National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
May 15, 2012 • Volume 9 / Number 10


Studies Support Expanded Role for Lenalidomide in Treating Multiple Myeloma

Woman pouring capsules from a pill bottle into her hand.

Maintenance therapy with the drug lenalidomide (Revlimid) substantially lengthens the time patients with multiple myeloma live without their cancers progressing, according to the results of three randomized placebo-controlled clinical trials published May 10 in the New England Journal of Medicine. Overall survival was also improved in one of the trials, but according to several researchers, that conclusion is less definitive.

The results also showed that lenalidomide maintenance therapy carries an increased risk of second primary cancers. Read more > >


Coverage of ASCO Annual Meeting

NCI at ASCO 2012The American Society of Clinical Oncology's 48th Annual Meeting will take place June 1–5 in Chicago, IL. Click on the tile to learn more about sessions with NCI staff and activities at the NCI exhibit booth. Look for highlights from the meeting in the May 29 and June 12 issues of the NCI Cancer Bulletin.



  • NIH Update

    • NIH, Industry, and Researchers Collaborate to Find New Uses for Existing Drugs
  • Notes

    • NCI's Ann O'Mara Receives American Pain Society Award
    • Cancer Classroom Webinar: The Social Determinants of Health
    • What You Need to Know About Cancer Booklets Updated

Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.

The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.

For more information about cancer, call 1-800-4-CANCER or visit

NCI Cancer Bulletin staff can be reached at

Featured Article

Studies Support Expanded Role for Lenalidomide in Treating Multiple Myeloma

Woman pouring capsules from a pill bottle into her hand.In three clinical trials, lenalidomide maintenance therapy substantially lengthened the time it took for multiple myeloma to progress.

Maintenance therapy with the drug lenalidomide (Revlimid) substantially lengthens the time patients with multiple myeloma live without their cancers progressing, according to the results of three randomized placebo-controlled clinical trials published May 10 in the New England Journal of Medicine. (See the table below for links to the study abstracts.) Overall survival was also improved in one of the trials, but according to several researchers, that conclusion is less definitive.

The results also showed that lenalidomide maintenance therapy carries an increased risk of second primary cancers. Largely in response to these findings, the Food and Drug Administration (FDA) last week issued an updated drug safety communication to warn physicians and patients about this increased risk.

Developing a second cancer is "a real risk, although it's small," according to Dr. Philip McCarthy of the Roswell Park Cancer Institute, who led one of the clinical trials, which was funded by NCI.

The risk of disease progression or death was greater for trial participants who received a placebo as maintenance therapy than for patients treated with lenalidomide, he added. "Physicians and patients will have to balance these [factors] out," he said. "For the vast majority of patients, though, I think it's reasonable to consider maintenance therapy with lenalidomide."

Slowing the Inevitable

In patients with multiple myeloma, standard treatment currently begins with induction therapy using two or more chemotherapy agents and, more recently, lenalidomide or bortezomib (Velcade), or both, in combination with a steroid. In patients who are younger than 65, this is often followed by an autologous stem cell transplant. (Because stem cell transplants can have significant side effects, their use is restricted in older or less-fit patients.)

The hope has been that, with less toxic drugs like lenalidomide and bortezomib, we could get the survival benefits without the side effects.

—Dr. Keith Stockerl-Goldstein

Following these treatments, many patients' cancers will stabilize or go into partial or complete remission. But the disease invariably returns in nearly all patients, often within several years, noted Dr. Ola Landgren, head of the Multiple Myeloma Section in NCI's Center for Cancer Research.

Various maintenance treatments—used to solidify the response to induction therapy and delay cancer progression as long as possible—have been investigated. In several trials, for example, maintenance therapy with thalidomide was shown to improve progression-free and possibly overall survival. But long-term treatment with thalidomide can cause debilitating side effects, including severe peripheral neuropathy, explained Dr. Keith Stockerl-Goldstein of Washington University's Siteman Cancer Center in St. Louis.

"A large number of patients drop off of thalidomide because of the toxicity," he said, which has limited its clinical use. "The hope has been that, with less toxic drugs like lenalidomide and bortezomib, we could get the survival benefits without the side effects."

Delaying Progression

The NCI-funded trial conducted in the United States and a trial conducted in Europe led by French researchers, compared maintenance therapy with lenalidomide or a placebo in patients (younger than 71 and 65, respectively) who had undergone a stem cell transplant. Both arms of the European trial also included "consolidation" treatment with lenalidomide—a short course of the drug at a higher dose, prior to maintenance therapy.

The third trial, conducted in Europe, Australia, and Israel, tested lenalidomide maintenance therapy against a placebo in newly diagnosed patients aged 65 and older. Patients had received induction therapy and were not candidates for a stem cell transplant.

In all three trials, lenalidomide maintenance therapy substantially lengthened the time it took for the patients' cancers to progress. (See the table below.)


Progression-Free Survival in Three Trials of Lenalidomide Maintenance Therapy for Multiple Myeloma

TrialStem Cell TransplantNumber of Patients Receiving Maintenance TherapyMedian Progression-Free Survival Results
United StatesYes46039 months
46 months
21 months*
27 months**
EuropeYes61441 months23 months
Europe, Australia, IsraelNo28431 months14 months

* Data from 2009, when study was unblinded
** After median follow-up of 34 months, including patients who crossed over


The U.S. trial also showed an improvement in overall survival at 3 years (88 percent versus 80 percent), despite the fact that some patients in the placebo arm later switched to maintenance treatment with lenalidomide beginning in December 2009, when the trial was unblinded—meaning patients and their physicians were told which treatment the patients were receiving.

