Sandra Kear

The advent of targeted and immunotherapeutic approaches to manage melanoma and other skin cancers are rapidly changing the management of these malignancies, posing challenges to clinicians. The

International Symposium on Melanoma and Other Cutaneous Malignancies

is a 1-day educational and scientific meeting that will address clinical topics aimed toward assisting oncology professionals to stay current and better serve their patients. The event will be held at the Eden Roc in Miami on February 20

This year&rsquo;s sessions will focus on immunotherapies, targeted therapies, regional therapy, and integrated medicine/patient care. The symposium will offer access to renowned international experts in the management of cutaneous malignancies.

Jeffrey Weber, MD, PhD, deputy director, Laura and Isaac Perlmutter Cancer Center and professor of medicine, NYU Langone Medical Center will co-chair this year&rsquo;s program with Omid Hamid, MD.

with Hamid, who is chief, translational research and immunotherapy and director, melanoma therapeutics at The Angeles Clinic and Research Institute in California.

What transformative treatments in melanoma will be discussed during the

to assist oncology professionals in their clinical practice?

There are multiple &lsquo;new&rsquo; therapies that have quickly progressed from trials to the clinic. The first of these would be oncolytic therapy with T-VEC (

. This is a therapy for local and in-transit melanoma that has shown significant activity. Given that T-VEC is a new immunotherapy, with special considerations for injection and delivery, we will focus on this new class of therapies with a great discussion from Robert H. Andtbacka, MD. We will also discuss the expanded role of oncolytic therapy in combination with standard checkpoint inhibition.

Speaking of checkpoint inhibition, its role in the adjuvant setting and in the control of difficult-to-treat situations, including brain metastases, will also be explored. Most physicians today are aware of the combination approval of ipilimumab and nivolumab. At this meeting we will focus on the most recent data in relation to efficacy, toxicity, and management.

One new feature of the meeting will be the Medical Crossfire between

and Michael B. Atkins, MD in relation to immunotherapy versus targeted therapy in the first-line setting. It promises to be not just interesting and educational, but fun also. &nbsp;I can&rsquo;t wait! &nbsp;

assist oncology professionals in designing personalized treatment regimens for patients?

Because the field has grown and treatment options have increased, the

will assist oncology professionals in understanding the role of newer therapies: targeted, immunological, and combinatorial for their patients. We will focus on the growing evidence related to predictive markers and prognostic markers that will help oncologists to make rational decisions in the first line and beyond. Newer data will be presented related to clinical options for patients who have now progressed on standard immunotherapy and targeted therapy, in an effort to emphasize the role of clinical trials in further improving patient outcomes. A participant in this meeting will get first-hand knowledge, based on experience, in relation to the newer therapies that have now been approved and are available in their clinics. It is hard to keep up with all of the data that has come out in the past 6 months in an ever-changing environmentat the

one can get top-of-the-line data from the pioneers in the field.  My favorite part of this meeting is the question and answer session and the patient cases that bring real-world situations in to the meeting.

What investigational strategies in late-stage development promise to further change the treatment of patients with melanoma in the near future?

Newer checkpoint inhibitors (GITR, OX40, and CD40), tumor micro-environment targets (such as CSF1R and IDO inhibitors), and local injectables (PV10 and T-VEC) have changed the landscape of immunotherapy for melanoma.

We have also seen the rise of bispecific antibodies, such as the Immunocore product, IMCgp100, which has shown minimal toxicity and the promise of response even in ocular melanoma. CAR-T therapy will also be discussed.

Of course, one cannot forget that the field of melanoma therapy has moved past single-agent therapy and is now focused on combinatorial therapy. With the recent approval of ipilimumab and nivolumab and the combination&rsquo;s high response rate, we are now focusing on combination therapy. At the

12th Annual International Symposium on Melanoma,

we will focus on newer combinations that have shown initial promises of higher response rates, with surprisingly low toxicities (IDO/pembrolizumab; TVEC/pembrolizumab; BRAF/MEK/PD-L1).

