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This is part 2 of a 2-part series on cancer programs around the country that are devising new approaches to translational medicine. Part 1 of this series published in the December 15 issue of CancerScope.

After The University of Texas MD Anderson Cancer Center (MDACC) in Houston announced its comprehensive Moon Shots program to attack cancer on many fronts, a joke started going around the Abramson Cancer Center of the University of Pennsylvania (Penn) in Philadelphia. “We said it's great that MD Anderson is shooting for the moon, but we're actually shooting for Mars, and we may hit it sooner than they hit the moon,” says Chi Van Dang, MD, PhD, director of the Abramson Cancer Center.

He is only half joking, he says, because some of the groundbreaking research at Penn is already generating promising results that may lead to further important strides in the fight against leukemia and, potentially, other cancers.

The research, led by Carl June, MD, director of translational research and a professor of pathology and laboratory medicine in the Abramson Cancer Center, has involved using genetically engineered versions of patients' own gene cells to treat adults with chronic lymphocytic leukemia and pediatric patients with acute lymphocytic leukemia. In the latter group, a couple of children for whom all other treatments had been exhausted and who were not expected to survive are now in complete remission after the experimental treatments, Dr. Dang says. “This is unprecedented to see this kind of turnaround,” he adds.

Investigators remove patients' T cells and reprogram them to attack tumor cells by genetically modifying them using a lentivirus vector. The vector encodes an antibody-like protein, called a chimeric antigen receptor (CAR), that directs the T cells to the leukemia cells and kills them. These cells also are designed to multiply within the patient's immune system so that they will provide permanent protection against the tumor cells, Dr. Dang says.

Based on this work, including a pilot study of patients with chronic lymphocytic leukemia published simultaneously last year, Novartis and Penn announced a global research and licensing agreement to further study and commercialize new cellular immunotherapies using CAR for additional cancers, including mesothelioma and breast and pancreatic cancer.1,2 The partnership will enable construction of a production facility necessary to develop the gene delivery system.

Ideas from the “Bottom Up”

DePinho, MD, assumed leadership of his cancer center in 2011. The Abramson Cancer Center has about 315 investigators spanning 8 schools and dozens of departments, and it treats approximately 10,000 to 11,000 patients per year with approximately 150 staff members. “We're not a huge enterprise, so we have to focus on our strengths, and I think being nimble is a good thing,” he says. “We can engage people and get them around the table very rapidly.”

Dr. Dang also believes in relying on the energy and drive of his faculty to develop ideas and goals from the bottom up versus from the top down. With that in mind, he has led the establishment of new organizational structures to parlay the latest scientific discoveries into clinical applications. The effort involves reinvesting University of Pennsylvania Health System funds into translational research through a new Translational Centers of Excellence program. Up to 5 such centers comprising members from across the institution are being created to solve problems in specific cancers. The initial investment is $3 million per center, with the goal of raising additional funds to make them self-sustaining.

Center leaders requested proposals from groups “anywhere along the spectrum where they can make an impact,” Dr. Dang says. External advisors reviewed the proposals, and health system leadership also participated in the process.

In the leukemia and hematologic malignancies area, for example, investigators are launching an individualized diagnostics effort that will rely on panels of genes to determine how patients will fare on specific treatments ranging from standard therapy to bone marrow transplants.

The breast cancer group, meanwhile, is focusing on disease relapse. About 40% of women relapse, and the biology is not well understood, says Dr. Dang. He notes that the team will be studying how the process occurs, looking for new biomarkers, and designing early detection strategies and new therapies.

In addition to the translational centers, the Abramson Cancer Center has a broad range of investigators who conduct in-depth study on cancers related to the BRCA gene. As a result, donors Mindy and Jon Gray have committed $25 million to launch the Basser Research Center for BRCA. It is the only center in the world to focus on this particular area of cancer, with the goal of bringing in molecular biologists to learn more about BRCA and to develop new molecular biomarkers. “The lessons they learn can be expanded to other areas besides BRCA,” Dr. Dang says. “We're also hoping that our research will enable patients who are carriers of these mutations to have more palatable options in the future.”

A Focus on Pathways

Meanwhile, another team of scientists on the West Coast is delving into the problem of prostate cancer. The leader of that group, Eric Small, MD, deputy director of the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, notes that the cancer field in general is moving toward “decision medicine,” and he points to the Stand Up To Cancer (SU2C) Dream Teams as important examples.

SU2C is an initiative launched by the entertainment industry with the American Association for Cancer Research serving as its scientific partner. SU2C's goal is to invest in teams of scientists, clinicians, technicians, and other experts who are addressing critical problems in cancer while at the same time removing bureaucratic obstacles to their success.

Dr. Small is the principal investigator of a newly announced dream team focused on prostate cancer, which received a 3-year, $10 million grant from SU2C and the Prostate Cancer Foundation. The multicenter team will be working on efforts to overcome therapeutic resistance to and develop new treatments for advanced disease.

Both UCSF and the Prostate Cancer Dream Team investigators believe they need to move beyond merely mutational analysis. Although it is still important to accomplish such analyses in faster, more accurate, and more efficient ways, “the problem is the needle in the haystack when you have 1000 or more mutations,” Dr. Small says. “You have to determine which [mutations] are the drivers and which are the passengers and which ones are actionable.”

That is why the dream team is focusing on pathways as opposed to individual mutations. They will identify the causes of resistance in some 500 patients with advanced prostate cancer in an effort to find more effective, tailored therapies and help patients avoid unnecessary treatment. After patient biopsies and blood samples are collected, they will undergo a comprehensive molecular assessment and pathway-based analysis. Scientists will then search for biomarker predictors of sensitivity to specific therapies, along with predictors of resistance to the therapies.

Logistical Challenges

Dr. Small concedes that the team will face challenges along the way. “The building of multidisciplinary teams in science hasn't been done very well in general,” he says. “One of the great things that MD Anderson's Moon Shots Program is doing is the acknowledgement that this type of science won't happen with the standard R01-funded mechanisms [which are restricted to specific research projects]. This is true cross-disciplinary work, and it's a challenge to get that done.”[1], [2]

Some of the Prostate Cancer Dream Team's logistical challenges have been reduced by the fact that they're all in the same time zone, which was done on purpose, Dr. Small says. Yet the bigger issue for team science in general remains a cultural one, and he wonders whether researchers can move beyond their own immediate fields to address broader challenges. “In many ways, we've already broken some of those barriers because we've already been working together through the Prostate Cancer Foundation,” he says. “UCSF also has been very collaborative because of our culture, but in environments where competition is a bigger issue, collaboration will have to be encouraged.”

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We're not a huge enterprise, so we have to focus on our strengths, and being nimble is a good thing. We can engage people and get them around the table very rapidly. —Chi Van Dang, MD, PhD

References

  • 1
    Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3:95ra73.
  • 2
    Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptormodified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725-733.