The unblinding occurred because an interim data analysis revealed the large difference in progression-free survival between the two groups. Patients receiving a placebo were then offered lenalidomide, and about two-thirds of the patients began taking the drug.

But this crossover "may make it difficult to see any improvement in the overall survival benefit over time," Dr. McCarthy said.

Second Cancers and Unanswered Questions

Although several side effects were more common in patients receiving lenalidomide, the most troubling was the development of a second primary cancer.

Studies have shown that multiple myeloma and its precursor condition, known as monoclonal gammopathy of undetermined significance, are independently associated with the development of a second primary cancer, namely acute myeloid leukemia, as well as myelodysplastic syndromes.

Numerous factors may influence the risk of a second cancer following multiple myeloma, Dr. Landgren noted. But the consistent finding in all three trials that more patients who received lenalidomide as a maintenance therapy developed a new primary cancer strongly implicates the drug. He agreed, however, that the observed excess risk, which was based on a small number of cases, is something that needs to be discussed with patients.

It "may be debatable" whether the trials' results establish a new standard of care for multiple myeloma, wrote Dr. Ashraf Badros of the University of Maryland Greenebaum Cancer Center in an accompanying editorial.

Dr. Stockerl-Goldstein agreed. Questions remain, he stressed, about the optimal duration of treatment, the lack of improved overall survival in the other two trials, and whether improved progression-free survival translates into better quality of life.

Such unknowns could also call into question the cost effectiveness of long-term treatment with lenalidomide, Dr. Badros wrote. A year of maintenance therapy could cost more than $160,000 for the drug alone, he calculated, not including lab tests, physician visits, and other costs.

In an effort to identify potential biomarkers that may indicate which patients are at greater risk of developing a second cancer following lenalidomide treatment or are most likely to benefit from maintenance therapy, Dr. Landgren and other NCI researchers have developed a program to analyze tumor samples from patients in the three trials. To increase the speed of this effort, Dr. Landgren said, the research team is also interested in analyzing samples from multiple myeloma patients not in clinical trials who develop second cancers.

Despite these unanswered questions, researchers are excited about the progress that has been made in this disease. After many years of no significant clinical advances in multiple myeloma, improved therapies have led to a threefold increase in survival over the last decade, Dr. Landgren noted.

Carmen Phillips

Cancer Research Highlights

Low-Dose Radioactive Iodine Destroys Thyroid Tissue Left after Surgery

A low dose of radioactive iodine given after surgery for thyroid cancer destroyed (ablated) residual thyroid tissue as effectively as a higher dose, with fewer side effects and less exposure to radiation, according to two European randomized controlled trials published May 3 in the New England Journal of Medicine. Both trials also showed that either administering thyrotropin alfa or withdrawing thyroid hormones before administering radioactive iodine was effective for thyroid ablation at both radioactive iodine dose levels.

Researchers from France and the United Kingdom enrolled 752 and 438 patients with low-risk thyroid cancer, respectively, in their trials (here and here). Both studies randomly assigned patients to receive either low-dose radioactive iodine (1.1 GBq) or high-dose radioactive iodine (3.7 GBq) several months after surgery.

For radioactive iodine treatment to work, thyroid-stimulating hormone (thyrotropin) levels must be elevated. The researchers therefore randomly assigned study participants in both dose groups to either withdrawal of the replacement thyroid hormones given after surgery (to allow the body’s own thyrotropin level to rise) or administration of recombinant thyrotropin (thyrotropin alfa). Although thyrotropin alfa causes less discomfort than the withdrawal of replacement thyroid hormones, there was some concern that the drug might interfere with the effectiveness of radioactive iodine treatment.

Low-dose and high-dose radioactive iodine resulted in similar numbers of successful ablations in both trials: about 95 percent of patients in the French trial and 85 percent of patients in the U.K. trial, which enrolled patients with larger tumors than the French trial. In both trials, at both dose levels, rates of successful ablation did not differ significantly between patients receiving thyrotropin alfa or those undergoing replacement thyroid hormone withdrawal.

Ablation of residual thyroid tissue with radioactive iodine makes it easier to monitor patients with low-risk disease for local or distant recurrence, and its use has been rising in the United States. One recent study found that the use of ablation in younger patients with low-risk thyroid cancer rose from about 3 percent in 1973 to about 40 percent in 2007.

But whether radioactive iodine improves survival for low-risk patients remains unknown. “That benefit is much harder to prove in low-risk individuals because their survival from this disease is so good to begin with,” explained Dr. Erik Alexander of Harvard Medical School, who co-authored an editorial accompanying the two trials. A trial testing whether radioactive iodine improves disease-free survival in low-risk patients was recently launched in the United Kingdom.

Sequencing Study Identifies Gene that May Contribute to Melanoma

Also in the News: Sunburn and Indoor Tanning Still Common

Two new reports show that young adults in the United States are engaging in behaviors that increase their risk of skin cancer. Although more people are using sunscreen, staying in the shade, and wearing long clothing down to the ankles to protect themselves from the sun, sunburn remains common, according to the first study; half of all adults 18 to 29 years old reported at least one sunburn in the past year.

A second study found that roughly 30 percent of non-Hispanic white women 18 to 25 years old use indoor tanning devices, greatly increasing their risk of skin cancer.

Both reports appeared in the May 11 Morbidity and Mortality Weekly Report.

