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Issue 24

In this Issue

Taking the Brakes Off the Immune System: New Cancer Immunotherapy Looks Promising in Early Clinical Trials
 

By Paul Courter, Science Writer

A new treatment strategy to strengthen T cell function has shown convincing activity and limited toxicity in Phase I and II clinical trials involving patients with advanced solid tumors. The results confirm the potential of a novel mechanism for generating a more vigorous anti-cancer immune response. Phase III trials will begin later this year.

Researchers from Seattle Cancer Care Alliance (SCCA) presented results of the Phase I study at the 2012 American Society of Clinical Oncology (ASCO) meeting in Chicago. In the study, they tested a monoclonal antibody that targets PD-L1 (programmed death ligand 1) and blocks its binding to the PD-1 co-inhibitory receptor found on activated T cells.

The PD-1 receptor is a negative regulator—a kind of brake—on the immune system. When PD-L1 binds to this receptor, it dampens T cell effector functions. Specifically, there is less T cell growth, less cytokine release, and increased apoptosis (programmed cell death) in T cells. Animal studies show that disrupting this PD-1/PD-L1 pathway—by blocking either PD-L1 or PD-1—prevents T cell braking and thereby augments antitumor activity.

Patients Who Are Out of Options

As reported at ASCO, 162 patients were given anti-PD-L1. About a third of all patients were treated at SCCA. They had a variety of tumors including melanoma, non-small cell lung, colorectal, renal cell, ovarian, pancreatic, gastric, or breast. All had failed to respond to standard therapies. “These were patients with refractory tumors,” says Scott S. Tykodi, MD, PhD, SCCA medical oncologist and principal investigator for the trial. “Most had been heavily pretreated and had developed a resistant phenotype.

“It’s difficult to get any treatment response in these types of patients,” says Tykodi. “Typically, they would be looking at hospice or supportive care. Expected survival is short. In renal cell carcinoma, for example, median survival in this group is probably six to eight months at best.”

Key Results with Anti-PD-L1

In the Phase I dose-escalation trial, the anti-PD-L1 monoclonal antibody (Bristol Myers Squibb MDX-1105 or BMS-936559) was given intravenously once every 14 days for up to 96 weeks. Patients were seen every six weeks for CT scanning. Response was defined as tumor shrinkage of greater than 30 percent and no new tumors.

Among the five tumor groups with more than 10 patients, three had multiple responders. At a dose of 10 mg/kg, objective responses were seen in three of 17 melanoma patients, two of 17 renal cell patients, and four of 25 lung patients. Seven of 16 patients with reduced tumor burden (objective or partial response, any dose) had durable responses lasting longer than a year.

Given the prognosis for these patients, Tykodi sees the results as convincing evidence of activity. The results in lung cancer patients were especially surprising. “Lung cancer is not thought to be immune sensitive,” he says. “Our lung specialists were excited to see responses of a year or more in such heavily pretreated patients.

“We’re optimistic,” he says. “And if you treat patients sooner in their course of disease, the probability is good that you’ll see even higher response rates.”

In terms of safety, anti-PD-L1 was generally well tolerated. There were no dose-limiting toxicities and most patients were treated at the maximum allowable dose of 10 mg/kg. The most common adverse events were fatigue, diarrhea, infusion reaction, arthralgia, rash, and pruritis.

Importantly, autoimmune side effects were less common and less severe than might be expected. By comparison, an already-approved anti-melanoma monoclonal antibody (ipilimumab, Yervoyä) that targets CTLA-4 (another inhibitory receptor on the T cell) causes significant autoimmune problems such as hepatitis and colitis.

Guess Who’s Been Riding the Immune Brakes

According to Tykodi, immune inhibitory pathways such as PD-1 and CTLA-4 evolved to allow temporary responses to transient challenges like infections. “It makes sense that there is a waxing and waning of immune effector cell populations,” he says. “You expand your lymphocytes during the infectious challenge then you shut off those cells when the infection clears. If you don’t turn it off, you risk horrible lymphoproliferative problems.”

