immunotherapy

Research Leader Discusses FDA-Funded Immunotherapy for Head and Neck Cancer

 
Source: www.onclive.com
Author: Gina Columbus
 
Brett-Miles
Brett Miles, MD, DDS

 

The investigational immunotherapy axalimogene filolisbac (ADXS11-001) has emerged as a potentially practice-changing agent in the treatment of HPV-related oropharyngeal cancer.

Shown to generate T cells directed against a cancer antigen and neutralize suppressor regulatory T cells and myeloid-derived suppressor cells that protect the tumor microenvironment from an immunologic attack and contribute to tumor growth, ADXS11-001 is the first of its kind—a therapeutic vaccine for the disease.

The agent is being examined in an ongoing phase II trial, which was reported as one of 18 recipients of research grants recently awarded by the FDA’s Office of Orphan Product Development. The grants, given to sites for product development in rare diseases, total more than $19 million. The ADXS11-001 grant provides collaborating researchers from Baylor College of Medicine and the Icahn School of Medicine at Mount Sinai with more than $1.1 million over 3 years.

Eligible patients for the phase II study are newly diagnosed with stage II to IV HPV16-positive oropharynx squamous cell carcinoma who are scheduled to receive ablative transoral robotic surgery.

In an interview with OncLive, the study’s surgical principal investigator, Brett Miles, MD, DDS, associate professor of Otolaryngology Head and Neck Surgery, co-chief, Division of Head and Neck Oncology, Icahn School of Medicine at Mount Sinai, discusses the potential of ADXS11-001 in HPV-associated head and neck cancer and other emerging therapies and treatment strategies.

OncLive: Congratulations on your study being awarded a research grant from the FDA. How does it feel to be selected and how will it help further the phase II research?

  1. Miles: Number one, the beauty of having this award is that it allows us to know that we are in line with what the FDA is interested in and, especially, what the National Institutes of Health (NIH) is interested in, in terms of immunotherapy for head and neck cancer. It gives a little bit of confirmation that our work is headed in the right direction from the standpoint of the major funding agencies.

    Certainly, having that NIH funding is actually going to allow us to propel this study along. We are getting some preliminary results that appear to be encouraging and we really need to confirm those results; this is going to allow us to do that. That is the most exciting part.

Can you provide an overview of ADXS11-001 and how it operates in the immune system?

This is a therapeutic vaccine for HPV-related head and neck cancer and other cancers that are HPV-related. It is contrasting to the preventative vaccines that are widely known, such as Gardasil, for example. Gardasil is a vaccine that if you have not been exposed to the virus, it allows your immune system to fight HPV infection before it happens. The concept behind ADXS11-001 is to allow your immune system to recognize and attack cells that have already been infected with HPV. Therefore, it is a therapeutic vaccine, not a preventative vaccine. It is the only one available for head and neck cancer at this time in a clinical trial.

This is an attenuated virus that is given to the patient in the form of two vaccines, and then it tricks the immune system into thinking that these cells are infected with the bacteria. However, what they are recognizing is the viral proteins. Therefore, they attack the cells that are infected with HPV. That is the theory.

We have administered it to several patients on the trial, and we just got some preliminary data back on the response, and we are seeing some definite changes in the immune system and in the cell surface markers in patients who have had the vaccine. We do not have quite enough data yet to interpret what those changes mean. In other words, we know the vaccine is causing some type of immune response; we are not sure if that vaccine is effectively killing tumor cells yet, and we have not confirmed what those T cells are doing. We are still gathering data for that. Hopefully, with the next batch of patients that we enroll, we will be able to tell if this is actually an effective therapy for this disease. That is kind of where we are right now.

How has the safety profile of ADXS11-001 been thus far?

Patients have been tolerating it quite well. In terms of toxicity, it is like an immunotherapy. Therefore, you may get rashes and low-grade fevers, kind of feeling like you have the flu, and some other things that are relatively standard with immunotherapies. Remember, anything that activates your immune system to a sufficient level to fight off a tumor infection is also going to cause some level of low-grade side effects. However, we have not seen any severe side effects or any major issues with it. We have seen some changes in blood pressure during the infusions, so we give the vaccine in the cancer center. It is two doses and you are supervised for several hours after administration of the vaccine. We have not seen any major toxicities with the vaccine, but the low-grade ones are relatively common. People know when their immune system has been activated, that’s for sure.

What other immunotherapy agents on the horizon do you see having promise in the treatment of head and neck cancer?