A whole-genome sequencing study of metastatic melanoma tumor samples has identified a gene, PREX2, that appears to be commonly mutated in melanoma and may play a role in driving the cancer’s growth and spread. Published online May 9 in Nature, the findings also indicate that rearrangements in chromosomes may contribute to melanoma’s progression and resistance to treatment, the authors wrote.

To conduct the study, Dr. Levi Garraway of Dana-Farber Cancer Institute and Harvard Medical School, and his colleagues from a number of U.S. and European institutions, performed whole-genome sequencing of 25 metastatic melanoma tumor samples and matched healthy tissue from the same patients.

They found that the number of mutated genes varied by the tumor’s location on the body. Tumors in areas that receive little sun exposure had the fewest genetic mutations, whereas those taken from areas that typically receive greater sun exposure had substantially more mutations. A tumor sample taken from a patient with a history of chronic sun exposure had the largest number of mutations.

Chromosomal rearrangements (also called translocations), within the same chromosome and between chromosomes, were common, the authors reported. Given the complexity and location of some of these rearrangements, they “may contribute importantly to melanoma genesis or progression,” the authors wrote.

Chromosomal rearrangements were frequently found near the gene PREX2. Although the most commonly mutated genes were BRAF and RAS, both of which have been linked to melanoma, PREX2 was also commonly mutated. An analysis of an additional 107 melanoma tumor samples confirmed the finding, with approximately 14 percent of the tumors harboring PREX2 mutations.

The researchers also showed that tumor growth was accelerated far more in mice implanted with melanocytes—the pigment-producing cells in which melanoma first develops—with PREX2 mutations than in mice implanted with melanocytes without such mutations.

PREX2 doesn’t appear to fit neatly into the mold of genes typically associated with cancer, they reported. “The pattern of mutations here looks a lot more like a tumor-suppressor gene, but from the functional experiments, it behaved more like an oncogene,” said study co-author Dr. Michael Berger of Memorial Sloan-Kettering Cancer Center in a news release.

Experimental Gene Therapy Protects Normal Cells from Toxic Effects of Chemotherapy

In a proof-of-concept study, a gene therapy technique designed to protect normal blood stem cells from the toxic effects of chemotherapy allowed three patients with glioblastoma to tolerate high doses of an experimental drug. All three patients survived longer than the median time for patients with this type of brain cancer, which has a poor prognosis. One patient remained alive without the disease progressing for more than 2 years after diagnosis. Dr. Hans-Peter Kiem of Fred Hutchinson Cancer Research Center and his colleagues published the findings May 9 in Science Translational Medicine.

The three patients had tumors that overexpressed a gene called MGMT. An experimental drug called O6-benzylguanine (O6-BG) inhibits the protein produced by MGMT and makes tumors more sensitive to anticancer drugs such as temozolomide, but it also increases the toxicity of chemotherapy to normal blood cells, including blood-forming stem cells. To make treatment with O6-BG tolerable, the researchers inserted a mutant MGMT gene called P140K, which makes cells resistant to O6-BG, into the patients’ blood stem cells.

The patients first underwent surgery to remove as much of their tumor as possible, followed by radiation therapy. Then stem cells were collected from their blood. The researchers cultured the stem cells in the lab and used a virus to deliver the mutant gene to the cells, in a process known as transduction. Next, the patients received the chemotherapy drug carmustine. Finally, the researchers infused the transduced stem cells into the patients, and the patients then received additional chemotherapy with O6-BG and temozolomide.

Each patient tolerated at least three cycles of combined drug treatment, and one patient received nine cycles. Normal blood cells containing the mutant MGMT gene were detected in the patients up to 14 months after stem cell transplantation. The researchers did not see any changes in the bone marrow indicative of leukemia during the study, although they plan to monitor the transduced stem cells in the remaining patient during follow-up. (One concern with gene therapy is that the foreign genes might insert themselves into the normal genome at a location that triggers a second cancer.)

The lack of toxicity seen in these patients and their relatively good survival “suggests that this approach will allow for administration of multiple cycles of this chemotherapy, possibly at higher, more-effective doses, potentially leading to better treatment outcomes,” concluded the authors.

Special Report

Unearthing Clues to Cancer Risk in the Aging Genome

Two new studies show that some people without cancer have large, structural chromosome abnormalities in a subset of their cells, including abnormalities that have been shown previously to occur primarily in blood cancers.

Illustration of one type of chromosome abnormality: deletion. (Illustration by Darryl Leja, NHGRI) Researchers found large, mosaic chromosome abnormalities, including deletions, in some members of the general population. (Illustration by Darryl Leja, NHGRI) [Enlarge]

The frequency of this genetic mosaicism—a mixture of normal and mutated cells of the same type (for example, blood, hair, or skin cells) within an individual—appears to increase with age, especially after age 50. It may also be associated with an increased risk of hematologic (blood) cancers and possibly some solid tumor types, researchers found.

The studies, published online (here and here) May 6 in Nature Genetics, "provide fascinating new information and data on the frequency and distribution of chromosomal aberrations in healthy individuals," commented Drs. Fredrik Mertens and Bertil Johansson of the Department of Clinical Genetics at Lund University Hospital in Sweden in an e-mail message. Drs. Mertens and Johansson were not involved in either study.

The findings could lead to new insights on how and why the risk of cancer increases with age and might eventually help identify people at higher-than-normal risk of developing certain cancers, explained Dr. Stephen Chanock, chief of NCI's Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics (DCEG), and a co-author of both studies.