Who will be the key speakers at the symposium, and what will be some of the key presentations of interest?

assistant professor of medicine at the hospital of the University of Pennsylvania will present on immunotherapy in the frontline setting. Michael Postow, MD, assistant attending physician and researcher at Memorial Sloan Kettering Cancer Center, will detail new and emerging options for immunotherapy. Michael B. Atkins, MD, deputy director and professor at the Lombardi Comprehensive Cancer Center will review adjuvant options. Jeffrey Weber, MD, PhD, deputy director and co-director of the melanoma program at NYU Langone Medical Center&rsquo;s Laura and Isaac Perlmutter Cancer Center will cover options available for the patient with BRAF-mutant disease.

With the approval of immunotherapies for treatment in melanoma, how will this symposium help oncology professionals to make treatment choices in the first-line setting?

As immunotherapy&rsquo;s role has increased in melanoma, so has its role in the care of other solid tumors. With the recent approvals in lung cancer and renal cell carcinoma and the breakthrough designation for Hodgkin, Merkel cell, and bladder cancer, we are on the verge of clinics that mimic my research programall patients being treated by immunotherapies and targeted therapies. Understanding the kinetics of response, toxicities, biomarker data, and role for combination therapy will be tantamount for success in the future for all of our patients. As combination therapies are coming for all of these solid tumors, this meeting can set the foundation for success and rationale treatment decision-making for a variety of patients.

For more information, or to register for the The

Articles

Omid Hamid, MD, discusses the upcoming Annual International Symposium on Melanoma and Other Cutaneous Malignancies.

International Symposium on Melanoma May Set Foundations for Clinical Decision Making

With three new drug approvals in November 2015, the treatment paradigm for multiple myeloma is rapidly evolving. At the American Society of Hematology (ASH) 57

Annual Meeting & Exposition, Ajai Chari, MD, presented results of a phase I/IIb study that explored the combination of ibrutinib and carfilzomib with or without dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma.

The study authors concluded that the combination of the three agents were well tolerated with no dose-limiting toxicities and no increase in severity of known toxicities for the individual drugs. The third cohort of the study that included the higher dose of ibrutinib (840 mg/d) along with carfilzomib and dexamethasone saw the most promising results with a preliminary overall response rate (ORR) of 58%, with one stringent complete response and three very good partial responses. Cohort 3b was established as the recommended phase II dose and is being further evaluated in the phase II portion of the study.

Can you detail the findings of the combination study of ibrutinib with carfilzomib in patients with relapsed, or relapsed/refractory multiple myeloma?

The carfilzomib and ibrutinib combination clinical trial is a phase Ib/II clinical trial done as a multi-institutional study in patients who are relapsed and refractory and have taken both bortezomib and an immunomodulatory drug in the past. The study summarizes the phase Ib safety, as well as the phase II expanded portion efficacy data.

The median prior lines of therapy for these patients was three. About a quarter of the patients had been exposed to carfilzomib and pomalidomide in the pasttruly a relapsed and refractory patient population.

This study was just one of several studies discussed at the ASH Annual Meeting, which currently focus on combination treatments in multiple myeloma.

spoke with Saad Usmani, MD, director of the Plasma Cells Disorder Program at the Levine Cancer Institute in Charlotte, North Carolina, about newly approved treatments, as well as these combination therapies currently in clinical trials.

The response rates that were seen with this combination, the whole group, were about 58%. A total of 58% partial response (PR) or better, and 67% clinical benefit rates. There were a subgroup of patients [that had] less than a PR, but still benefited from being on therapy. In terms of safety, there were no significant dose-limiting toxicities (DLT) seen, and the cohorts in the phase Ib portion filled up fairly quickly. Since these are very encouraging results, I believe there are plans to do a further dose expansion and perhaps plan a phase III study in the future.

Were there adverse events (AEs) experienced by patients in the study?

Nothing unexpected. We do appreciate, that within relapsed/refractory patients, there are infectious complications or certain complications that are already known and attributable to carfilzomib and ibrutinib, but the combination didn't see any new safety signals.

Do you think more combination therapies, such as this one, are on the horizon for treating multiple myeloma?

Yes, I believe so. The main idea is to develop different platforms from the classical immunomodulatory drug/proteasome inhibitor platform and try to approach the disease, perhaps, differently mechanistically. As the myeloma cells, malignant myeloma cells, become savvy with these relapses, you find specific ways of targeting those patients with relapsed/refractory myeloma. I think the main challenge will be, &ldquo;Which combination works for which patient?&rdquo; We will be relying more on molecular profiling of patients, and determining therapies based on that.