One other study, that we have not yet opened but we are going to do, is combining the ADXS11-001 vaccine with MEDI4736, a PD-L1 inhibitor. That study will be for patients who have metastatic or recurrent disease. This ought to be kind of interesting because then you are attacking the immune system from two different angles. It is going to compare ADXS11-001 monotherapy with the PD-L1 monotherapy with a third arm that has both agents combined. I am not sure when that trial is going to be open, but that is the one coming up on the horizon.

Aside from immunotherapy, what other treatment-related research in head and neck cancer are you interested in seeing the results of?

The other main trial is our robotic surgery trial, which is called a de-escalation trial. As you may be aware, patients with HPV-related head and neck cancer have a good prognosis. One of the problems is, when they get standard concurrent chemoradiotherapy, they have a lot of functional morbidity. We have an ongoing robotics trial that basically treats patients with robotic surgery upfront and then they get standard chemotherapy with a reduced dose of radiation, a reduced dose of radiation, or no radiation based on their pathology.

We are hoping to offer the same cure rate for these earlier-stage HPV-related cancers, but with a more functional long-term outcome by tailoring what the patient gets, based on the pathology report, after the minimally invasive robotic surgery. That is something we are currently accruing for, and we are really excited to see if our survival data is comparable, which we think it will be. Our functional outcomes, based on the data we have, should certainly be improved over standard therapy.

There was research presented at the 2015 ASCO Annual Meeting that showed that reducing radiation and chemotherapy dosage in low-risk HPV-associated oropharyngeal squamous cell carcinoma may prevent disease recurrence while still improving quality of life. Can you comment on this study?

Both of these studies are consistent with the prevailing thoughts on de-escalation of therapy in appropriately selected patients. When properly stratified, many patients can enjoy high rates of oncologic cure, with reduced long-term morbidity. It highlights the difficult balance between administering just enough therapy to cure the cancer, without permanently destroying the quality of life in terms of speech and swallowing.

The investigational immunotherapy axalimogene filolisbac (ADXS11-001) has emerged as a potentially practice-changing agent in the treatment of HPV-related oropharyngeal cancer.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

September, 2015|Oral Cancer News|

FDA Grant Forwards Listeria-Based Throat Cancer Vaccine

Source: www.targetedonc.com
Author: Sandra Kear
 
Sikora

An experimental immunotherapy for human papillomavirus-, or HPV-, related throat cancers, which is driven by the Listeria bacteria (that wreaks havoc when ingested), may now move forward due to a $1.1 million dollar grant from the FDA to researchers at Baylor College of Medicine.

 
“Immunotherapy, such as axalimogene filolisbac, which targets HPV proteins expressed in cancer cells is a great example of using a cancer’s own unique biology against it.” said principal investigator Andrew Sikora, MD, PhD, leader of the head and neck cancer program in the NCI Comprehensive Designated Dan L. Duncan Cancer Center and an associate professor of otolaryngology at Baylor College, in an interview with Targeted Oncology.

 

“This is hopefully the first step toward development of more targeted treatment approaches that reduce side effects and cancer treatment-related morbidity by uniquely targeting only virus-infected cells.” 
The Listeria-based HPV immunotherapy, axalimogene filolisbac (ADXS11-001), is developed by Advaxis, and functions by stimulating an immune response against HPV proteins, thus killing infected cells.

 
The drug is currently being evaluated in phase I-II study3 alone or in combination with MedImmune’s durvalumab, in patients with cervical or HPV-positive head and neck cancer. The study has three arms: axalimogene filolisbac alone, durvalumab alone, and the two drugs combined. Primary outcomes established for the study are: number of subjects with adverse events (AEs) in each dose level, number of subjects with AEs in the combination dose, and progression-free survival.

 
Patients must have measurable disease by RECIST criteria, as well as histologically diagnosed squamous cell cancer of the head and neck or squamous, nonsquamous, adenosquamous, carcinoma, or adenocarcinoma of the cervix. HPV positivity is not required for cervical cancer. Enrolled patients must be ≥18 years of age with a performance status of 0 or 1. Females must have a negative pregnancy test, and patients must agree to use two methods of birth control 120 days after the last treatment dose. The estimated study completion date is December 2019.

 
“We continue to accrue patients for this trial and collect blood and tumor specimens. Immune studies are best done in batches, so every time we have the specimens from 5 to 6 patients available, we can start another round of studies looking at things like T-cell responses, changes in immune cell profiles, altered serum cytokines, etc.” Sikora said. “At the end of it, each different assay provides a different snapshot of how the immune system works, and we hope to put them together to comprehensively understand what is happening to the immune system in these patients and how to use this information to put together the next round of clinical trials.”

 
Sikora will collaborate with the Icahn School of Medicine at Mount Sinai in New York City and with Advaxis. The grant was given by the FDA’s Orphan Products Grants Program, which supports clinical development of new treatments for rare diseases or conditions where no current treatment exists or superior treatments are needed.