Fortuitous Findings

The studies were conducted by two large groups, one led by NCI's DCEG and one comprising members of the NIH-funded Gene Environment Association Studies (GENEVA) consortium, which is directed by NIH's National Human Genome Research Institute (NHGRI).

Researchers first noticed the chromosome anomalies while doing quality control checks on data from genome-wide association studies (GWAS). These studies use single nucleotide polymorphism (SNP) microarray analysis to identify common genetic variants associated with cancer and other diseases. GWAS investigators found that DNA from cells assumed to be normal—mainly from blood samples, as well as buccal and saliva samples—contained unexpected structural abnormalities. The abnormalities occurred in a subset of analyzed cells from given individuals.

Illustration of one type of chromosome abnormality: duplication. (Illustration by Darryl Leja, NHGRI)Duplications, another type of chromosome abnormality, were also found in a some members of the general population. (Illustration by Darryl Leja, NHGRI) [Enlarge]

Many chromosome abnormalities originate as errors in eggs or sperm prior to fertilization. Therefore, the abnormalities are present in every cell of the body. Some abnormalities, however, can occur during an embryo's development or later in life. The result is acquired (noninherited) mosaicism, in which only a fraction of cells have the abnormality.

Chromosomal mosaicism has been shown to cause miscarriage, birth defects, developmental delay, and cancer, "but these are the first large-scale studies describing large [mosaic] chromosome abnormalities in people from the general population," said Dr. Cathy Laurie, a statistical geneticist at the University of Washington and one of the lead authors of the GENEVA study.

To determine the frequency of mosaicism in the general population, the NCI-led investigators looked for signs of large (greater than 2 million DNA base pairs) mosaic chromosome abnormalities in more than 31,000 case subjects with cancer and 26,000 control subjects without cancer from 13 GWAS of cancer. At the same time, GENEVA researchers looked for chromosome abnormalities larger than 50,000 base pairs in about 50,000 individuals from 12 GWAS, which looked mainly at conditions other than cancer.

In both studies, researchers found that mosaicism occurred in less than 0.5 percent of people younger than 50, but, after age 50, the percentage rose rapidly to about 2 to 3 percent in those older than 75, noted study author Dr. Anastasia Wise, an epidemiologist at NHGRI and program director for GENEVA.

These findings are intriguing because the incidence of many cancers also increases with age, Dr. Wise commented.

Cancer Connections

In the NCI-led studies, "we saw mosaicism in the cancer-free control subjects, as well as in the cancer case subjects. So we wanted to go to the next step and ask, 'What does it mean, and could it be a risk factor for cancer?'" explained Dr. Chanock.

The NCI-led study showed that the risk of leukemia was substantially higher among those with mosaic abnormalities. And GENEVA investigators estimated that the risk of all hematologic cancers (leukemia, lymphoma, and myeloma) was 10 times higher for mosaic individuals than for non-mosaic individuals.

When Dr. Chanock and his colleagues compared the subset of people who developed non-blood-based cancers and the corresponding cancer-free control subjects, they found that the risk of solid tumors, especially lung and kidney cancer, was also higher in mosaic individuals than in non-mosaic individuals. However, the correlation between mosaicism and solid tumors was not as strong as that for hematologic cancers.

Dr. Chanock emphasized that the presence of chromosome anomalies in a subset of blood cells may be an early marker of hematologic and possibly other cancers, as well as other diseases that are more common in older people. Dr. Laurie added, "The surprising thing is that the vast majority of people [in both studies] did not have a history of hematologic cancer, and we still found structural abnormalities in their blood cells." 

Cataloging Chromosome Changes

The chromosome abnormalities that researchers detected included duplications and deletions of large sections of chromosomes or entire chromosomes. They also included abnormalities known as copy-neutral loss of heterozygosity, in which a person ends up with two identical copies of a partial or whole chromosome.

These are the first large-scale studies describing large [mosaic] chromosome abnormalities in people from the general population.

—Dr. Cathy Laurie

When the researchers compared the anomalies they detected with those in the Mitelman Database, a catalog of chromosome aberrations found in cancer (developed by Dr. Felix Mitelman in collaboration with Drs. Johansson and Mertens), they found significant overlaps. And some of the chromosome regions that were commonly deleted, or missing, in their samples contained genes previously associated with cancer, they discovered.

"It has been known for some time that acquired chromosome aberrations accumulate with increasing age, and that the overall level of chromosome aberrations is associated with cancer risk," Drs. Mertens and Johansson wrote. "What is new and exciting in the two studies is the use of SNP array analysis, which allows much more extensive analysis of these aberrations, both in terms of resolution and in terms of number of individuals analyzed," than is possible with classical cytogenetic analysis.

Although the findings for hematologic cancers (and for solid tumors in the NCI-led study) were statistically significant, they were based on a small number of cancer cases from studies not designed to look at clinical outcomes. Further studies, some of which are under way, are needed to understand how genetic mosaicism may influence the risk of these and other cancers.

The studies will need to follow large numbers of healthy people over time and examine repeated blood samples from them. This could reveal whether mosaic chromosome abnormalities are stable and whether people with these anomalies are more likely to develop cancer and other diseases, explained Dr. Laurie.

Future research will also explore the origins of mosaic events seen in older individuals. "They may occur at birth and sit at a very low and undetectable level, and then later in life the proverbial genie is let out of the bottle," explained Dr. Chanock. However, he said, "I think most people would put money on the second hypothesis, which is that as you grow older the mechanisms of DNA repair deteriorate" and the genome becomes less stable.