Can you provide information about the phase II study with carfilzomib and filanesib?

The carfilzomib with or without filanesib is a randomized phase II study, again, done in a multi-institutional fashion. Jeff Zonder, MD, will be presenting these data at ASH this year. The study was a 2-to-1 randomization between carfilzomib, along with filanesib, and the other arm was carfilzomib, or commercial carfilzomib on its own. This particular study was going to be a segue into a broader phase III study, which would have mirrored the current design.

Overall, the combination of carfilzomib and filanesib did have activity. I think it was around 48%. In the carfilzomib-only arm, which included patients with high-medium prior lines of therapy, the response rate was around 14%. The combination of carfilzomib and filanesib [arm] saw an overall response rate of about 35%.

In terms of safety, I think myelosuppression has been recognized as a side effect of filanesib. There were grade 3 anemias, thrombocytopenias, and neutropenias that were seen in about one-quarter of patients, but they were, for the most part, reversible. Neutropenia was certainly reversible. The regimen was quite efficacious, and even in patients with high-risk cytogenetic features. The main question in follow-up to the study, now that we're seeing different dosing of carfilzomib coming out (in fact, in many studies being presented at ASH this year), is which would be the right carfilzomib dose to pick for the next phase III study with this combination?

There will definitely be a phase III study, correct?

Yes, and I do want to highlight the fact that this is yet another example of a different platform. Filanesib is a kinase and spindle protein inhibitor. Even though, intuitively, myeloma is a less proliferative disease, when it comes to relapsed/refractory disease, that proliferative component tends to be much higher, especially in high-risk patients. It [the combination] does certainly have its place in the field, and I think this combination is the right step forward. Finding the right carfilzomib dose will be the next question.

What is the mechanism of action for filanesib?  How does the drug work, and what kind of research still needs to be done with this drug?

We know quite a lot about this drug. Outside of myelosuppression, honestly, we don't see a lot of major safety signals. The way this drug is supposed to work is to stop the cell during mitosis, or cell division, by binding to the kinase and spindle protein, a specific kinase and spindle protein called KSB5. If we know about its mechanism of action, I think it's [the challenge is] finding the right partner and the dosage. I think adding it to the proteasome inhibitor (PI) platform is a good idea. It would be worthwhile to check it with other platform drugs such as immunomodulatory drugs (IMiDS), and now monoclonal antibodies.

Can you give an overview of the daratumumab as monotherapy study?

Sure. Daratumumab just got FDA approved less than a week ago. The current abstract talking about the clinical efficacy of daratumumab monotherapy is actually a combined analysis of two clinical trials. One is the phase II registration study that led to this drug's approval, and the other is a subset of patients from the original phase I/II trial, the GEN501 trial, where a subset of patients received the currently approved dose at 16 milligrams per kilogram.

A total of 148 patients were evaluated for response and safety signals, and the overall response rate that was found was around 31%. These patients had a median of 5 prior lines of therapy. Almost half of the patients who were exposed to both carfilzomib and pomalidomide, regardless of the prior lines of therapythe kind of drugs they were exposed to&mdash;the overall response rates were very similar. All subsets of patients benefited.

The only safety signal in the side effect profile was perhaps infusion reactions the first time the patients get the infusion. That appears to happen in less than half of the patients, mostly grade 1 and grade 2 infusion reactions that are mitigated by standard of care, supportive care measures. The patients are able to complete the infusions, and then it doesn't happen the second or the third time around. So it's once and done.

The key highlight of this presentation is not just that the patients who were on daratumumab and responding were benefiting, it appears that patients who even get a minimal response or stable disease, they appear to have some overall survival (OS) benefit, PFS, and OS benefit.

Do you foresee any ongoing trials? Should there be any more done with other combinations of daratumumab?

There are several large phase III trials, both in the upfront setting, as well as in the first relapse setting that are ongoing. Daratumumab in the upfront setting, has been combined with BTD, or with RVD, with VMP in the first, in the transplant ineligible setting. There's a large randomized phase III study looking at daratumumab with len/dex versus len/dex. The same holds true for the first-line setting as well. There's a combination trial comparing daratumumab with len/dex versus len/dex and daratumumab, bortezomib/dex versus bortezomib/dex. There's a lot of effort being put forth in developing this drug and trying to move it to the upfront setting. There's also a provocative phase II trials in a smaller group of myeloma patients that is being initiated.