But in cancer, the immune challenge persists. Ideally, more T cells would remain active. Unfortunately, they don’t and new evidence suggests why: many tumors actually start hitting the T cell brakes to evade immune destruction.

“Many renal cell tumors express PD-L1,” says Tykodi, “and researchers have now shown that patients with PD-L1-expressing renal tumors tend to have a much worse prognosis. So by blocking that signal to inactivate the T cell, we move in the other direction and we augment T cell function.

“It fascinates me,” says Tykodi, “that after more than 10 years of trying to develop cancer vaccines, we find better immune anti-cancer results by blocking inhibitory signals rather than by stimulating the effector cells.”

Upcoming Studies to Target PD-1 Receptor

Results of early-phase studies with anti-PD-1 (i.e., a monoclonal antibody targeting the PD receptor rather than the ligand) were also presented at ASCO. As in the anti-PD-L1 study, responses were also seen in melanoma, renal cell carcinoma, and non-small cell lung cancer patients.

Based on the similarity of results with anti-PD1 and anti-PDL1 to date, the drug company sponsor will likely test only the anti-PD-1 agent in Phase III oncology trials. In these and other upcoming randomized and double-blind trials, researchers will evaluate key questions regarding:

  • Safety and efficacy versus established second-line agents (e.g., verolimus)
  • Combination therapy that prevents immune deactivation and simultaneously stimulates immune response (e.g., with a cancer vaccine, interleukin 2, or interleukin 21)
  • Pretreatment screening of tumors for PD-L1 expression to target treatment.

“We are excited about the biology of this new treatment pathway,” says Tykodi. “SCCA will be involved in the multicenter Phase III study of anti-PD-1 for renal cell carcinoma. We will likely start enrolling in the summer or fall of 2012. Also this year, we will initiate two new early-phase trials with anti-PD-1—one in combination with IL-21 for lung and renal cell cancers and the other with a different manufacturer’s anti-PD-1 agent for melanoma.”


Immunotherapy for Treating Lung Cancer

By Leah M. Grant

Immunotherapy, a novel therapeutic approach being studied for treating cancer, holds promise as an alternative to traditional treatments such as chemotherapy, surgery, and radiation. Unlike most traditional therapies that attack a cancer directly, immunotherapy is based on exploiting the cancer-fighting properties of a patient’s own immune system. Researchers believe immunotherapy stops or slows the growth of cancer cells, prevents cancer from spreading, and allows the immune system to be more effective in killing cancer cells. Immunotherapy may be used alone or in combination with other treatments, like chemotherapy, radiation, or even other immunotherapies.

Immunotherapy may be categorized as passive or active. Passive immunotherapy includes immune system components, such as antibodies, made outside the body. It does not rely on the patient’s body to attack the cancer. Active immunotherapy, typically a vaccine, stimulates the patient’s own immune system to fight the cancer. Non-specific immunotherapies do not target a specific cell or antigen, but rather generally stimulate the immune system in a way that may result in activity against cancer cells.

Because of its theoretical specificity and potential for long-term disease control without the typical side effects associated with chemotherapy, immunotherapy may be an attractive therapeutic approach for lung cancer. Vaccine therapies, monoclonal antibodies, and other immunotherapy approaches are being investigated in various stages of clinical trials.

The doctors at SCCA work closely alongside and collaborate with scientists at Fred Hutchinson Cancer Research Center, a world-renowned center in immunotherapy research. The Hutchinson Center, under principal investigator Martin A. “Mac” Cheever, MD, leads 27 North American research institutions that make up the Cancer Immunotherapy Trials Network (CITN). The CITN unites top academic immunologists to conduct multi-center research on immunotherapies to fight cancer.

“SCCA has expertise in immunotherapy and was one of the first cancer centers involved in immunotherapy clinical trials to enroll patients onto the anti-PD-L1 clinical trials and find astonishing activity in lung cancer,” says Laura Q. M. Chow, MD, a medical oncologist at SCCA. Chow is dedicated to clinical research, new cancer drug development, and early phase clinical trials for patients with lung, head and neck, and esophageal cancers. “We have a number of interesting immunotherapies we are studying in the clinic that show therapeutic promise, including anti-PD-1 and anti-PD-L1.”