Elia Ben-Ari


This is the second article in a two-part series on a form of immunotherapy for cancer called adoptive cell transfer (ACT). The first article described a type of ACT that uses tumor-infiltrating lymphocytes to treat advanced melanoma. The second article describes genetically engineered T cells that are being studied for the treatment of a variety of cancers, as well as hurdles in translating ACT from an experimental treatment to one commonly used in the clinic.

Complex Immune-Based Cancer Treatment Shows Signs of Progress

An illustration showing autologous and genetically engineered tumor-infiltrating lymphocytes being isolated, grown in cell culture, and infused with interleukin-2 into the patient. (Image from S. Rosenberg [2011] Nature Reviews Clinical Oncology, 8:577-585)Adoptive cell transfer therapy involves collecting T cells from a patient, growing them in cell culture, and infusing them into the patient. Enlarge the image to read the full caption. (Image from S. Rosenberg [2011] Nature Reviews Clinical Oncology, 8:577-585) [Enlarge]

Published in Science in 2006, the results of a 15-patient clinical trial conducted by NCI researchers represented a milestone of sorts for the burgeoning field of adoptive cell transfer (ACT) as a treatment for cancer.

Two of the patients in the trial had a complete remission of their advanced melanoma following the one-time only treatment, which consisted of collecting lymphocytes from a trial participant, genetically modifying and growing the lymphocytes in the laboratory until the cells numbered in the billions, and then infusing the cultured cells into the patient a short time later.

At the time, Dr. Steven Rosenberg of the Surgery Branch in NCI's Center for Cancer Research and his colleagues had already had some remarkable successes in treating patients with advanced melanoma using a similar form of ACT, in which patients were treated with T cells, known as tumor-infiltrating lymphocytes (TILs), that had been taken directly from the patients' own tumor samples.

But with this publication in Science, Surgery Branch researchers were announcing the first reported use of T cells—collected from patients' blood, not their tumors—that had been genetically engineered to enhance their antitumor capabilities before being infused into the patient.

In large part because melanoma seems to elicit a stronger immune response than most cancers, it has been a proving ground for ACT. But with advances in the genetic engineering of T cells, that has rapidly started to change.

"[These advances have] really expanded the number of cancers for which ACT could be a viable treatment option," said Dr. Richard Morgan of the Surgery Branch, which has performed the most trials of ACT as a cancer treatment to date.

Serious hurdles must be overcome, however, if any form of ACT is to become widely available, acknowledged Dr. Michel Sadelain of Memorial Sloan-Kettering Cancer Center, who is involved in several ACT trials at his institution. After all, these therapies consist of live immune-system cells that have been altered in the laboratory by highly complex processes, not mass-produced pills or injectable drugs that can be stored for long periods on a shelf or in a refrigerator, ready to be administered to multiple patients.

Although there are still many skeptics, "the number of people who are starting to believe in the potential of these types of cell-based therapies is growing," Dr. Sadelain said.

Building a Better T Cell

TIL therapy is the most extensively tested type of ACT to date, but approaches using genetically engineered T cells are slowly catching up. 

T cells collected from melanoma tumors are often already primed to attack cancer cells. But in other tumor types, infiltrating T cells are too few or difficult to isolate, Dr. Sadelain explained.

That fact led researchers to investigate whether they could introduce specific genes into T cells to augment their tumor-attacking capabilities, with a focus on engineering the cells to express antitumor receptors. These receptors act like docking stations on a T cell's surface, recognizing and binding to specific targets (antigens) on or within cancer cells—and, ideally, only cancer cells.

The first efforts to genetically modify T cells, which date back nearly two decades, "didn't work at all," Dr. Sadelain said. "Now it's much more effective, and we have a plethora of methods available to modify patients' T cells."

Much of the work has focused on engineering the cells to express T-cell receptors (TCRs) or chimeric-antigen receptors (CARs). The genetic material the T cells need to produce these receptors is typically delivered by viral vectors—viruses stripped of their ability to cause illness but that retain the capacity to integrate into cells' DNA.

The number of people who are starting to believe in the potential of these types of cell-based therapies is growing.

—Dr. Sadelain

Both receptor types have their limitations. Because the primary components of CARs are bits of an antibody, they can bind only to antigens that reside on the surface of cancer cells. TCRs, on the other hand, can be used to target antigens on the surface of and inside cells. However, TCRs need to be genetically matched to bits of patient-specific immune system proteins on cancer cells, adding another layer of complexity and potential restriction.

"Which [receptor type] you use is fundamentally an issue of biology," Dr. Morgan said.

Finding the right antigen targets—those that are commonly expressed on cancer cells but not on healthy cells—is "a significant barrier," he added, and remains a rate-limiting step in ACT research.

Regardless, both approaches are being put to the test.

Since the 2006 melanoma trial, which used TCR-expressing T cells, NCI researchers have reported excellent responses in several pilot trials. In 2010, they reported the first trial using CAR-expressing T cells that target the antigen CD19 (which they developed, based in part, on work from Dr. Sadelain's laboratory) in a patient with follicular lymphoma. Having received two cycles of treatment, this patient has been responding for nearly 3 years, Dr. Rosenberg said. Another eight patients with lymphoma or leukemia have also been treated, seven of whom have had tumor regressions, including three complete remissions.  

Researchers at the Baylor College of Medicine, led by Dr. Malcolm Brenner, have reported results of a trial in which several children with neuroblastoma achieved complete remissions following treatment with CAR-expressing T cells targeted to the antigen GD2.