 
“The grant from the FDA is a total game changer, because not only does it make it possible for us to fully complete accrual of the trial, but it gives us the opportunity to perform really cutting-edge analyses on the samples collected. We now have the opportunity to use nearly every tool at our disposal to meticulously profile and understand how this therapy drives antitumor immune responses,” said Sikora.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

September, 2015|Oral Cancer News|

An HPV-E6/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression

Source: www.nature.com
Author: A E Rice, Y E Latchman, J P Balint, J H Lee, E S Gabitzsch and F R Jones
 

We have investigated if immunotherapy against human papilloma virus (HPV) using a viral gene delivery platform to immunize against HPV 16 genes E6 and E7 (Ad5 [E1-, E2b-]-E6/E7) combined with programmed death-ligand 1 (PD-1) blockade could increase therapeutic effect as compared to the vaccine alone. Ad5 [E1-, E2b-]-E6/E7 as a single agent induced HPV-E6/E7 cell-mediated immunity. Immunotherapy using Ad5 [E1-, E2b-]-E6/E7 resulted in clearance of small tumors and an overall survival benefit in mice with larger established tumors. When immunotherapy was combined with immune checkpoint blockade, an increased level of anti-tumor activity against large tumors was observed. Analysis of the tumor microenvironment in Ad5 [E1-, E2b-]-E6/E7 treated mice revealed elevated CD8+ tumor infiltrating lymphocytes (TILs); however, we observed induction of suppressive mechanisms such as programmed death-ligand 1 (PD-L1) expression on tumor cells and an increase in PD-1+ TILs. When Ad5 [E1-, E2b-]-E6/E7 immunotherapy was combined with anti-PD-1 antibody, we observed CD8+ TILs at the same level but a reduction in tumor PD-L1 expression on tumor cells and reduced PD-1+ TILs providing a mechanism by which combination therapy favors a tumor clearance state and a rationale for pairing antigen-specific vaccines with checkpoint inhibitors in future clinical trials.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

September, 2015|Oral Cancer News|

AstraZeneca joins the world of immunotherapy against cancer

Source: www.youthhealthmag.com
Author: staff

Cancer drug companies have been fighting lately in a completely different and interesting arena: immunotherapy. The competition is indeed heating up that firms such as AstraZeneca are willing to pay millions of dollars for promising treatments. AstraZeneca, through its research company called MedImmune, has just recently announced its decision to purchase a novel drug INO-3112 from Inovio, based in Pennsylvania, for a staggering price tag of $727 million.

INO-3112 is a drug for immunotherapy, a new way of combating cancer by boosting the body’s immune system. This then allows the antibodies and specific cells to fight off the tumor. The treatment may also provide synthetic proteins to boost the body’s fighting chance.

MedImmune believes that with the proper immunotherapy protocol for the patient, conventional methods such as chemotherapy and radiotherapy, which have plenty of serious risks, can now be significantly reduced, if not eliminated. In fact, patients may no longer have to go through surgery, which is a common first-line treatment.

While AstraZeneca already has immunotherapy products in the market, the acquisition of INO-3112 will make it an instrument for combination therapies.

As for Inovio, the drug, which is still not approved, is currently in the advanced stages of the clinical trials. It will be intended for treating head and neck cancers, as well as cervical cancer. While there are already cervical cancer vaccines, they cite the rather poor record of them. Their drug, on the other hand, will work on modifying DNA sequencing that will trigger the manufacture of certain T-cells, which will then curb tumor growth.

So far, MedImmune has already paid its down payment of $27.5 million. The remaining amount will be given as the research and drug reach certain milestones. The company will also pay for the research.

The partnership is also set to increase the revenues of Inovio as it receives a share in the drug’s sale. Both will also be working on cancer vaccines.

August, 2015|Oral Cancer News|

HPV16 Antibodies Signal Even Better Oral Cancer Outcomes

Source: www.medscape.com
Author: Neil Osterweil
 

Another prognostic tool may be in the offing for clinicians to use in evaluating patients with oropharyngeal cancers, new research suggests.

The presence in serum of three antibodies to human papillomavirus type 16 (HPV16) was predictive of better progression-free and overall survival in these patients, according to Kristina R. Dahlstrom, PhD, from the University of Texas MD Anderson Cancer Center, in Houston, and colleagues.

Patients whose serum was positive for the presence of three specific antibodies to “early” (E) proteins involved in replication and growth of HPV16 had dramatically better rates of overall survival (OS) and progression-free survival (PFS) compared with patients whose serum was negative for the antibodies, they reported online June 15 in Clinical Cancer Research.

