Monthly Archives: August 2016

New method of cancer immunotherapy developed

Source: www.nextbigfuture.com
Author: staff

A team of Stanford ChEM-H scientists has discovered a novel form of cancer immunotherapy, which works by removing certain sugars from the surface of cancer cells and making those cells visible to the immune system.

Scientists have long known that if certain sugars are present on a tumor, it is less likely to respond well to therapies. But nobody knew what that halo of sugars was doing, in part because such a small number of labs study the glycocalyx.

Evidence had been mounting within those few labs that do study the glycocalyx, including Bertozzi’s, that a subset of sugars called sialic acids act as a signal for the innate immune system to ignore the otherwise suspicious-looking tumor. Eliminate those sugars, and maybe innate immune cells would be more likely to recognize and attack the cancer cells, Bertozzi thought.

And essentially that’s exactly what happened.

Current immunotherapies on the market work by blocking one of the inhibitory signals that are recognized by the adaptive immune system. Block those and the balance tilts in such a way that the immune system will attack the now recognizable cancer.

Bertozzi’s approach provides a second way of tiling the balance in favor of attack, this time for the innate immune system. She said this study shows just one example of how it could work, but her sugar-removing lawnmower could be used on a wide variety of cell types, not just those expressing HER2, and on different types of sugars.

PNAS – Precision glycocalyx editing as a strategy for cancer immunotherapy

PNAS – Precision glycocalyx editing as a strategy for cancer immunotherapy [Supplemental information]

Significance
Successful tumors are able to evade the immune system, which is otherwise capable of killing transformed cells. Therapies that prevent this evasion have become revolutionary treatments for incurable cancers. One mechanism of evasion is the presentation of sugars, called sialic acids, within the cell surface’s sugar coating, or glycocalyx. Here, we designed biotherapeutic molecules, termed “antibody–enzyme conjugates,” that selectively remove sialic acids from tumor cells. The antibody directs the enzyme to the cancer cells, the enzyme cleaves the sugars, and then the antibody directs immune cells to kill the desialylated cancer cells. The conjugate increased tumor cell killing compared with the antibody alone. Editing the cancer cell glycocalyx with an antibody–enzyme conjugate represents a promising approach to cancer immune therapy.

Abstract
Cell surface sialosides constitute a central axis of immune modulation that is exploited by tumors to evade both innate and adaptive immune destruction. Therapeutic strategies that target tumor-associated sialosides may therefore potentiate antitumor immunity. Here, we report the development of antibody–sialidase conjugates that enhance tumor cell susceptibility to antibody-dependent cell-mediated cytotoxicity (ADCC) by selective desialylation of the tumor cell glycocalyx. We chemically fused a recombinant sialidase to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab through a C-terminal aldehyde tag. The antibody–sialidase conjugate desialylated tumor cells in a HER2-dependent manner, reduced binding by natural killer (NK) cell inhibitory sialic acid-binding Ig-like lectin (Siglec) receptors, and enhanced binding to the NK-activating receptor natural killer group 2D (NKG2D). Sialidase conjugation to trastuzumab enhanced ADCC against tumor cells expressing moderate levels of HER2, suggesting a therapeutic strategy for cancer patients with lower HER2 levels or inherent trastuzumab resistance. Precision glycocalyx editing with antibody–enzyme conjugates is therefore a promising avenue for cancer immune therapy.

Source:
Stanford University, Proceedings of the National Academy of Sciences of the United States of America
PNAS

August, 2016|Oral Cancer News|

Expert says Nivolumab Poised to Change Standard of Care in SCCHN

Source: www.onclive.com
Author: Laura Panjwani

Robert-Ferris

Nivolumab (Opdivo) is a game-changing agent for the treatment of patients with squamous cell carcinoma of the head and neck (SCCHN), according to Robert L. Ferris, MD, PhD.

“Recent findings have shown us that this agent is really the new standard-of-care option for all platinum-refractory patients with head and neck cancer,” says Ferris, vice chair for Clinical Operations, associate director for Translational Research, and co-leader of the Cancer Immunology Program at the University of Pittsburgh Cancer Institute. “This is regardless of whether patients are PD-L1–positive or negative or whether they are HPV-positive or negative.”

The PD-L1 inhibitor received a priority review designation by the FDA in July 2016 based on the CheckMate-141 study, which demonstrated a median overall survival (OS) with nivolumab of 7.5 months compared with 5.1 months with investigator’s choice of therapy (HR, 0.70; 95% CI, 0.51-0.96; P = .0101) in patients with recurrent or metastatic SCCHN.

The objective response rate (ORR) was 13.3% with nivolumab and 5.8% for investigator’s choice. The FDA is scheduled to make a decision on the application for the PD-1 inhibitor by November 11, 2016, as part of the Prescription Drug User Fee Act.

