The Academy: June 9, 2010

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University of Alabama, Birmingham

Second-Generation Monoclonal Antibody Demonstrates Benefit in Treatment-Resistant Follicular Lymphoma

Results from early-stage, preliminary (phase I) data presented by a team of University of Alabama researchers suggests that a second-generation, highly targeted monoclonal antibody may offer new hope for patients with follicular lymphoma (a particularly difficult to treat subtype of non-Hodgkin’s lymphoma) who have failed other treatments.

In all, 22 immune-cell variant patients have enrolled in the study and received regular treatment with the experimental agent AME-133v. Of the participants, 20 had received unsuccessful prior treatment with rituximab (Rituxan) and 19 had also had chemotherapy. For the dose escalation phase of the study, 20 of the 22 participating patients were eligible to be evaluated. Researchers reported that the agent was well tolerated at all dosages. Only two (10%) participants reported anything beyond minor (grade I) adverse events. For the interim analysis of clinical benefit, 16 of the 22 subjects were evaluable. Of 16 patients that have been analyzed so far, four (25%) have attained either a partial response (PR) or a complete response (CR) to the novel therapy AME- 133v. Two of the four responding subjects demonstrated PR and two showed CR.

Commenting on the results, Andres Forero, MD, the study’s lead investigator, University of Alabama, Birmingham, Comprehensive Cancer Center, stated, “These first results suggest that AME- 133v provides a mechanism of action that may be more potent and ultimately more effective than the treatments we have on hand for a subset of patients with this cancer (who demonstrate immune cell variation or mutation). Monoclonal antibodies were the first successful targeted therapy for cancer, and we have now moved on to a whole new class of second-generation antibodies for the treatment of many different lymphomas. This is an exciting time.”

According to Dr. Forero, the interim results are robust enough to warrant continued study. “Given these encouraging (phase I) results, patients are currently being enrolled in a phase II study,” he reported.

The majority of patients in the study (20 of 22) either did not initially respond to—or relapsed after—the use of rituximab, the first monoclonal antibody therapy approved for use in lympho- ma treatment. AME-133v is a second-generation therapy that is believed to be a more specific treatment for follicular lymphoma in general, compared with rituximab, but is also thought to offer particular benefits for those patients who have a variant in the immune cells needed to attack the cancer.

Although treatment with rituximab as a single agent has resulted in significant responses in patients with almost every subtype of B-cell lymphoma, including follicular lymphoma, recent evidence has shown that some patients with effector immune cells that carry a mutation in the receptor protein FcγRIIIa 158-F do not have the same response. This is an issue that is related to the patient’s own biological makeup, not to the cancer cells themselves, he adds. There are three different classes of Fcγ receptors to which the monoclonal antibody binds on leukocyte effector cells—T helper cells—that direct other immune cells to the antigen. Response to rituximab depends on variants in the receptors these helper cells use.

AME-133v is an anti-CD20 antibody engineered to bind more strongly to these variant receptors. In preclinical studies, it demonstrated a 10-fold improvement in killing power of human B cells, compared with rituximab, researchers reported.

“AME-133v appears to be capable of binding with high specificity to cell-surface antigens, resulting in targeted killing of malignant cells, relative sparing of normal tissues, and low toxicity,” Dr. Forero concluded.

The data were presented during a recent poster session at the annual meeting of the American Association for Cancer Research in San Diego.

University of Buffalo

Gum Disease and Human Papillomavirus Linked to Tongue Cancer

The presence of gum disease in conjunction with human papillomavirus (HPV) can markedly increase tongue cancer risk, according to a new study conducted by researchers at the University at Buffalo School of Dental Medicine.

Previous studies have found that periodontitis, which destroys connective tissue and bone supporting the teeth, and HPV, each pose increased risks of cancer in the head, neck or tongue. The University of Buffalo research, however, is the first to suggest that the two conditions may work in tandem.

In a study of 30 patients newly diagnosed with squamous cell carcinoma on the base of the tongue, 63% (19 patients) had tumors testing positive for a common type of HPV. In addition, 90% of the patients with HPV-positive tumors had periodontitis, and 79% of patients whose tumors showed no presence of HPV did not have periodontitis.

“Evidence of periodontitis—HPV synergy has important practical implications, because there is a safe treatment for periodontitis but no treatment for HPV infection. If these results are confirmed by other studies, this has tremendous relevance in predicting and intervening in the initiation and prognosis of HPV-related diseases, including head and neck cancers,” stated lead investigator Mine Tezal, MD, Department of Oral Diagnostic Sciences, University of Buffalo, in a prepared statement released when these data were announced.