In many ways the anti-CD38 monoclonal antibodies are an extremely promising new platform drug that are being combined with available regimens, and the advantage here is the safety profile.

Can you comment on the recent approval of daratumumab for multiple myeloma, and the significance of it?

When patients get to a double-refractory stage or beyond three prior lines of therapy, their PFS with each subsequent line of therapy tends to be shorted, and we're generally running out of options.

Saad Usmani, MD, discusses newly approved treatments, as well as these combination therapies currently in clinical trials.

New Age of Myeloma Management Offers Personalized Combination Treatments: A Q&A With Saad Usmani

With numerous newly approved drugs for patients with early-stage multiple myeloma reaching the clinics, understanding what drugs, combinations, and sequences to use has become an important area of research. Several recent studies have demonstrated increased efficacy with nominally increased adverse events in these triplet arms.

A paper, presented at the 57th Annual Meeting and Expedition of the American Hematology Association (ASH) looked at results of the randomized phase III SWOG S0777

trial, which studied bortezomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (without an intent for immediate autologous stem cell transplant).

The study authors concluded that the addition of bortezomib to&nbsp;lenalidomide and dexamethasone for induction therapy in previously untreated myeloma resulted in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and also an increased overall survival (OS).&nbsp;The triplet combination showed an acceptable safety and tolerability profile despite increased neurotoxicity. The authors believe that this could represent a potential new standard of care.

S. Vincent Rajkumar, MD, professor of Medicine at the Mayo Clinic, Rochester, Minnesota, and chair of the ECOG Myeloma committee, as well as the Mayo Clinic Myeloma Amyloidosis Dysproteinemia Group spoke with

during the 2015 American Hematology Society (ASH) annual meeting to discuss this trial and other recent trials of triplet therapies in the treatment of early-stage multiple myeloma.

: Please provide an overview of the study on bortezomib, lenalidomide, and dexamethasone versus lenalidomide plus dexamethasone in patients with previously untreated multiple myeloma.

Brian Durie, MD, presented the SWOG study, which compared lenalidomide, bortezomib, and dexamethasone versus lenalidomide and dexamethasone. This is a classic triplet versus doublet study. It was conducted in patients with newly-diagnosed multiple myeloma. Patients were treated until progression, and the key findings of the study were that the response rates were much higher with the triplet combination compared with lenalidomide and dexamethasone. Progression-free survival (PFS) was longer. But the most important finding is that overall survival (OS) was also prolonged significantly with the bortezomib, lenalidomide, dexamethasone combination.

This, of course, is a major finding. It is one of the first trials in which a modern triplet has come out on top in OS. And as a result, at the Mayo Clinic, we have changed our guidelines to bortezomib, len/dex as our standard for frontline therapy.

How do you think that this information will impact clinical practice?

I think in clinical practice there have been a number of regimens used in multiple myeloma for frontline therapy in the United States. The NCCN, for example, on their website recommends approximately 20 different regimens for newly-diagnosed myeloma. This actually gives physicians more clarity, I think. Today, this is probably the only regimen, modern regimen, which has a clear OS benefit over the other competitors. I think maybe there'll be some more uniformity in practice in that unless there are problems with cost or lack of access or availability, I think bortezomib, len/dex would be kind of a standard frontline regimen for patients [with untreated multiple myeloma].

We do recommend nowadays a different dosing schedule for bortezomib than was used in the trial. The once-weekly subcutaneous schedule is what we are using, and that's what we would continue to use.

The tolerability between the two different arms was similar. Were there any additional toxicities found?

Mostly the same. There's always going to be extra side effects when you use a triplet combination, and those were seen, but they were, by and large, as expected and not something that we cannot manage. Neuropathy was much higher than what we'd like to see. However, like I said, if we use the once-weekly subcutaneous schedule of bortezomib, which should be much lower, and may even prove to be more efficacious because we can give treatment for a longer period of time.

Do you foresee any other combinations with bortezomib that you think might occur for this population?

The other combination that's being used with bortezomib, the other two combinations are bortezomib, thalidomide, dex, and bortezomib, cyclophosphamide, dex; those have been used in the United States as well. We heard about another trial yesterday where bortezomib, thalidomide, and dex was compared with bortezomib, cyclophosphamide, and dex, and the bortezomib, thalidomide, and dex [arm] had higher response rates.