Ferris was the lead author on an analysis that further evaluated preliminary data from CheckMate-141, which was presented at the 2016 ASCO Annual Meeting. In an interview with OncLive, he discusses the findings of this study, potential biomarkers for nivolumab, and questions that remain regarding the use of the immunotherapy in SCCHN.

OncLive: What were the updated findings from CheckMate-141 presented at ASCO?

Ferris: The data that were presented at the 2016 ASCO Annual Meeting were further evaluations and follow-up on some preliminary data—originally presented at the 2016 AACR Annual Meeting—that listed the OS results.

At ASCO, we recapped the primary endpoint of OS as an important endpoint for immunotherapies because response rate and progression-free survival may not be as accurate. Ultimately, the FDA and people at large want OS. In this study, OS was 36% at 1 year in the nivolumab-treated arm and 16.6% in the comparator arm, which was investigator’s choice of single-agent chemotherapy, consisting of methotrexate, docetaxel, or cetuximab. In this phase III randomized trial, nivolumab was given in a 2:1 randomization: 240 patients received nivolumab and 120 received investigator’s choice.

Also at ASCO, we presented further evaluations consisting of what the regimens are in the comparator arm. There was about 20% each of docetaxel and methotrexate and 12% of cetuximab. Approximately 60% of the patients had prior cetuximab exposure and we stratified by cetuximab as a prior therapy. We also demonstrated the ORR, which was 13.3% in the nivolumab-treated arm versus 5.8% in the investigator’s choice arm.

Therefore, there was an improvement in overall response, but the difference seemed more modest than the OS benefit—which was a doubling—with 20% more patients alive at 1 year. This reinforces the concept that perhaps response rate may not be the best endpoint. Progression-free survival (PFS) was double at 6 months, with about 20% in the nivolumab arm versus about 9.9% in the investigator’s choice arm. The median PFS was not different, but the 6-month PFS was twice as high. The time to response was about 2 months in each arm at the first assessment.

Your analysis also looked at biomarkers. Can you discuss these findings and their significance?

The p16 or HPV-positive group had a better hazard ratio for OS than the overall study population. The hazard ratio was .73 for the overall population, using a preplanned interim analysis. With the HPV-positive group, we had a hazard ratio of .55 and the HPV-negative group had a hazard ratio of .99. It is still favoring the nivolumab-treated patients but, with the curves separated earlier in the HPV-positive group, one could see the improvement with nivolumab at about 1 to 2 months. It took 7 or 8 months with the HPV-negative group to show a separation of the curves in favor of nivolumab.

We looked at PD-L1 levels, and PD-L1—using a 1% or above level—had an improvement in the PD-L1–positive patients in favor of nivolumab in terms of OS and ORR. When we looked at 5% and 10% thresholds of PD-L1, the OS did not seem to improve. Therefore, in all levels above 1%, the OS was similarly beneficial over the PD-L1 less-than-1% group. However, essentially all levels of PD-L1–positivity and PD-L1–negativity still favored nivolumab, but the benefit was more when its levels were greater than 1%.

We could combine HPV status with PD-L1 status and look at subsets; however, essentially every subset benefited, whether it was PD-L1–negative or positive. This indicates that, in this group of patients, who progress within 6 months of platinum-based therapy, that no current systemic therapeutic options benefit patients as well as nivolumab.

With regard to these findings, what are you most excited about?

Head and neck cancer is a difficult disease. Until recently, we didn’t know the impact of this enrichment for HPV-positive virus-induced subsets and we didn’t know if this was an immune responsive cancer. Clearly, it is. We have all of the hallmarks that we have seen for a bright future—based on the melanoma data—and a series of other cancers indicating response rates in the 15% to 20% range, suggesting that we now have a platform of the PD-1 pathway to combine with other checkpoints and to integrate earlier in disease with radiation and chemotherapy.

We have a demonstration of head and neck cancer as an immune-responsive cancer. We are beginning to get an idea of the biomarkers and starting to be able to segment patients who will benefit. Now, we have a large comparative trial with an OS endpoint and tissue to look at biomarkers to try and understand what the best future combinations will be.

What are some questions that you still hope to answer regarding nivolumab in head and neck cancer?

We have to get down deeper into the nonresponders. We should acknowledge that the majority of patients neither had a response nor benefited. Understanding who is more likely to benefit is useful, but we also need to understand the levels of alternative checkpoint receptors or other biomarkers of resistance.

We have sequential lymphocyte specimens from the peripheral blood, tissues, and serum so those are intensively under evaluation. There are interferon gamma signatures that have risen from the melanoma checkpoint field that will certainty be applied, as well.

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

August, 2016|Oral Cancer News|

NYU Expert Says Cancer Pain Varies by Tumor Type

Source: www.onclive.com
Author: Jane de Lartigue, PhD

Brian L. Schmidt, DDS, MD, PhD, is a specialist in head and neck cancers whose research focus includes an exploration of the biological and molecular mechanisms of pain related to cancer and associated treatments.