Dr. Tezal added that “persistence of HPV infection is the strongest risk factor for carcinogenesis. Thus, the identification of factors that influence the persistence of HPV infection is critical to facilitate efforts to prevent head and neck cancers. This study implicates that chronic inflammation and co-infection with oral bacteria may be significant factors in the natural history of HPV infection.”

Most people contract HPV infection at least once in their lives, but one’s immune system often fights it off without incident.

Dr. Tezal presented the findings during the annual meeting of the American Association of Dental Research in Dallas.

Georgetown University Medical Center

Researchers Penetrate Key Ewing’s Sarcoma Mystery

Disclosing a discovery that sheds light on the mechanisms of Ewing’s Sarcoma and is likely to be applicable to advances in the treatment of the disease, Georgetown University Medical Center researchers have identified a molecule that disrupts the oncogene that causes Ewing’s sarcoma, a cancer that strikes children and young adults and can cause tumors to grow anywhere in the body.

According to the research findings of the Georgetown team, Ewing’s sarcoma occurs when there’s an exchange of DNA between two chromosomes, a process called translocation. The EWS gene on chromosome 22 fuses to the FLI1 gene on chromosome 11, creating a new gene called EWS-FLI1, which produces the fusion protein that causes the cancer.

If further research shows that this newly identified molecule is effective, it could offer the first targeted therapy to treat Ewing’s sarcoma, the researchers said. The molecule works through a so-called protein—protein interaction and could provide a model upon which to design other therapies.

“I think this holds really wonderful promise as a unique way of targeting fusion proteins,” stated lead investigator Jeffrey Toretsky, MD, Lombardi Comprehensive Cancer Center, Georgetown University, Washington D.C. “People thought it wasn’t possible to have a small molecule that can bind between flexible proteins, but we have shown that it can be done,” explained Dr. Toretsky, who noted that the study was conducted in laboratory cells, so further research is needed before the molecule can be tested in humans.

The study was presented by Dr. Toretsky at the annual meeting of the American Association for Cancer Research in San Diego.

The current standard treatment regimen for Ewing’s sarcoma involves a combination of five different chemotherapy drugs. Although the therapy is somewhat efficacious (an estimated 60% to 70% of patients survive over time), many patients experience lingering health effects from the multiple lines of chemotherapy required.

Case Western Reserve University School of Medicine

Throat Cancer Linked to Obesity

For the past few decades, incidence of both throat cancer and obesity has been on the rise. These two increases may not exist independently of each other, according to new research data from Case Western Reserve University School of Medicine scientists. The Case Western study team makes the case that the two health conditions, which, at first glance, appear to be completely unrelated to one another, may actually be intimately connected. In fact, the Case Western researchers are asserting that our weight-gain as a society may very well be a prime mover fueling the increase in throat cancer.

Specifically, the rising incidence of throat cancer, also referred to as cancer of the esophagus or esophageal adenocarcinoma, may be related to the underlying cause behind rising American obesity rates: increasing intake of total and refined carbohydrates.

The researchers, all associated with Case Western Reserve University and University Hospitals of Cleveland, in Ohio, compared National Cancer Institute data for esophageal adenocarcinoma (1973—2001) and food consumption information from the National Nutrient Data Bank (1909–1997). The researchers found a trend toward higher intakes of refined carbohydrates; those with more starch and lower nutrient levels than carbohydrates obtained from whole grains and minimally processed foods.

The incidence of esophageal adenocarcinoma increased over the review period and “strongly correlated” with carbohydrate consumption. This cancer is also known to be strongly associated with gastroesophageal reflux disease (GERD), which, in turn, is associated with obesity and a high carbohydrate intake.

By contrast, they noted a decrease in the rates of squamous cell cancer of the esophagus, which is more closely associated with smoking rather than reflux disease and obesity.

“The similarity in these trends gives further evidence for the association of carbohydrate intake, obesity, and related measures with cancer,” stated lead investigator Cheryl L. Thompson, MD, Case Western Reserve University.

Dr. Thompson and colleagues cautioned, however, that such observations do not necessarily reflect individual risk for esophageal adenocarcinoma. Additional research is needed to assess individual risk from high intake of refined carbohydrates, added Dr. Thompson.

The findings, concluded researchers, highlight the importance of limiting refined carbohydrates in the American diet.