The programmed death-1 (PD-1) receptor and its ligand (PD-L1) are expressed in a number of immune system cells, cancer cells, and cells that fight infection and their expression has been linked to poor prognosis in a number of cancers. PD-1 activation by binding with PD-L1 leads to inhibition of the immune system and the high expression of these proteins and protein pathways allows for immune system tolerance—the ability for cancer cells and chronic viruses, such as hepatitis, to hide from destruction by the immune system. By blocking either PD-1 or PD-L1 with antibodies, the immune system can be reinvigorated to recognize and destroy cancer cells.

Immunotherapy agents are demonstrating for the first time that lung cancer can be treated as an immunological disease. In the past, further chemotherapy or other therapies have largely been ineffective for lung cancer patients who have progressed despite two or more lines of chemotherapy. In contrast, immunotherapy has shown responses, dramatic tumor regressions, improved survival, and an excellent quality of life with minimal side effects, even in patients who have failed all prior and multiple lines of chemotherapy.

The Lung Cancer Program at SCCA is the largest, most experienced program of its kind in the Pacific Northwest and has a large number of molecularly targeted therapy trials and novel treatment combination trials for lung cancer patients ongoing as well as a number of new anti-PD-1 antibody clinical trials that are expected to start soon, which will be highlighted in the Clinical Trials Monthly newsletter and on the website. SCCA’s Phase I Clinical Trials Program also has a lot of interesting new therapy options for patients who have exhausted standard treatment options.

Immunotherapy Trials

“Immunotherapy appears to be the new promising leading edge treatment for lung cancer. Preliminarily, it is starting to look more active than traditional chemotherapy, with fewer of the typical side effects of chemotherapy,” says Chow.

Two current anti-PD-1 and anti-PD-L1 trials clinical trials are:

  • MDX-1106 (BMS-936558) is a fully human monoclonal antibody specific for PD-1 (Programmed Death-1). MDX-1106 binds to and blocks the activation of PD-1 by its ligands PD-L1 and PD-L2, resulting in the activation of T cells and cell-mediated immune responses against tumor cells or pathogens.
  • MDX-1105 (BMS-936559) is a fully human monoclonal antibody against the protein ligand PD-L1 (Programmed Death-1 Ligand 1). Its mechanism of action is to block binding of the ligand with PD-1 on tumor cells, thereby reversing T cell inhibition.

“After many years of treating patients with chemotherapy, we are seeing responses in patients treated on the MDX-1105 study that we have never seen before in lung cancer. We enrolled more than 35 patients on this trial and had some excellent outcomes in response and improved survival,” says Chow. “One of my patients, featured in the SCCA lung cancer section of our website, continues to enjoy a good quality of life and remains active—cycling, hiking, and working—while on this drug.”

The results of the MDX-1105 and MDX-1106 studies were presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).
 

Cost Effective Screening for Lung Cancer

In detecting lung cancer at its earliest stage, and having it surgically removed, a person can expect a five-year survival rate of nearly 70 percent. In contrast, patients with locally advanced or metastatic lung cancer at the time of diagnosis have a five-year survival rate of less than 5 percent. These statistics come from the results of the National Lung Screening Trial that was published in June 2011.

“This study is important in helping make the argument to health insurance companies that CT screening for lung cancer in high risk individuals is a cost-effective service for policy  holders and is in the best interest of the insurance provider, as well as the patient,” says David K. Madtes, MD, director of SCCA’s Lung Cancer Early Detection & Prevention Clinic.

CT screening for lung cancer in high risk individuals is now considered more cost effective than screening for cervical, breast, and colorectal cancers, especially when you look at the cost of treating lung cancer and the statistics of surviving the disease when it’s at an advanced stage.