He is the director of the New York University (NYU) Oral Cancer Center and of the Bluestone Center for Clinical Research, and a professor of oral and maxillofacial surgery at the NYU School of Dentistry. In June 2016, the National Institutes of Health awarded Schmidt and colleagues a $1.2 million grant to study gene therapy for the treatment of patients with oral cancer pain.

Schmidt talked to OncLive about the difficulties of studying cancer pain and developing new drugs.

OncLive: How has our understanding of the mechanisms of cancer pain changed in the past decade?
Schmidt: The field was developed probably in about 1999. That’s the first publication that I’m aware of that looked at mechanisms in terms of using preclinical models, and by that I mean animal models. Before that time we really had no understanding of basic mechanisms, so there’s been significant advancement over the last 10 years.

Could you briefly describe our current understanding of how cancer pain develops?

Let me tell you what it’s not, because I think that’s important. For many years, people were writing about it but we weren’t testing the possible mechanisms, and what people were writing turned out probably not to be true.

It was initially thought that the pain was due to the cancers growing and pressing on the nerves and we clearly don’t think that’s the underlying mechanism now. Possibly in some cancers that plays a role, but this whole idea of “pressing” really doesn’t work because it’s pretty hard to compress a nerve and there are actually a number of tumors that are not cancer that can compress nerves and those don’t hurt.

There might be a circumstance, for example, if you had a cancer in a perfect location, either let’s say in your leg where the femoral nerve is, or in the paravertebral skeleton where you have what are called spinal roots. In these cases, the cancer could press on the nerve and it would hurt, but that’s probably not a common mechanism.

Probably the best explanation for cancer pain we have is that the cancers produce a number of different molecules—and that depends on the type of cancer—that sensitize the nerves, which makes them respond to stimuli that’s normally not painful. And so the nerves that are surrounding the cancer become fragile, for lack of a better term, and those nerves fire in response to minimal stimuli.

What is the most effective therapy currently available?
I can tell you what’s most commonly used and its effectiveness is highly variable. We’re basically using the same drugs that have been used for thousands of years for pain, which are the opioids. So the narcotics—morphine, fentanyl, methadone, oxycodone, hydrocodone—that entire class of drugs. That’s what’s most commonly used.

Have researchers made any headway in developing drugs that target the underlying causes of cancer pain?
No, they haven’t. Probably the biggest development, and it’s not really targeted therapy, but the biggest development has been for cancers that go to the bone. Those include breast cancer, prostate cancer, multiple myeloma, lung cancer—those cancers go to the bone and cause a lot of bone pain.

We started using a class of drugs called bisphos phonates, which inhibit the cells that break down bone. They specifically inhibit a cell type called osteoclasts. Those drugs work for some patients who have bone metastasis. But we have not discovered true targeted therapies, and one of the challenges has been that the same obstacle that is present for oncologists treating the cancer has also proved an issue for pain physicians, which is that these cancers all behave differently, even within a specific type of cancer, so one colon cancer doesn’t behave like another one, for example.

So, where some cancer patients respond better to a particular drug than others, we think that the challenge of treating cancer pain is going to be the same—the drug will work for one patient but not for another. There is a class of drugs with an unusual mechanism of action—they are monoclonal antibodies that bind nerve growth factor. The history of those drugs has been interesting. Pfizer was the first company that produced one of these drugs and tested it in a clinical trial for low back pain, but the trial was stopped because patients on the drug were requiring hip replacement and it’s not entirely clear why. So there was a hold on the drug, but recently the FDA opened up the drug and so it’s going to be tested again.

It is thought that tanezumab would be very good for cancer pain, and Pfizer and Eli Lilly have joined together to test the drug. They’re both interested in seeing how it works for cancer pain.

What are the key unanswered questions relating to the effective treatment of cancer pain?
The key challenge, as I mentioned earlier, is going to be that all of the cancers behave differently, so they are independent of each other. It’s not like osteoarthritic pain, where the mechanism for causing osteoarthritic pain is, if not the same, then very similar between patients. Cancers are not that way. Even if you were to take a glimpse at the cancer at a fixed point in time, let’s say across 2 patients, now if you add the dimension of time, because cancers change over time, then in a patient 1 drug might be effective for a short time but then the cancer will change and it won’t be effective any longer. Again, this is similar to what oncologists face in treating cancer, where a drug is effective for a couple of months, but then patients stop responding and the tumor grows back.

Another challenge is that cancer pain clinical trials are also very difficult to recruit for because the patients are sick or dying, so they typically don’t want to enroll in studies. They are often on a lot of drugs. So of all the clinical trials, they are probably the most difficult for which to recruit.

August, 2016|Oral Cancer News|