In the United States, we do have the option of using lenalidomide, which is a more modern immunomodulatory drug than thalidomide, and that's why bortezomib, len/dex will take over here.

We are doing a trial right now in ECOG [Eastern Cooperative Oncology Group] looking at bortezomib, len/dex versus carfilzomib len/dex. Carfilzomib len/dex, of course, is a little bit more cumbersome but may have more response rates, and time will tell us how that fares against this bortezomib, len/dex combination.

Can you talk about some of the recent FDA approvals that have occurred and what this means for the field?

Yes. We have had two new drug approvals in 2013: carfilzomib and pomalidomide. Earlier this year, panobinostat was approved. More exciting right now is that in 3 weeks, the FDA approved three drugs: ixazomib, daratumumab, and elotuzumab. Two of these are monoclonal antibodies: elotuzumab and daratumumb; the first monoclonal antibodies we've ever had in multiple myeloma. They target different antigens. Elotuzumab targets SLAM-F 7, daratumumab targets CD38. The third drug that was approved is ixazomib, which is the first, oral proteasome inhibitor to be approved.

I expect all three of them to have a major impact in the treatment of multiple myeloma. It's such an exciting time that it's almost unprecedented that the FDA is here at ASH, and there will be a joint FDA/ASH symposium tomorrow evening, where we will be discussing how these new drugs are going to be impacting clinical practice. We&rsquo;re going to have the FDA present the rationale for why they approved the three drugs. Then Paul Richardson, MD, and myself will be discussing how these new drugs should be used in clinical practice.

What do you think, with all these new agents now available, will be the optimal sequencing? When is the best time to use them all and how?

I think this is going to be a big problem, because I think we need to be very cautious not to jump in with the latest phase II study and change practice, because sometimes that may end up giving us the wrong outcome. It's important to wait for well-designed phase III trials, except perhaps in the high-risk population, where you might need things to move a little bit quicker. It's going to be challenging to incorporate new antibodies into frontline therapy because frontline therapy is already associated with such an excellent outcome.

You are talking about 80% 3-year, 4-year survival rates, and it's going to be hard to improve on them in a short period of time. We have to look at new surrogate endpoints, and one of them that is very prominent now is MRD-[minimal residual disease-]negative state. If we can get to MRD-negative state and use it as a surrogate endpoint for better long-term outcomes, then I think we'll be able to answer these questions in a more rapid fashion. I think the key is well-designed randomized trials. Use really intelligent, smart endpoints, and then find the answers into how best to use these drugs.

There's also some pretty important data on daratumumab that was presented. Can you comment on that?

Daratumumab is the latest drug approved that's a monoclonal antibody against CD38. So far, the results have been with monotherapy primarily. In monotherapy, in the relapsed refractory setting, it works in about 30% of patients who have failed everything else. In this meeting, we have data on daratumumab combined with lenalidomide and dexamethasone into a nice triplet combination, and in the same relapsed refractory population, you are seeing a high level of response, 88% is being reported, and that is very exciting for the field.

With numerous newly approved drugs for patients with early-stage multiple myeloma reaching the clinics, understanding what drugs, combinations, and sequences to use has become an important area of research. Several recent studies have demonstrated increased efficacy with nominally increased adverse events in these triplet arms.


Triplets in Newly Diagnosed Multiple Myeloma: A Q&A With S. Vincent Rajkumar, MD 

The phase III PILLAR trial, which is studying the novel immunotherapy algenpantucel-L combined with chemotherapy in patients with locally advanced, unresectable pancreatic cancer, has completed its enrollment with over 300 patients, according to a press release

from the manufacturer, NewLink Genetics Corporation.

&ldquo;Obtaining a treatment response with conventional therapies has been difficult. The hope is that combining these therapies with algenpantucel-L immunotherapy will result in an increased rate of tumor down-staging such that we can get more patients to surgical resection, which is the most effective treatment for pancreatic cancer,&rdquo; said Harish Lavu, MD, associate professor of surgery, Thomas Jefferson University, and lead investigator for PILLAR, in an interview with

will randomize patients with borderline resectable or locally advanced, unresectable pancreatic cancer who have an ECOG performance status of &le;1, to either an algenpantucel-L plus chemotherapy arm or chemotherapy alone arm. Patients receiving algenpantucel-L will be given 300 million cells by interdermal injection on days 1 and 8, followed up by doses every 2 weeks for up to 18 doses. These will be combined with FOLFIRINOX administered on days 22, 36, 50, and 64. The chemotherapy-alone arm will receive FOLFIRINOX on days 1, 15, 29, 43, and 57.

