cetuximab resistance.

These data suggest a need for further study of palbociclib in patients with recurring or metastatic HNSCC, according to a related editorial by Garth W. Strohbehn, MD, hematology/oncology fellow at University of Chicago, and Everett E. Vokes, MD, professor of medicine and radiation oncology physician-in-chief at University of Chicago Medicine.

“However, we should be circumspect about the prospect of CDK 4/6 inhibitors as standardized, cost-effective therapies in recurrent and metastatic HNSCC,” the authors wrote. “Bringing this class of drugs to head and neck oncology clinics, as either monotherapies or immunotherapy partners, will require appropriately controlled studies linked to biomarker evaluation with both survival and cost-effectiveness endpoints.” – by Jennifer Byrne

Source:
Adkins D, et al. Lancet Oncol. 2019;doi:10.1016/S1470-2045(19)30405-X.
Strohbehn GW and Vokes EE. Lancet Oncol. 2019;doi:10.1016/S1470-2045(19)30484-X.

Disclosures: Adkins reports research funding from Pfizer as part of the work presented in the study; personal fees for advisory/consultant roles from Celgene, Cue Biopharma, Eli Lilly, Loxo Oncology, Merck and Pfizer; and research funding from AstraZeneca, Atara, Blueprint Medicine, Bristol-Myers Squibb, Celgene, CellCeutix, Celldex, Eli Lilly, Enzychem, Exelixis, Gliknik, Kura, Matrix Biomed, Medimmune Innate, Novartis, Pfizer and Polaris outside the submitted work. Please see the study for all other authors’ relevant financial disclosures. Vokes reports consultant/advisory roles with AbbVie, Amgen, AstraZeneca, Bristol-Myers, Celgene, EMD Serono, Genentech, Merck, Novartis and Regeneron. Strohbehn reports no relevant financial disclosures.

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