The American Lung Association now endorses the use of low-dose CT lung cancer screening as well. When screening detects a problem If a low-dose CT screening finds something concerning a possible lung cancer, patients will be referred to the SCCA Lung Cancer Early Detection & Prevention Clinic, SCCA’s gateway to rapid diagnosis and treatment for lung cancer. For all other findings, patients will be directed back to their primary care provider.

If you have patients who are current or previous smokers who meet the high risk criteria, consider encouraging them to take advantage of the low-dose CT lung cancer screening offered by SCCA.

“The CT concept is in the early stages,” says Madtes, who acknowledges there is ambivalence in the community about it. But he argues that “it’s important to see the value in screening for patients. In the aforementioned trial, the well-designed trial showed that CT screening definitely, clearly saves lives.”

More information about low-dose CT screening at SCCA for the early detection of lung cancer can be found online at www.seattlecca.org/low-dose-ct-screening.cfm.


New Multi-Center Trial Opens Soon for Haploidentical and Cord Blood Transplants

By Sally James

A new trial that will randomize patients between two alternative donor stem cell protocols will be recruiting patients at Seattle Cancer Care Alliance (SCCA) soon. Paul O’Donnell, MD, PhD, medical director of the Adult Stem Cell Transplant Service at SCCA describes the trial as a comparison of two alternative donor types, haploidentical (HLA-mismatched) family members (including parents, children, and about half of a patient’s siblings) versus unrelated umbilical cord blood. This study is being coordinated nationwide by the Blood and Marrow Transplant Clinical Trial Network.

“Patients who may not have had a chance at a matched donor transplant will have more opportunities through the growth of these alternative donor options,” O’Donnell says. In some cases, patients of mixed ethnic heritage can have the most difficulty finding matches, and may benefit the most from these studies.

Looking for alternatives

Only 30 percent of bone marrow transplant patients have matched sibling donors. Another 35 percent will find matched unrelated donors, leaving the remaining 35 percent looking for alternatives. “For a long time, matched unrelated donors have been the alternative donors of choice,” O’Donnell says. “Our outcomes using such donors consistently outperform many other centers. But now we are able to offer patients who can’t find a matched unrelated donor the option of transplant using a haploidentical donor or unrelated cord blood.”

Across the country, findings indicate that transplant outcomes using haploidentical or cord blood donors are very similar to matched donors, according to O’Donnell. “The incidences of acute or chronic graft versus host disease are surprisingly similar or less than matched donors  using current protocols,” he says.

O’Donnell is one of three principal investigators and the trial is hoping to include about 40 centers around the nation enrolling 410 leukemia and lymphoma patients. The trial will be open for four years and patients will be followed for three years after their transplant.

Because the trial is opening across the country at many centers, O’Donnell is hoping that doctors and potential patients will hear about it and know that patients can enroll within a reasonable distance of their own home state. More information about this trial is on the SCCA  website at: https://web.emmes.com/study/bmt2/protocol/1101_protocol/1101_protocol.html.
 

Non-Chemotherapy Treatment for Follicular Lymphoma

Follicular lymphoma is an indolent lymphoma, a member of the non-Hodgkin’s lymphoma family, of which there are about 60. It is an incurable disease, but it is controllable for many patients.

In a new international, randomized study at SCCA, the RELEVANCE trial hopes to provide a better treatment for newly diagnosed follicular lymphoma patients. This trial will help determine whether a new combination of approved drugs, lenalidomide and rituximab, neither of which are chemotherapies, is more effective than the standard of care. “We are looking for high response
rates and longer response rates,” says Edward N. Libby, MD, lead investigator on the RELEVANCE trial at SCCA.

Unique to this study is lenalidomide (Revlimid), which has been added in for maintenance—small doses over long periods of time. “Revlimid affects the immune system in ways to help kill cancer, but we don’t know exactly how this works,” Libby says. Revlimid is currently used to treat multiple myeloma and myelodysplasia.