Patients with active metastases were disqualified for the study, as were those receiving immunosuppressive therapy or chronic systemic corticosteroid therapy. The study's primary endpoint is overall survival (OS) with a secondary endpoint being progression-free survival. Frequency and grade of adverse events (AEs) of the combination therapy will also be observed. The estimated study completion date is June 2017.

Algenpantucel-L, is also being studied in the larger phase III IMPRESS trial. This trial includes 722 patients with surgically resected pancreatic cancer.

The phase III IMPRESS trial followed positive results from the IMPRESS phase II trial, where patients administered algenpantucel-L plus standard of care therapy experienced an 81% disease-free survival (DFS) and an OS of 96%.

The phase II multicenter, open label trial

evaluated algenpantucel-L plus chemotherapy in 69 patients with resected pancreatic cancer in the adjuvant setting. Patients received either 100 million cells/dose or 300 million cells/dose given intradermally with gemcitabine 1000 mg/m

, within 6 weeks following surgery. Patients completing therapy received up to 14 doses of algenpantucel-L. The primary objective was DFS defined as the percentage of patients with no disease recurrence 12 months following surgery. Secondary objectives included OS and toxicity. Grade 3 AEs were <12% and included fatigue, injection site reaction, pain, and lymphopenia.

Algenpantucel-L has received fast-track status and orphan drug designation from the FDA. NewLink Genetics and the FDA agreed in January 2010 on a Special Protocol Assessment regarding the trial design, clinical endpoints, and a statistical analyses plan for IMPRESS to be used in support of a Biologic License Application (BLA).

According to the NewLink Genetics&rsquo; website,

algenpantucel-L consists of two altered pancreatic cancer cell lines (HAPa-1 and HAPa-2) modified to express galactose-

-1,3-galactose, or alpha-gal, a mammalian oligosaccharide epitope found in most organisms&rsquo; cell membranes, but not in primates.

Proposed mechanism of action for algenpantucel-L. Image courtesy of NewLink Genetic Corporation.

The premise behind the mechanism of action for algenpantucel-L is that pre-existing anti-alpha-gal antibodies target the drug in vivo. Algenpantucel-L cell debris may then be taken up and processed by the immune system. Cancer-specific antigens resulting from this process may then be shared by cancer cells in the patient, which allows the immune system to recognize and destroy the cancer.

&ldquo;The drug works to train the patient&rsquo;s immune system to recognize their pancreatic cancer as being foreign and to mount an immune response against it,&rdquo; Lavu said. &ldquo;There is an unmet need among patients with locally advanced as well as resectable pancreatic cancer. This trial is designed to test whether or not algenpantucel-L is effective in improving outcomes among these patients.&rdquo;&nbsp;

NewLink Genetics. December 15, 2015. NewLink Genetics Corporation completes enrollment of phase 3 PILLAR trial evaluating algenpantucel-L for patients with locally advanced pancreatic cancer.

http://investors.linkp.com/releasedetail.cfm?ReleaseID=946998

ClinicalTrials.gov Identifier: NCT01836432.

https://clinicaltrials.gov/ct2/show/study/NCT01836432?view=record

Nasdaq GlobeNewswire. NewLink Genetics IMPRESS phase 3 pancreatic cancer trial with algenpantucel-L to continue following second interim analysis.

http://globenewswire.com/news-release/2015/05/11/734701/10133840/en/NewLink-Genetics-IMPRESS-Phase-3-Pancreatic-Cancer-Trial-with-Algenpantucel-L-to-Continue-Following-Second-Interim-Analysis.html

http://www.newlinkgenetics.com/platforms/hyperacute-immunotherapies/pancreatic-cancer/

Commins SP and Platts-Mills TA. Delayed anaphylaxis to red meat in patients with IgE specific for galactose alpha-1,3-galactose (alpha-gal).

. 2013 Feb;13(1):72-7. doi: 10.1007/s11882-012-0315-y.