Specifically, for those patients whose serum was positive for any E antibodies, 5-year estimated OS was 87.4%, compared with 42.2% for patients whose sereum was negative for all E antibodies (P < .001). The respective 5-year PFS rates were 82.9% and 46.1% (P < .001).

“These results hint at a prognostic stratification of patients with HPV-related oropharynx cancer reflecting humoral immune response to HPV type 16 E proteins and thus may help in choosing immunotherapy approaches for such patients in future,” said senior author Erich M. Sturgis, MD, MPH, a surgeon at MD Anderson, in comments to Medscape Medical News.

Currently, the serology results are not strong enough to be used as clinical decision tools for choosing current therapies, she added.

Their findings also suggest that vaccine-based immunotherapy targeted against HPV16 E-antigens combined with other immunotherapies such as checkpoint inhibitors might be effective against recurrent or metastatic HPV16-positive cancers of the oral cavity and pharynx, said Dr Sturgis.

The findings appear to further illuminate what is going on immunologically in these patients, said an expert not involved with the research.

“This is certainly an interesting study that builds upon our early understanding of the role of the host’s immune response in determining outcomes in HPV-associated oropharynx cancers,” commented Lori J Wirth, MD, a head and neck cancer specialist at the Massachusetts General Hospital Cancer Center, in Boston.

“We know from responses experienced by HPV-positive oropharyngeal squamous cell carcinoma patients enrolled in early clinical trials investigating checkpoint inhibitors that the host immune system can be exploited for a therapeutic end. The more we know about the host immune response to this virally mediated cancer, the better we’ll get at taking advantage of it,” she told Medscape Medical News.

More Cancers, Better Outcomes

Earlier studies have shown that although the incidence of HPV-related head and neck cancers is rising, patients with oropharyngeal squamous cell carcinomas positive for HPV16 have significantly better prognoses than patients with the same cancers not related to HPV infections.

To see whether they could identify prognostic biomarkers in patients with HPV-related oropharyngeal cancers, the investigators used enzyme-linked immunosorbent assasy to quantify immunoglobulin G antibodies to both early antigens (E1 and E4-E7) to the viral capsid proteins L1 and L2, and to the N-terminal and C-terminal fragments of E2 (NE2, CE2).

Among serum samples taken from 209 patients with oropharyngeal cancers at diagnosis, at the end of treatment, and during follow-up, PFS was significantly better for patients testing positive for any E antigen (P < .001), but not for patients testing positive for any L antigen. Therefore, for all subsequent analyses, the investigators focused only on patients testing positive for E antigens.

In multivariable models adjusted for age, smoking status, and treatment, the hazard ratio (HR) for death for patients with any E antibodies was 0.20 (95% confidence interval [CI], 0.1 – 0.4).

The HR for progression for those with any E antibodies was 0.20; (95% CI, 0.1 – 0.5).

The investigators also found that serum positivity for NE2, E1, and E6 were were all strongly associated with better OS and PFS, with respective HRs of 0.20, 0.30, and 0.30 (all significant, as shown by 95% CI).

“Specific antibody status has the potential to be a useful prognostic indicator that may identify subsets of patients diagnosed with HPV16-positive tumors who may benefit from altered monitoring and/or treatments. In addition, the suggestion that immune response to HPV16 antigens is important to cancer outcomes suggests the potential of augmenting immune responses to improve treatment of patients with HPV-driven oropharyngeal carcinoma,” the investigators write.

The study was supported by grants from the National Institutes of Health. Dr Sturgis and Dr Wirth have reported no relevant financial relationships.

Clin Cancer Res. 2015:21:2861-2869. Abstract

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

Keytruda doubles efficacy of only targeted therapy for head and neck cancer

Source: www.curetoday.com
Author: Lauren M. Green

The immunotherapy Keytruda (pembrolizumab), in a recent study, proved twice as effective for the treatment of head and neck cancer as Erbitux (cetuximab), the only targeted therapy indicated as a therapy for the disease.

The multisite study offers the largest experience to date of how immunotherapy can be deployed in patients with head and neck cancer, and could change the way the disease is treated. The findings were announced May 29 during the annual meeting of the American Society of Clinical Oncology, a gathering of nearly 30,000 oncology professionals taking place in Chicago.

Keytruda is an antibody designed to disable the protein PD-1 so it cannot do its job of keeping the immune system in check; this allows T cells to become more active in recognizing and fighting cancer cells. In the study, investigators found that the drug produced broad and durable responses in patients with advanced head and neck cancer.

Fifty-six percent of patients in the study experienced some tumor shrinkage with Keytruda, and 86 percent of those patients continued to respond to treatment at data cutoff on March 23, 2015. Keytruda produced an overall response rate (ORR) of 25 percent, and it proved active in both HPV (human papillomavirus)-positive and HPV-negative patients.