And late last year, Dr. Carl June of the University of Pennsylvania Abramson Cancer Center reported early findings from three patients with chronic lymphocytic leukemia who were treated with CD19-targeted CAR T cells. Two of the patients had complete remission, and one had a partial remission.

The groups leading this research have intensively studied their patients after treatment to better understand exactly how the infused T cells behave in the body, with some intriguing results.

In the patients in the Abramson trial, Dr. June explained, "We found that each infused CAR T cell or progeny from those T cells killed between 1,000 and 93,000 tumor cells." This massive tumor cell die-off represented anywhere from 3 to 7 pounds of tumor "melting away," he said.

Researchers have found that a small percentage of the engineered T cells remains in the body for some time, some taking up residence in the bone marrow, where they presumably can be spurred into action should the cancer try to resurrect itself.

Although recent experience with ACT has been positive, like other therapies it's not universally effective and it has side effects, including high fevers and other problems that have required prolonged hospitalizations. In one instance, a patient with advanced colorectal cancer died within days of treatment, apparently as a result of a cytokine storm—a massive, unchecked immune response initiated by the ACT infusion.

Transitioning to a Larger Setting

A number of things must happen if ACT is to become a broadly available therapy, many in the field agree. Expanding its use is one of the most critical, said Dr. Brenner, who directs Baylor's Center for Cell and Gene Therapy.

"Until we can show that we can treat a wider range of diseases, we're not going to get the resources we need…to treat a wider range of diseases," he quipped last fall at an NCI-sponsored conference on immunotherapy. With a number of ACT trials under way, progress is being made on that front. (See the table.)

Examples of Human Trials Testing ACT with TCRs/CARs

InstitutionCancer Types
NCIMelanoma, glioblastoma, sarcoma, pancreatic cancer, mesothelioma
Abramson Cancer CenterLeukemia, multiple myeloma, mesothelioma, ovarian cancer, sarcoma
Baylor College of MedicineGlioblastoma, head and neck cancers
City of Hope Cancer CenterGlioma, lymphoma
Memorial Sloan-KetteringLeukemia, lymphoma, prostate cancer

Researchers are also beginning to get buy-in from pharmaceutical and biotechnology companies, which have the resources and infrastructure to bring new therapies to market.

Each infused CAR T cell or progeny from those T cells killed between 1,000 and 93,000 tumor cells.

—Dr. Carl June

NCI, for example, has a research agreement with Genesis Biopharma, Inc., to develop production-scale manufacturing processes for TILs and advance the treatment into larger clinical trials. Other researchers in the field say that they've discussed commercial development with companies and hope to reach agreements in the near future.

Dr. Rosenberg believes one potential clinical model for ACT that wouldn't necessarily require industry involvement is bone marrow transplantation, which is available around the country at centers with dedicated transplant programs.

The Food and Drug Administration's 2010 approval of the prostate cancer vaccine sipuleucel-T (Provenge), meanwhile, has provided a successful industry model to follow, Dr. Morgan noted.

As the process for engineering and growing cells becomes more efficient and streamlined, ACT may also be a highly cost-effective treatment. At Abramson, the research team can now produce 10 billion CAR-expressing T cells in 10 days at a cost of approximately $15,000—a price, Dr. June pointed out, that compares favorably with many of the newer targeted therapies, which can cost twice that amount for one month's treatment.

"There is definitely room for improvement," Dr. June said. The technology for engineering and growing the cells will improve, he continued, and with more research and funding, new methods for identifying target antigens will be developed as well.

Carmen Phillips

A Closer Look

"Rewiring" Cells to Treat an Aggressive Breast Cancer

Image showing the range of cellular responses to chemotherapy. (Photo courtesy of Neil Ganem, David Pellman, and Michael Yaffe)A new treatment approach aims to make breast cancer cells more susceptible to chemotherapy. Yellow cells responded (many will die), red cells are alive but not dividing, and green cells are growing and dividing.  (Photo courtesy of Neil Ganem, David Pellman, and Michael Yaffe)

Cancer cells develop genetic changes over time, and this is one reason that a drug may stop working in a patient. Such changes often alter signaling pathways that control cell growth. A new study suggests that learning more about how these pathways function in cancer cells and using this knowledge to "rewire" signaling networks could lead to novel treatments.

In the study, published May 11 in Cell, researchers treated breast cancer cells in the lab with targeted therapy and chemotherapy. Rather than giving the treatments simultaneously, however, the investigators pretreated the cells with a targeted drug, which made the cells more susceptible to chemotherapy.

"This study suggests that you can therapeutically rewire cancer cells to increase their sensitivity to chemotherapy," said lead investigator Dr. Michael Yaffe of the Massachusetts Institute of Technology (MIT). "Cells are complex systems," he continued. "We're blocking one pathway, and then allowing the rewiring to occur."

Sensitizing Cancer Cells

In the sequential approach, the researchers first exposed the cells to erlotinib (Tarceva), which blocks the activity of a protein called epidermal growth factor receptor (EGFR). Then, after at least 24 hours, the cells were exposed to doxorubicin, a commonly used chemotherapy drug.

Dr. Yaffe and his colleagues used cells from women with triple-negative breast cancer, an aggressive form of the disease that disproportionately affects younger women and African Americans. New treatments are needed, and based on the study results, the researchers have begun to plan a clinical trial.

"These are exciting findings," said Dr. Dan Gallahan of NCI's Division of Cancer Biology. "They suggest that we can use knowledge of signaling pathways to make cancer cells more sensitive to drugs we already have, such as first-line chemotherapy agents."