The phase III PILLAR trial studying the novel immunotherapy, algenpantucel-L combined with chemotherapy in patients with locally advanced, unresectable pancreatic cancer, has completed enrollment with over 300 patients.

Novel Immunotherapy for Pancreatic Cancer May Allow for Resection of the Unresectable 

Breaking the blood-brain barrier has presented a frustrating hindrance for medical oncologists in the treatment of brain cancers like glioblastoma multiforme (GBM). Xu Ting, PhD, of Lawrence Berkeley National Laboratory (Berkeley Lab), in collaboration with Katherine Ferrara at University of California (UC) Davis and Krystof Bankiewicz of UC San Francisco, along with their colleagues, have conducted preclinical trials

of a novel drug nanocarrier, 3HM, that may offer a solution to this obstacle.

Xu, associate professor, Departments of Materials Science & Engineering and Chemistry at UC Berkeley, specializes in design, synthesis, and characterization of

designed peptides. According to a Berkeley Lab news release, Xu developed 3HM (coiled-coil 3-helix micelles), a new family of nanocarriers, which were formed from the self-assembly of amphiphilic peptides and polymers.

3HM was tested on GBM tumors in rats, and imaged using co-registered positron emission tomography (PET) and magnetic resonance (MR) imaging (

). The researchers investigated how a nanocarrier's size affects the pharmacokinetics and biodistribution in rodents with a GBM xenograft in an effort to compare the 3HM nanocarrier with the larger, FDA-approved nano-delivery systems. According to the news release, the team demonstrated that 3HM can cross the blood-brain barrier and accumulate inside GBM tumors at nearly double the concentration rate.

PET and MR imaging of mouse models showing coronal and transverse sections comparing conventional liposomal delivery system with 3HM.

&ldquo;[The results] showed the feasibility to have nanocarriers accumulate in GBM tumor tissue selectively while maintaining optimal pharmacokinetics and biodistribution. They opened a viable path to access GBM via IV injection therapeutically,&rdquo; Xu said, in an interview with

. The findings led Xu and her colleagues to question why 3HM behaves so well

, whether or not they can fully understand the design principle, and if they can improve upon the design for other neurological diseases.

&ldquo;Our 3HM nanocarriers show very good attributes for the treatment of brain cancers in terms of long circulation, deep tumor penetration, and low accumulation in off-target organs such as the liver and spleen,&rdquo; said Xu in the news release.

The researchers have studied 3HM for other cancer types as well, according to Xu. &ldquo;Up to this point, all the results are very consistent that 3HM has circulation half-live of about 30 hrs, selective accumulation in a variety of tumor tissue, very deep tumor penetration, and very low accumulation in other vital organs,&rdquo; she said.

According to the Berkeley Labs news release, GBM therapeutics are transported across the blood brain barrier in liposomes that are approximately 110 nanometers in size; the 3HM nanocarriers developed by Xu and her colleagues are only about 20 nanometers in size. The news release maintained that the smaller size and unique hierarchical structure of the 3HM nanocarriers allowed greater access to rat GBM tumors than did the 110-nanometer liposomes.

Xu and her colleagues stumbled on the idea for 3HM while studying the hierarchical assembly of amphiphilic peptide-polymer conjugates. She and her group noticed the unusual behavior of the micelles, notably their unusual kinetic stability in the 20 nanometer-size range. She and her team then looked into the critical needs for nanocarriers with these attributes and identified the treatment of GBM cancer as a potential application.

&ldquo;I thought our 3HM hybrid materials could bring new therapeutic opportunities for GBM, but I did not expect it to happen so quickly,&rdquo; said Xu in the news release. Xu has been awarded a patent for the 3HM technology and would like to take this technology to the next level of trials.

&ldquo;We really want to do further tests of drug-loaded 3HM as potential therapeutics for different types of cancers,&rdquo; Xu said. &ldquo;We just need to find partners in the biomedical field who share common interests.&rdquo;

Berkeley Lab News Center. Nanocarriers may carry new hope for brain cancer therapy. http://newscenter.lbl.gov/2015/11/19/nanocarriers-may-carry-hope-for-brain-cancer/. Accessed November 19, 2015

Seo JW, Ang JC, Mahakian LM, et al. Self-assembled 20-nm 64Cu-micelles enhance accumulation in rat glioblastoma. J Control Release. 2015;220(28A):51-60.