“The efficacy was remarkable — pembrolizumab seems to be roughly twice as effective, when measured by response, as our only targeted therapy, cetuximab,” said Tanguy Seiwart, an assistant professor of medicine and associate leader of the head and neck cancer program at the University of Chicago, who presented the results in a press briefing during the ASCO meeting. “We have high hopes that immunotherapy will change the way we treat head and neck cancer.”

Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) has a poor prognosis with a median overall survival (OS) of 13 months in patients treated in the first-line setting, and six months in previously treated patients. Previously treated patients made up the majority of the population of the study, which built on earlier findings from the KEYNOTE-012 study (NCT01848834). In that study, Keytruda — administered at 10 mg/kg every two weeks — had a 20 percent response rate in patients with advanced HNSCC whose tumors were positive for the protein PD-L1.

The findings reported May 29 were based on results from an expansion of that first trial, which involved 132 patients with advanced HNSCC who were recruited regardless of their PD-L1 or HPV status. Importantly, said Seiwert, patients in this cohort received a fixed dose of Keytruda (200 mg every three weeks), representing “a very convenient dosing schedule.”

Eligible patients had measureable disease based on RECIST 1.1 response evaluation criteria and an ECOG performance status of 0 or 1. The majority of enrollees were male (83 percent), and 56.8 percent had received two or more lines of therapy for disease recurrence. Radiographic imaging was used to assess tumor response every eight weeks. Patients were treated as long as they didn’t show progression of disease or as long as they demonstrated clinical improvement, Seiwert explained.

Of 117 evaluable patients, 29 (24.8 percent; [95 percent confidence interval (CI), 17.3–33.6]) responded to treatment with Keytruda. For patients with HPV-positive HNSCC, the ORR was 20.6 percent, and in the HPV-negative cohort, ORR was 27.2 percent.

“In addition to the 25 percent response rate,” said Seiwert, “about 25 percent also had stable disease, so when we take these together, we have a disease control rate of about 50 percent, which is remarkable in this disease, especially in a heavily pretreated population.”

Moreover, he said, about two-thirds of patients had received two or more prior lines of therapy, which generally is an indicator of a very poor prognosis.

For the 56 percent of patients whose tumors decreased in size, Seiwert said the responses often occurred early at eight or 16 weeks, although there were a few outliers with late responses.

“Importantly, those patients who did respond oftentimes continued to have responses — 86 percent of patients had durable responses in this cohort,” he continued, adding that not only are responders remaining on the therapy, but so are many patients who have stable disease, with a total of 40 patients staying on the drug.

“Overall, and in keeping with what we already know about pembrolizumab, this was a very well-tolerated agent,” said Seiwert, “certainly better tolerated than what we usually see in head and neck cancer with aggressive chemotherapy and radiotherapy.”

Serious side effects were reported in fewer than 10 percent of patients. The most common side effects were fatigue (15.2 percent of patients), hypothyroidism (9.1 percent), and decreased appetite and rash, each occurring in 7.6 percent of patients. Four patients discontinued treatment due to immune-related side effects: two due to grade 2 interstitial lung disease and grade 3 colitis, respectively, and two patients for grade 3 pneumonitis.

Analysis of the findings based on biomarker status is ongoing, and Seiwert is hopeful that with the emergence of new potential biomarkers, researchers will be able to pinpoint which patients with HNSCC are most likely to benefit from the immunotherapy.

For example, another related study that Seiwert and colleagues are reporting at ASCO (abstract 6017) has shown that the expression of the gene signature interferon-gamma in head and neck tumors had a very strong negative predictive value of response to Keytruda. “In the future, these results may help us, if validated, to determine which patients should or should not [be given] pembrolizumab,” Seiwert said.

Pembrolizumab versus standard treatment for HNSCC also is being evaluated in two phase 3 trials that are currently recruiting participants (NCT02252042 and NCT02358031).

Source:
Seiwert TY, Haddad RI, Gupta S, et al. Antitumor activity of the anti-PD-1 antibody pembrolizumab in biomarker-unselected patients with R/M head and neck cancer: preliminary results from the KEYNOTE-012 expansion cohort. J Clin Oncol. 2015;(suppl; abstr LBA6008) – See more at: http://www.curetoday.com/articles/keytruda-doubles-efficacy-of-only-targeted-therapy-for-head-and-neck-cancer/2#sthash.44VvpPH4.dpuf

Pembrolizumab immunotherapy effective in recurrent, metastatic head and neck cancer

Source: www.cancertherapyadvisor.com
Author: Debra Hughes, MS

Pembrolizumab immunotherapy is effective for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), results of the KEYNOTE-012 trial presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting have shown.