University of Arizona

Preventive Colon Cancer Combo Radically Decreases Disease Risk

In newly released research, scientists from the University of Arizona are touting a new drug therapy combination that they assert has the potential to revolutionize colon cancer treatment.

The University of Arizona data demonstrated that the novel treatment—a combination of the drug DFMO (difluoromethylornithine) with sulindac (Clinoril), an anti-inflammatory medication— slashes the disease threat in high-risk patients by as much as 90%.

The drug regimen was evaluated in a preventive context: the study subject population who received the therapy did not yet have colon cancer but had all developed precancerous colon polyps, a major and significant risk factor for the eventual development of the disease.

Research findings indicated that overall, the likelihood of the development of more dangerous polyps was cut by 70% in patients who underwent combination therapy for a period of three years. In the highest risk group— patients who had large or multiple polyps— the risk of recurrence was decreased by 95%. The 95% drop in risk represents more than a doubling of preventive effect when compared with other known colon cancer therapies, including aspirin.

“This has really hit a home run,” said David S. Alberts, MD, director of the Arizona Cancer Center, where about 50 of the 300 patients in the study were tested and where much of the basic research and patient analysis was conducted.

“It is by a long shot the most effective therapy we have found to prevent this cancer, with very little toxicity,” Dr. Alberts said.

In a cautionary note, researchers warned that the DFMO-sulindac therapy faces at least two more years of clinical trials before it will be “ready for primetime” use in the United States.

“Although the five clinical trials we have completed show this therapy to be no more toxic than plain aspirin, we are always concerned about that issue and want further testing before this goes to the general population,” said study co-investigator Eugene Gerner, MD, University of Arizona Cancer Center, Tucson.

Results were presented at the annual meeting of the American Association for Cancer Research in San Diego.

University of California, Los Angeles

Novel Drug Delivery System Driven by Spectacular Technology

At first glance, it sounds like something out of a futuristic science fiction film or an episode of `Star Trek’: cancer therapies delivered via tiny machines, so small that they fit inside the human cell. The seemingly unbelievable medical advance is not fictional, however. Rather, it is the result of research and development efforts led by a team from the Nano Machine Center at the University of California, Los Angeles’s NanoSystems Institute.

For such a complex technology, the “nanoimpeller” device has a relatively straightforward mechanism of action. Anticancer drugs are collected and stored inside the tiny pores of the microscopic machine, which then releases the drugs into cancer cells in response to light. The drugs continue to be released, in a steady, controlled manner, in response to continued directional lighting cues controlled remotely by the physician conducting the procedure, until the cancer cell dies. According to its creators, the nanoimpeller is the first light-powered nanomachine able to operate inside a living human cell.

To create the nanoimpeller, the researchers used mesoporous silica nanoparticles and coated the interiors of the pores with azobenzene, a chemical that changes characteristics when exposed to light.

Laboratory tests were conducted using a number of types of human cancer cells, including colon and pancreatic cancer cells. The nanoimpellers were loaded into the cancer cells in the dark. When light was directed at them, the nanoimpellers released their contents into the cells.

“The achievement here is gaining precise control of the amount of drugs that are released by controlling the light exposure. Controlled release to a specific location is the key issue, and the release is only activated by where the light is shining,” stated Fuyu Tamanoi, MD, Jonsson Comprehensive Cancer Center, UCLA.

Dr. Tamanoi and colleague Jeffrey Zink, MD, said this system “has potential applications for precise drug delivery and might be the next generation for novel platform for the treatment of cancers such as colon and stomach cancer. The fact that one can operate the mechanism by remote control means that one can administer repeated small-dosage releases to achieve greater control of the drug’s effect.”

Small.

The research was published on-line in the nanoscience journal

M.D. Anderson Cancer Center

Gene Therapy Yields First Product Candidate of its Kind

At the recent annual meeting of the American Society of Gene Therapy in Boston, it was announced that a gene therapy invented at The University of Texas M. D. Anderson Cancer Center has become the first treatment to succeed in a U.S. phase III clinical trial for cancer.

The trial showed that p53 expression in the patient’s tumor before treatment is a reliable biomarker for how to treat head and neck cancer. Patients with a favorable p53 profile who received the novel agent had a median survival of 7.2 months, compared with 2.7 months for those whose tumor expressed high levels of mutant p53 before treatment. Patients with this unfavorable profile were better off taking chemotherapy, resulting in median survival of 5.9 months. Patients treated with the gene therapy experienced far fewer harmful side effects such as pneumonia than those who received chemotherapy. The incidence of inflammation of the mouth lining and a decrease in white blood cells, for example, both dropped to zero for those receiving the agent.