As a Phase III trial, and because this disease is slow growing, patients often don’t require treatment right away. “A key to this trial is that it is open only to newly diagnosed patients who need treatment upon diagnosis because of their symptoms,” Libby says. “If there are large masses of tumors in the body, the patient has anemia, recurrent fevers, chills or sweats, or has tumors obstructing an organ.” Both of the study drugs have been approved for treatment in other diseases. Patients gaining control of their disease will have rituximab every three weeks and lenalidomide three out of four weeks until which time  maintenance therapy can begin.

This is a randomized study, so there is a 50/50 chance that a patient will receive standard rituximab chemotherapy treatment, or the study therapy. More information about this study is available online at www.seattlecca.org/clinical-trials/lymphoma-NCT01476787.cfm.
 

Provider Profile: Dr. Edward Libby

Before he became a physician, Edward Libby, MD, wanted to be a musician. “But after a few years pursuing music, I realized that I wasn’t talented enough, so I went to college.”

Libby started out planning to go to nursing school. (His mother was a registered nurse.) “One summer early in college, I volunteered to help in the operating room at a local hospital. From the first moment I saw surgeons cutting with a scalpel, I knew I had to be a doctor. It was simply too exciting to miss out on!”

It was during his fellowship that Libby realized that oncology doctors often had deep relationships with their patients and were close with almost all of them. “We are happy when there is good news and we cry when things aren’t going well,” he says. “The combination of science, art, and humanism in medicine is, in my opinion, best exemplified in oncology.”

Libby joined SCCA to advance his research career. “Combining research with patient care is what gets me up in the morning and makes me excited to come to work,” he says. “I believe strongly in scientific research to advance the treatment of patients with cancer. The goal(s) are to cure more patients or to prolong disease-free time without cancer (make cancer a chronic disease), and to reduce the side effects of treatment.”

His research interests include finding new treatments for blood cancers, in particular, multiple myeloma, Waldenstrom’s macroglobulinemia, amyloidosis, and the lymphomas. “My hope is to participate (with my patients) in the discovery and application of new drugs and other therapies for patients with these diseases,” says Libby.

The opportunity to participate in and lead clinical research at SCCA is outstanding, according to Libby. He is involved in all types of clinical research, including for newly diagnosed and relapsed/refractory disease, and for patients with multiple myeloma, plasma cell diseases, and lymphoma. “My research group is actively studying new drugs, new combinations of drugs, and new diagnostic techniques for patients with myeloma and lymphoma,” he says.

“I believe strongly in scientific research to advance the treatment of patients with cancer.”

These examples of progress are already occurring in many cancers. Libby says, “I am fortunate to be involved in blood cancers because some of the most important and groundbreaking advances in oncology are being produced for patients with hematologic malignancies.”
 

Continuing Medical Education

Comprehensive Oncology Review Course

Returning in 2012, Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, and UW Medicine are offering the Comprehensive Oncology Review Course on September 22-25, 2012 at the W Hotel in Seattle.

This four-day program will incorporate data supporting guideline-based recommendations and recent advances regarding therapeutic options for patients with malignant solid tumor disorders. At the end of the course, physicians will leave with a comprehensive syllabus, a self assessment, and a deeper understanding of the pathogenesis, diagnostic evaluation, and therapeutic modalities available for common solid tumor malignancies. There will be a case-based review session and discussions. The course is designed to help prepare you for certifying and re-certifying exams as applicable. Don’t miss the most informative CME of the year. www.uwcme.org


Adult Bone Marrow Transplant News

The SCCA Adult Bone Marrow Transplant News is a publication presenting the latest information on bone marrow transplant research at SCCA, providing up-to-date information for all health care professionals caring for transplant patients.

Pediatric Bone Marrow Transplant News

Read about important outcomes research at the Hutchinson Center that may benefit your patients.

Clinical Trials Monthly

Each issue of Clinical Trials Monthly highlights several of the more than 200 clinical trials that are currently recruiting patients at SCCA.

The Leading Edge Newsletter

Each quarterly Leading Edge newsletter will highlight a new topic to give you the latest news on leading-edge therapies that SCCA physicians are offering.