After being exposed to erlotinib, about 40 percent of the cell lines tested in the study responded to doxorubicin. Seventy-two hours after the time-delayed administration of the two drugs, none of the cells that had responded were still alive, the researchers found.

Erlotinib made the cancer cells "exquisitely sensitive to a DNA-damaging agent," noted Dr. Gallahan, who is also director of NCI's Integrative Cancer Biology Program (ICBP), which helped fund the study.

"We know that cancer cells evolve and develop resistance to therapies," Dr. Gallahan continued. "This study illustrates how new information about the signaling pathways in cancer cells that emerge from a systems-biology approach can be used to manipulate the cancer."

Clues from Systems Biology

Dr. Yaffe's lab studies how cells respond to DNA damage and how cells integrate information. Recently, the lab developed new ways to simultaneously study multiple signaling pathways and networks within cells—an approach that is sometimes called systems biology. 

These findings suggest that we can use knowledge of signaling pathways to make cancer cells more sensitive to drugs we already have.

—Dr. Dan Gallahan

In the first phase of the study, the researchers tested the effects that combinations of drugs given at different time intervals had on cancer cells. Hoping to move rapidly to a clinical trial if they found a positive result, the researchers focused on drugs that are already approved or being tested in patients.

"Based on experiments in the lab, we reasoned that it might be possible to take cells that were not particularly sensitive to a drug and convert them to a state in which they are sensitive," explained Dr. Yaffe. The general idea of changing the state of a cell is not new, he noted, but the approach evaluated in the current study had not been tried in triple-negative breast cancer.

Previous clinical trials combining erlotinib and chemotherapy without the specific time-staggered dosing had produced only modest results, Dr. Yaffe noted. His team also tested their approach in mice and observed positive results.

The researchers also found that another signaling pathway associated with cell death was activated in the cells that responded to the time-staggered approach. "The systems biology analysis was able to show why the time-staggered administration was so effective at killing the cancer cells," said Dr. Yaffe. 

Erlotinib seemed to "unmask" a signaling pathway associated with programmed cell death, or apoptosis, that was not available in untreated cells. This pathway involves a protein known as caspase-8, which could be a marker of response to the treatment, the authors said.

The cells that showed the most dramatic response to the time-staggered administration had high levels of signaling through EGFR, regardless of whether EGFR itself was mutated, or expressed at high or low levels. 

Additional experiments suggested that other combinations of targeted drugs and DNA-damaging agents used in the same fashion may work for some lung cancers.

Future Challenges

The systems biology analysis was able to show why the time-staggered administration was so effective at killing the cancer cells.

—Dr. Michael Yaffe

As he looks to the future, Dr. Yaffe sees two primary challenges. One is finding ways to measure EGFR activity in human tumors as a marker to identify candidates for the treatment. The other challenge is the heterogeneity of tumors. If a tumor has a population of cells actively signaling through EGFR and another population that is not, this approach might not kill the population that is not signaling through EGFR.

"Tumor heterogeneity is always an issue [when treating cancer], and our approach does not get around that," said Dr. Yaffe. Nonetheless, he continued, this approach has the potential to improve treatment for some women with triple-negative breast cancer using drugs that are already available.

As a next step, the researchers are collaborating with engineers at MIT to try to develop a therapy that combines the two drugs and has the delay built in. One possibility is a coated nanoparticle with an EGFR inhibitor on the outside and doxorubicin on the inside, which the researchers are preparing to test in mice.

"We don't have a great understanding of the crosstalk between signaling pathways, and that is a major limitation in using targeted anticancer drugs," said Dr. Yaffe. But he is optimistic that it will be possible to improve cancer treatments "with drugs we already have by using systems biology to understand how best to combine these agents."

Edward R. Winstead

Featured Clinical Trial

Experimental Antibody for Treatment-Resistant Liver Cancer

Name of the Trial
TRC 105 for Liver Cancer that Has Not Responded to Sorafenib (NCI-11-C-0181). See the protocol summary.

Dr. Tim Greten Dr. Tim Greten

Principal Investigator
Dr. Tim Greten, NCI Center for Cancer Research

Why This Trial Is Important
Liver cancer is the sixth most common type of cancer and the third leading cause of cancer death worldwide. Although it is relatively rare in the United States, its incidence has been increasing steadily. Among the various types of liver cancer, hepatocellular carcinoma and cholangiocarcinoma are the two main types diagnosed in adults, with hepatocellular carcinoma accounting for roughly three-quarters of cases.

Surgery (resection) to remove the tumor is the preferred treatment for patients with early-stage hepatocellular carcinoma. Unfortunately, most patients are ineligible for surgery because of the location of the tumor within the liver, coexisting medical conditions (such as cirrhosis), or both.

Patients with unresectable, localized hepatocellular carcinoma may be treated with other types of local therapy, such as radiofrequency ablation, transarterial chemoembolization, or liver transplantation. In some cases, these treatments may lead to longer survival. Until recently, however, systemic therapies have offered little benefit for patients with unresectable liver cancer.

A phase III trial in 2008 showed that patients with advanced disease who received the drug sorafenib—a multikinase inhibitor that blocks important molecular pathways in the tumor cell and inhibits tumor angiogenesis (the growth of new blood vessels to a tumor)—tended to live longer and experienced a longer time to progression than those who received a placebo. Not all patients benefit from sorafenib therapy, though, and doctors are eager to find more effective systemic agents for liver cancer.

TRC105 is an experimental monoclonal antibody with a strong rationale for use in hepatocellular cancer. Like sorafenib, TRC105 interferes with a tumor's ability to recruit the new blood vessels necessary for growth, but TRC105 targets a different molecular pathway than those targeted by sorafenib. 