“Cells become cancerous because p53 no longer functions. Restoring p53 works unlike any current cancer treatment because it treats the cancer genome. The important finding is that patients who benefit from treatment can be identified with the p53 biomarker. The biomarker will enable physicians to personalize treatment,” said the drug’s inventor Jack Roth, MD, professor in M. D. Anderson’s Department of Thoracic & Cardiovascular Surgery and Director of M. D. Anderson’s W.M. Keck Center for Innovative Cancer Therapies.

The modified adenovirus that expresses the tumor-suppressing gene p53 will be branded as Advexin and targeted at the treatment of endstage head and neck cancer. The p53 gene is inactivated in many types of cancer. Its normal role is to halt the division of a defective cell and then force the cell to kill itself. The therapy, if approved, will be marketed by Austin, Texas—based Introgen Therapeutics, Inc. Dr. Roth cofounded the company and the University of Texas System is a key shareholder.

Dr. Roth’s lab has been developing gene therapy for cancer since 1990. All basic and preclinical work on the modified adenovirus was done at M. D. Anderson. The first phase I clinical trial was conducted by Gary Clayman, MD, DDS, professor in M. D. Anderson’s Department of head and neck surgery. Dr. Clayman also enrolled patients in the phase II and III clinical trials conducted by Introgen.

Dr. Roth and colleagues deleted an important region of the adenovirus’ genome, preventing it from replicating. They installed a genomic segment that expresses p53. When injected into a tumor, the p53 adenovirus burrows into the cancer cell’s nucleus. However, instead of replicating in a typical viral manner, it expresses p53, resulting in cell death. Dr. Clayman’s phase I trial provided the first indicator that p53 expression in the tumor before treatment could be an accurate biomarker for p53 therapy.

The researchers are now focused on ways to deliver p53 and other tumor-suppressing genes systemically—through intravenous delivery. Advexin has to be injected straight into the tumor, but that’s not workable for many cancers. Head and neck cancer kills patients by recurring, not spreading to other organs, but most cancer deaths involve metastasis. By wrapping tumor-suppressing genes in tiny balls of fat, Roth and colleagues hope to be able to treat more invasive cancers. Injected nanoparticles gather mainly in tumors, where they are taken up and dissolved, leaving the tumor-suppressor gene at work in the cell.

Memorial Sloan-Kettering Cancer Center

Acupuncture May Play a Role in Alleviating Cancer Pain Symptoms

New data from a randomized, controlled trial found that acupuncture provided significant reductions in pain, dysfunction, and dry mouth in head and neck cancer patients after neck dissection. The study was led by David Pfister, MD, Chief of the Head and Neck Medical Oncology Service, and Barrie Cassileth, PhD, Chief of the Integrative Medicine Service, at Memorial Sloan-Kettering Cancer Center (MSKCC), New York City.

Seventy patients participated in the study and were randomized to receive either acupuncture or usual care, which includes recommendations of physical therapy exercises and the use of anti-inflammatory drugs. For all of the patients, at least three months had elapsed since their surgery and radiation treatments. The treatment group received four sessions of acupuncture over the course of approximately four weeks. Both groups were evaluated using the Constant-Murley scale, a composite measure of pain, function, and activities of daily living.

Pain and mobility improved in 39% of the patients receiving acupuncture, compared with a 7% improvement in the group that received usual care. An added benefit of acupuncture was significant reduction of reported xerostomia, or extreme dry mouth. This distressing problem, common among patients with cancer following radiotherapy in the head and neck, is addressed with only limited success by mainstream means.

“Chronic pain and shoulder mobility problems are common after such surgery, adversely affecting quality of life as well as employability for certain occupations,” stated Dr. Pfister. Nerve-sparing and other modified radical techniques that preserve certain structures without compromising disease control reduce the incidence of these problems but do not eliminate them entirely. Dr. Pfister added, “Unfortunately, available conventional methods of treatment for pain and dysfunction following neck surgery often have limited benefits, leaving much room for improvement.”

Acupuncture, a component of traditional Chinese medicine, originated more than 2,000 years ago. Treatment involves stimulation of one or more predetermined points on the body with needles, heat, pressure, or electricity for therapeutic effect. It is already being used in the palliative care of cancer to alleviate pain and chronic fatigue and to reduce postoperative chemotherapy-induced nausea and vomiting.