A team of scientists have conducted preclinical trials of a novel drug nanocarrier, 3HM, that may offer a solution to breaking the blood-brain barrier in the treatment of brain cancers like glioblastoma multiforme.

Novel Nanocarrier Could Penetrate Blood-Brain Barrier in Glioblastoma

Banner MD Anderson Cancer Center and other select medical centers nationwide are now offering blue-light cystoscopy (BLC) imaging to better detect papillary cancer of the bladder.

While white-light cystoscopy (WLC) has been the mainstay for viewing suspicious lesions during surgery to remove these tumors, a press release from Banner maintains that harder-to-see tumors may be missed using this methodology alone.

&ldquo;The potential of blue-light cystoscopy and Cysview is to identify more bladder tumors and aid in a more complete resection, which is very important in optimally treating bladder cancer,&rdquo; said Joseph Mashni Jr, MD, a surgeon at Banner MD Anderson, in the press release.

BLC works by illuminating the tumorous tissues with a fluorescent chemical called hexaminolevulinate HCI (Cysview).

The chemical is placed in the bladder and absorbed by cancer cells, turning them hot pink under the blue light.

Cysview is FDA approved for use with BLC for cystoscopic detection of non-muscle invasive papillary cancer&nbsp;of the&nbsp;bladder&nbsp;among patients suspected or known to have lesion(s) on the basis of a prior&nbsp;cystoscopy. According to the Cysview website, the agent is used with KARL STORZ D-Light C Photodynamic Diagnostic System in the blue-light setting as an adjunct to the white-light setting.

Prior to imaging, a catheter is inserted into the urethra and about 2 ounces of the imaging solution is placed inside the bladder. This is left in place for 1 hour so that the bladder is ready for cystoscopy.

After first using white light, the doctor switches to the blue-light mode. The absorption of the imaging agent allows other hard-to-see tumors to become more visible, standing out against normal bladder tissue and making it easier for the doctor to identify and remove them.

Recurrence is common in patients with non-muscle-invasive bladder cancer (NMIBC), prompting the necessity of thorough follow-up imaging. Sylvester et al estimate recurrence rates (5 years post diagnosis) of 31% to 78% in low- and high-risk subgroups, respectively.

studied the safety and cost effectiveness of the blue-light method in 2013. They compared BLC to WLC at the time of initial transurethral resection of the bladder tumor (TURBT). Three potential outcomes established in the study included: recurrence monitoring for patients with proven NMIBC, ongoing monitoring for patients in whom no bladder cancer was found, and muscle-invasive surveillance for patients diagnosed and treated for MIBC. Data showed that patients in the BLC group avoided higher cancer burden for recurrent or progressive disease upon follow-up, with an 11% improvement.

According to the Cysview website, the imaging agent is not a replacement for random bladder biopsies or other procedures used in the detection of bladder cancer, and it is not for repetitive use.

Banner Health [press release]. Blue light procedure helps Banner MD Anderson doctor better detect bladder cancer. http://www.bannerhealth.com/About+Us/News+Center/Press+Releases/Blue+light+procedure+helps+Banner+MD+Anderson+doctor+better+detect+bladder+cancer.htm. Accessed November 17, 2015.

Cysview. What is blue light cystoscopy with Cysview? https://www.cysview.com/blue-light-cystoscopy-with-cysview-2/what-is-blue-light-cystoscopy-with-cysview/. Accessed November 17, 2015.&nbsp;

The University of Texas MD Anderson Cancer Center. Bladder cancer: blue light cystoscopy. http://www.mdanderson.org/patient-and-cancer-information/cancer-information/cancer-types/bladder-cancer/diagnosis/cysview.html. Accessed November 17, 2015.

Sylvester R, van der Meijden A, Oosterlinck W, et al. (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials.&nbsp;Eur Urol&nbsp;49(3):466-475;.

Garfield S, Gavaghan M, Armstrong S, Jones J (2013) The cost-effectiveness of blue light cystoscopy in bladder cancer detection: United States projections based on clinical data showing 4.5 years of follow up after a single hexaminolevulinate hydrochloride instillation.&nbsp;Can J Urol&nbsp;20(2):6682-6689.

Select medical centers nationwide are now offering blue-light cystoscopy imaging to better detect papillary cancer of the bladder.