In this trial, patients with unresectable hepatocellular carcinoma who are ineligible for liver transplants or other localized therapies, and who did not benefit from or could not tolerate treatment with sorafenib, will be treated with intravenous TRC105 every 2 weeks. Doctors will assess the patients' stage of disease every 8 weeks and determine the time to disease progression.

"Hepatocellular carcinomas are highly vascularized tumors of the liver, and we know from our experience with sorafenib that targeting angiogenesis is a potentially effective strategy," said Dr. Greten.

"TRC105 is an antibody that recognizes and binds to a molecule called endoglin, or CD105, that is expressed on proliferating endothelial cells within the tumor. Endoglin is a receptor protein that plays a critical role in tumor angiogenesis. Once TRC105 binds to endoglin, it activates the immune system to destroy the endothelial cells," he explained.

For More Information
See the lists of eligibility criteria and trial contact information or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.

An archive of "Featured Clinical Trial" columns is available at

NIH Update

NIH, Industry, and Researchers Collaborate to Find New Uses for Existing Drugs

Researcher using a pipette with an orange liquid. NIH's National Center for Advancing Translational Sciences (NCATS) recently unveiled a collaborative program that will allow researchers to find new uses for existing drug compounds.

The initiative, Discovering New Therapeutic Uses for Existing Molecules, is the result of NCATS's initial partnership with Pfizer, AstraZeneca, and Eli Lilly, which have agreed to make dozens of their compounds available to researchers.

The collaboration will give researchers access to compounds that already have cleared several key steps in the development process, including safety testing in humans—part of the therapeutic pipeline that traditionally has been difficult for researchers to access.  

Some compounds prove to be ineffective for the specific use for which they were developed, but new research may reveal that they work well for a different therapeutic use. One example is thalidomide, which was abandoned as a treatment for morning sickness when it was found to cause birth defects but was later discovered to be an effective treatment for multiple myeloma.

In recent years, researchers have identified the causes of more than 4,500 diseases. But it has proven difficult to turn this knowledge into new therapies; effective treatments exist for only about 250 of these conditions.

"Clearly, we need to speed the pace at which we are turning discoveries into better health outcomes," NIH Director Dr. Francis S. Collins said in a statement. "NIH looks forward to working with our partners in industry and academia to tackle an urgent need that is beyond the scope of any one organization or sector."

NCATS was established last year to help address this gap. The center supports rigorous scientific research designed to move basic research findings into new treatments for patients.

The president's fiscal year 2013 budget proposed $575 million for NCATS, of which about $20 million will support research grants of up to 3 years for preclinical and clinical feasibility studies. These studies will test more than 20 compounds against a variety of diseases and conditions.

The pilot program incorporates innovative template agreements designed to streamline the legal and administrative process for participation by multiple organizations. The templates also provide a roadmap for handling intellectual property rights. Industry partners will retain ownership of their compounds, and academic research partners will hold property rights to their discoveries and the right to publish the results of their research.

For more details about this program please see the Notice of Intent and Request for Information or visit the NCATS program webpage.


NCI's Ann O'Mara Receives American Pain Society Award

Dr. Ann O'Mara Dr. Ann O'Mara

The American Pain Society recently awarded the John and Emma Bonica Public Service Award to Dr. Ann O'Mara, head of palliative research in NCI's Division of Cancer Prevention.

The award is named for John Bonica, a leader in the pain treatment movement, and his wife, Emma. The award honors outstanding contributions by an individual or organization to further knowledge about pain through public education, dissemination of information, public service, or other efforts.

Dr. O'Mara has conducted research on end-of-life care and on the education of nurses and physicians about palliative care. Her publications have focused primarily on quality-of-life issues facing patients with cancer and their families through all stages of the disease. She manages a portfolio of symptom management, palliative care, and end-of-life care research projects. Most of these projects cover adverse effects associated with cancer and its treatment, including pain, chemotherapy-induced neuropathy, fatigue, sleep disturbances, and psychosocial issues such as distress, anxiety, and depression.

Cancer Classroom Webinar: The Social Determinants of Health

Cancer Classroom logo As part of the Cancer Classroom Series, NCI will offer a webinar titled "Social Determinants of Health: Implications for Cancer Control" on June 5, 2:00–3:00 p.m. ET.

Dr. Shobha Srinivasan will provide an overview of the complex social structures and economic systems that are responsible for most health inequalities, their influence on cancer, and implications for cancer control. These social structures and economic systems include the social and physical environment, health services, and structural and societal factors.

At the end of the presentation, participants will be able to

  • identify factors related to social determinants of health;
  • describe the relationship between social determinants of health and health inequalities;
  • discuss how social determinants of health may influence cancer and cancer control; and
  • identify NCI resources for cancer screening, education, and outreach.

The Cancer Classroom Series provides early-career public health professionals and those new to oncology the educational guidance, tools, and resources necessary to address cancer as a public health issue.

Workshops are free, but preregistration is required and space is limited. To register for "Social Determinants of Health" or to find out about upcoming sessions, visit the series website.

What You Need to Know About Cancer Booklets Updated

Two booklets in NCI's What You Need to Know (WYNTK) series have been updated:

Booklets in the WYNTK series are for people who have been recently diagnosed with cancer and want to learn about stages, treatment options, sources of support, and follow-up care. The booklets offer lists of questions about treatment options that people can take to their next doctor appointment.

The publications are available online in HTML and PDF formats, and some are available in print.