At a fixed dose of 200 mg intravenously every 3 weeks, pembrolizumab “was well tolerated and demonstrated a clinically meaningful overall response rate of 24.8% in patients with recurrent/metastatic SCCHN,” reported Tanguy Y. Seiwert, MD, an assistant professor of medicine, and associate HNC program leader at The University of Chicago in Chicago, IL.

However, “it is important to note that response rate may underestimate the rate of benefit in patients, and ultimately we need to assess survival,” said Dr. Seiwert in an ASCO press release.

“We know from other diseases where the experience with immunotherapy is larger, that patients who have disease stabilization or even initially experience disease progression upon receiving immunotherapy ultimately may derive significant benefit that can translate into longer survival.”

Pembrolizumab (MK-3475), a humanized monoclonal antibody that blocks interaction of PD-1 with its ligands, PD-L1 and PD-L2, promotes activity of tumor-specific effector T cells.

Previously, the KEYNOTE 012 study had demonstrated clinical activity of pembrolizumab 10 mg/kg every 2 weeks in patients with recurrent/metastatic SCCHN enriched for PD-L1–positive tumors. Response rate was 20%. Dr. Seiwert reported on the study’s larger SCCHN expansion cohort, irrespective of PD-L1 expression or HPV status, using a 3-weekly fixed dose.

The primary end point was overall response rate per investigator assessment (RECIST 1.1). Secondary objectives included progression-free survival and overall survival.

A total of 132 patients with recurrent/metastatic SCCHN were enrolled and evaluated every 8 weeks with radiographic imaging. Mean age was 60 years, 83.3% were male, and 37.9% had 3 or more lines of therapy for recurrent disease.

At a median follow-up of 5.7 months (range: 0.2-8.7 months), the overall response rate was 24.8%, with 7 of the 34 patients who were HPV-positive and 22 of the 81 patients who were HPV-negative responding.

Among all responders, there was one complete response and 26 partial responses. Median time to response was 9.0 weeks (range: 7.6-18 weeks). Median duration of response was not reached, he said. A total of 40 patients remain on therapy, and 86% of responding patients (25 of 29) remain in response.

Drug-related adverse events (AEs) of any grade occurred in 59.8% of all enrolled patients; drug-related grade 3 or higher AEs occurred in 9.8% of patients.

The most common drug-related AEs (≥5%) of any grade were fatigue (15.2%), hypothyroidism (9.1%), decreased appetite (7.6%), rash (7.6%), dry skin (6.8%), pyrexia (6.8%), arthralgia (5.3%), nausea (5.3%), and decrease in weight (5.3%).

“This is yet another exciting example where PD-1 immunotherapy might work better and more reliably than existing drugs, and with fewer side effects,” said ASCO Expert Gregory A. Masters, MD, in a press release.

“The diversity of patients who responded is greater than in any previous clinical trial. But we still need larger studies and longer follow-up to assess the impact of this treatment on patient survival.”

Pembrolizumab is currently being evaluated in two phase 3 trials to investigate its clinical benefit compared with standard of care chemotherapy, Dr. Seiwart said.

Reference:
Seiwert TY, Haddad RI, Gupta S, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. J Clin Oncol. 2015;33:(suppl; abstr LBA6008).

Merck immunotherapy appears effective in head and neck cancer – study | Reuters

Source: www.firstpress.com
Author: Bill Berkrot

 

A Merck & Co drug that helps the immune system fight cancer was about twice as effective as the current standard therapy for patients with recurrent or advanced head and neck cancers, according to study data released on Friday.

A quarter of the 132 patients who received the drug, Keytruda (pembrolizumab), saw their tumors shrink by at least 30 percent. Fifty-six percent of patients experienced at least some tumor shrinkage in the ongoing single drug Phase I study dubbed Keynote-012, researchers reported.

“This is remarkable because we don’t usually see this level of activity with new agents. We have a track record of failure,” said Dr. Tanguy Seiwert, lead investigator of the study from the University of Chicago.

Advanced head and neck cancer is currently treated with Eli Lilly’s Erbitux, known chemically as cetuximab, which typically has a response rate of 10 percent to 13 percent.

“The only thing that works is cetuximab and this looks at least twice as good,” said Seiwert, who was presenting the Keytruda data at the American Society of Clinical Oncology meeting in Chicago.

ADVERTISING

Merck shares rose more than 1 percent to $60.43 on the New York Stock Exchange.

Keytruda and Opdivo from Bristol-Myers Squibb Co are at the forefront of a promising new class of drugs called PD-1 inhibitors that block a mechanism tumors use to evade the immune system. Keytruda is approved to treat advanced melanoma and awaits a decision for use in lung cancer. It is being tested against 30 types of cancer alone and in various combinations.

While overall survival data was not yet available, Keytruda and Opdivo have extended survival for some patients in other cancers.

“Response rate doesn’t do this justice,” Seiwert said. “A fraction of those patients will probably have long term survival. It can really make a difference for some patients who have incurable metastatic disease.”

The drug appeared to work as well for patients whose cancer tested positive for human papillomavirus as those who were HPV negative. Some older treatments may be less effective in HPV positive patients, researchers said.

Keytruda was well tolerated with few side effects, Seiwert said. Serious immune-related side effects, such as inflammation of the lungs or colon, were reported in a very small number of patients in the study.

Head and neck cancer is the sixth most common cancer worldwide. Patients with recurrent or metastatic head and neck cancer are usually expected to live about 10 to 12 months.

Reporting by Bill Berkrot in New York; Editing by Diane Craft.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

Harnessing the immune system to fight cancer

Source: www.npr.org
Author: staff

When Barbara Marder was diagnosed with lung cancer three years ago, she had part of her right lung removed, went through a round of chemotherapy and tried to move on with her life.

“I had hoped that everything was fine — that I would not create difficulty for my children, that I would get to see my grandchildren grow up,” says Marder, 73, of Arnold, Md.

But a routine scan a year later found bad news: The cancer was back — this time in her other lung.

“I was very disappointed,” says Marder. She knew her prognosis was grim. “I decided at that point that … I should think about the fact that perhaps this was going to advance rapidly at this point. And check and make sure: Is my will in order? What should I do so that my children aren’t left with a mess to clean up in my house?”

But Marder didn’t give up. She started exploring her options, which eventually brought her to Johns Hopkins in Baltimore, where doctors are testing a new type of cancer treatment known as immunotherapy.

“Immunotherapy for cancer means developing treatments to harness your immune system and using your own immune system to fight the cancer,” says Dr. Julie Brahmer, an associate professor of oncology and Marder’s doctor.

Scientists have been trying to do this for decades. After all, our immune systems can fight off all kinds of health threats. So, why not cancer? But nothing seemed to really work.

“It’s been very frustrating,” Brahmer says.

But scientists recently discovered that cancer takes a page from Harry Potter: It puts on a kind of invisibility cloak.

“Cancer can keep the immune system from recognizing that it’s bad and keep it from attacking itself,” Brahmer says.

Now scientists have found a way around this.

“The breakthrough is in therapies called ‘checkpoint inhibitors,’ ” Brahmer says.

Checkpoint inhibitors are drugs that pull off cancer’s invisibility cloak by blocking the switch that turns it on.

“It prevents that invisibility cloak or that force field or shield … from going up,” Brahmer says, “so it can’t shield itself from the immune system.”

And these drugs seem to be working, at least for some patients — melting away the toughest tumors, such as some melanomas, the deadliest kind of skin cancer.

npr-immuno

Click image to animate

“They seem to be working quite well for multiple different cancers,” Brahmer says, including kidney cancer, bladder cancer, head and neck cancers, lymphoma and even perhaps breast and lung cancers.

So Marder volunteered for one of Brahmer’s studies testing a checkpoint inhibitor called nivolumab, or Opdivo, for lung cancer. Within weeks of starting her infusions, the tumors in her left lung began to disappear.

“That was very, very exciting. It really changed my perspective. I thought, ‘Jeepers,’ ” Marder says.

Checkpoint inhibitors can cause serious side effects when the immune system attacks healthy cells, causing dangerous, even sometimes life-threatening organ damage. But so far that appears to be relatively rare.

Most patients just get a little tired. Some, like Marder, get an itchy rash. But compared with traditional chemotherapy, it’s easier in most cases.

“You can live a great life,” Brahmer says, “travel and try to live your life as normally as possible. That’s definitely different than chemotherapy.”

One big question is, how long will these drugs keep working? Traditional chemotherapy often stops working with time — the length of effectiveness varies depending on the patient, the type of cancer and the stage at which it was diagnosed. But so far checkpoint inhibitors seem to keep going a lot longer, even in patients who have stopped responding to standard chemotherapy. No one knows yet how much longer.

But Brahmer says so far it looks promising.

“We’re reporting three-year survival rates in [lung cancer] patients who we would say typically should not be around,” Brahmer says.

For melanoma, researchers have followed patients for even longer, she says.

When Marder went back for a checkup more than a year after starting her treatment, there was still no sign of her cancer. Marder was thrilled.

“I’m very fortunate,” she says.

But another big question about these drugs is how much they cost: more than $120,000 for each round. That has drawn some intense criticism.

“Cancer immunotherapy is the most exciting thing we have going on in the field,” says Dr. Peter Bach, director of the Center for Health Policy and Outcomes at the Memorial Sloan Kettering Cancer Center in New York. “It’s frustrating that the companies are gouging the U.S. system with their prices.”

The companies that make checkpoint inhibitors defend their price tags and say they will help make sure patients can afford them.

“Any patient who needs access to a checkpoint inhibitor made by Bristol-Myers Squibb will have access through a robust patient-assistance program,” says Michael Giordano, who heads oncology drug development at the company.

Brahmer hopes doctors will figure out a way to cut the costs and says patients may not have to stay on the drugs indefinitely. That’s because when patients stop taking them, immune system cells known as T-cells seem to remember how to keep the body cancer-free.

“We think that over time your immune system creates memory,” Brahmer says.

The T-cells remember how to attack the tumor and stop the cancer from putting up a shield. “So those T-cells continually keep that cancer under control. Even without treatment,” Brahmer says.

Brahmer might try that for Marder. But for now, she’s coming back every two weeks to receive infusions, and because she is in a study, Marder doesn’t have to pay for the drug.

Brahmer knows she and other researchers will have to treat many more patients for a lot longer to really know just how well these checkpoint inhibitors work, and for how long. Many scientists suspect it will take a combination of checkpoint inhibitors to get the most out of our immune systems to fight cancer.

“We’re trying to figure out how to personalize this treatment,” Brahmer says. “Who needs just one checkpoint inhibitor? Who needs a combination to really unleash the immune system? That’s where this is probably headed.”

NPR’s documentary Cancer: The Emperor of All Maladies will air on PBS in March.

February, 2015|Oral Cancer News|

Number of immune cells in tumors could soon help predict and treat cancers

Source: www.science20.com
Authors: Emma King, University of Southampton and Christian Ottensmeier, University of Southampton

Immune cells in the blood primarily defend us against infection. But we’re now learning that these cells can also keep us free from cancer. Patients with less efficient immune systems such as organ transplant recipients or those with untreated HIV, for example, are more susceptible to cancers. It is also becoming increasingly apparent that we can use immune cells to predict survival in people who do develop cancer. And that, in fact, there are immune cells within cancers.

Head and neck cancer underway

Head and neck cancer underway

The number of immune cells inside a tumor can hugely vary: some patients have vast numbers while some have very few. In a recent study, we showed that in head and neck cancers, the survival of a patient depends on how many immune cells are within the tumor. This could be a valuable way of individualizing cancer treatments.

Patients with lots of immune cells, for example, could be offered less toxic cancer treatment while those with few immune cells may need more aggressive treatment to improve their chances of survival.

Not all immune cells within the tumor are able to “attack” the cancer. By looking at specific cell markers – proteins on the cell exterior that allow us to see whether, for example, cells are exhausted – we can determine which individual immune cells in the tumor will be effective in tackling the cancer, or if they are exhausted and not able to perform any useful function. It’s possible that these exhausted cells could be reinvigorated to become useful again with targeted immunotherapy treatments currently in development.

These include vaccines, so if a cancer has been caused by a virus, we can vaccinate the patient with a short segment of the same virus to encourage the immune system to react to it. Around 30% of head and neck cancers, for example, are the result of human papillomavirus (HPV). There has been a 225% increase in these types of cancers over the past 15-20 years and in the US, HPV will cause more of these cancers than cervical ones. In these cases, cancer cells continue to express part of the HPV on their surface. The hope is that following vaccination, immune cells will be better able to identify these HPV cancer cells and kill them.

For people who simply don’t have many immune cells in tumors, specific, targeted immunotherapy could be one option. But also broader “brush stroke” treatments. These broader treatments cover all immunotherapies that encourage a patient’s immune system in a fairly non-specific way. Our immune cells are normally very tightly regulated and include many fail-safe systems to prevent them from over-reacting primarily to infections. General immunotherapy takes the brakes off and allows the immune cells to react to the cancer cells.

It may be that a combination of specific vaccine and non-specific immune treatments could be enough in combination to tip the balance in favor of the patient’s immune system so that it is able to overcome the cancer.

We’re going to further investigate how immune cells might help us to fight cancer and two head and neck cancer immunotherapy trials are due to start at the University of Southampton in the next six months.

One of these trials will look at a HPV cancer vaccine, while the other will investigate a non-specific immunotherapy molecule for those 70% of patients that develop head and neck cancer independent of HPV. Our hope is that within five years the results of these trials could influence the way we treat cancers.The Conversation

Note: This article was originally published on The Conversation.

September, 2014|Oral Cancer News|