Tuesday, April 28, 2015

Clinical trial will use mice to guide treatment choices in soft-tissue sarcoma

Mice in Champions lab.
By Suzie Siegel

Cancer treatments have been tested on mice for years. Now a new technology uses mice to determine which treatments may best fight an individual patient’s sarcoma.

The TumorGraft technology “provides options for patients in difficult situations when, often as doctors, we are not sure how to treat people,” said medical oncologist Justin Stebbing, a professor of cancer medicine and oncology at London’s Imperial College. “In doing so, it advances the frontiers of science and medicine, but in a practical way, giving clinicians information on treatment choices – what is likely to work, and as importantly, what is likely to not work.”

Champions Oncology soon hopes to open a phase II clinical trial of its TumorGrafts for patients with soft-tissue sarcoma, Chief Medical Officer Angela Davies said. About 200 people whose sarcoma has recurred or metastasized will be enrolled at sarcoma centers across the United States and Canada.

“We have plans for clinical trials in many different tumor types,” she said. “We currently are partnering with academic centers conducting a clinical trial in breast cancer and advanced non-small-cell lung cancer, with plans for a trial in head-and-neck cancer and colorectal cancer to start within the next 12 months.”

In the sarcoma trial, she said, patients will start standard treatments while waiting for results from the TumorGraft process, which can take 4-6 months. The trial will accept only patients who are expected to survive at least six months and who are healthy enough to undergo systemic therapy, such as chemo. If the initial treatment fails, the TumorGrafts may help a doctor choose which treatments to try next.

Until a clinical trial validates the process, a U.S. doctor can’t use it to justify delaying or changing treatment in a patient with advanced sarcoma, said Sujana Movva, a sarcoma medical oncologist at Fox Chase Cancer Center in Philadelphia.

Dr. Sujana Movva

Dr. Movva helped design the trial, which was discussed last fall at the annual meeting of the Connective Tissue Oncology Society in Berlin. Other physicians involved in the research were from Massachusetts General Hospital in Boston; University of Michigan, Ann Arbor; Oregon Health & Science University, Portland; Mount Sinai Hospital, New York; Rutgers Cancer Institute of New Jersey, New Brunswick; Johns Hopkins University, Baltimore; M.D. Anderson Cancer Center, Houston; Sarcoma Oncology Center, Santa Monica, Calif.; University of California, Los Angeles; and University of Pennsylvania, Philadelphia.  

Dr. Stebbing serves on Champions’ Scientific Advisory Committee, as does medical oncologist George Demetri, director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute in Boston.

Before surgery, patients can ask for a piece of their tumor and its surroundings to be saved for Champions. The fresh tissue will be implanted into one or more immunodeficient mice. If the graft grows, it will be divided again and implanted in more mice. Grafts also will be preserved for future testing.

These grafts are called patient-derived xenografts (PDX) or patient-derived tumor xenografts (PDTX).

“Champions can test chemotherapy, targeted agents, monoclonal antibodies and antiangiogenics as single agents or in combination,” said Dr. Davies, a medical oncologist. Immunotherapies cannot be tested now, but scientists are working on a mouse model with a humanized immune system engrafted.

“No model system is perfect,” Dr. Movva said, “but it is the best ‘in-vivo’ testing available so far.”

The Hackensack, N.J., company began testing different cancers in 2007, with the greatest number of tests in sarcoma, Dr. Davies said. “The rare and heterogeneous nature of sarcomas and the lack of well-defined treatment strategies make sarcoma well-suited to a personalized approach.”

More than 150 sarcoma patients have tried TumorGrafts, she said. “We managed to grow approximately 100 tumors. Currently, we have 60 successful mice models for sarcoma patients.” That translates into a 65-percent success rate for growing sarcomas in mice, she said, “and 67 percent of patients for whom a model was successfully developed decided to proceed with drug sensitivity testing in the model.”

Implantation costs about $2,000, she said. Testing one therapy costs an additional $2,500-$3,000, and the cost mounts as more therapies are tested. The upcoming clinical trial would be free to patients, however. A successful phase III trial could lead to insurance coverage for TumorGrafts.

Some sarcoma patients choose to do chemosensitivity or chemoresistance tests in which their cancer cells are grown in a Petri dish. TumorGrafts have an advantage because they preserve the biological characteristics of the original human tumor, Dr. Davies said.

“Previous work has shown that implanted tumors are able to spontaneously metastasize,” Dr. Movva said. “This suggests that there is interaction between the tumor and its microenvironment, which may therefore mimic the patient response better.”

Genetic testing can help people with certain cancers, but researchers have found few targeted therapies for people with sarcoma, she said. There are more than 70 subtypes of sarcoma, and chemo is less effective in many of them than in more common cancers.

“A recent paper by Stebbing et al. summarizes the clinical experience of 29 patients,” she said. “A few of these patients did have DNA sequencing of their tumors, which guided the physician in selection of drugs for the sensitivity testing.”

In 13 cases, treatments that worked in the mice also helped the patients. “A few patients derived benefit from drugs not normally prescribed for patients with soft-tissue sarcoma,” Dr. Movva said. Grafts failed for seven patients. Six died before data from the mice became available. In three cases, there was no correlation between the mice and the patients.

“It is unclear, therefore, if this approach (using a PDX model to direct care) is better than participating in a phase I trial, for example,” Dr. Movva said. Nevertheless, “patients should definitely consider participating in the TumorGraft clinical trial when it becomes available. This will help determine how well the PDX model predicts patient response and also help sort out some of the issues related to engraftment rates and feasibility.”

Other companies have developed PDX models for research. But Champions is the only one that sells them to individual patients, Dr. Davies said.

Tuesday, April 7, 2015

Treating Cancer with Viruses: What about Sarcoma?

Everyone is talking about the recent television reports on the use of viruses to treat cancer. The very general concept behind these treatments is that viruses can be adapted to kill cancerous cells while leaving healthy cells unaffected. This field of treatment is called Oncolytic Virotherapy. But if you've found your way to this article, you’re most likely thinking: “This is great… but what about sarcoma?”

The Sarcoma Alliance has put together this blog post as a way to provide a general overview of what oncolytic virotherapy is and how it is being studied in sarcoma. This is not a comprehensive look at all of the research that has been done pertaining to sarcoma, nor is it intended to reach conclusions about the future of oncolytic virotherapy as a sarcoma treatment. If you are interested in the studies listed below or want to learn more, we encourage you to speak with your or your loved one's treating sarcoma specialist.

While some research has been performed on sarcoma oncolytic virotherapy, there are still many challenges to developing these treatments. For example, viruses are attracted to cells with certain specific markers, so if a sarcoma cell does not have the marker for a specific virus, it won’t be attacked.  Additionally, many tumor cells mutate rapidly, which can lead to markers on only some of a tumor’s cells.  Conversely, if the sarcoma cells have the same type of cell markers that normal cells have, the virus might attack too many healthy cells. However, in spite of these potential complications, some preliminary studies on the efficacy of oncolytic virotherapy as a sarcoma treatment show promise. 

Several types of virotherapy have been studied in sarcomas, including:
  • Using viruses to directly attack the sarcoma.  Since viruses kill cells, if they can be genetically “tweaked” to attack only a sarcoma, this may work well.
  • Using vaccine viruses to attack the sarcoma. Vaccine viruses won’t cause disease, and since they have been used in vaccines they are known to be safe.  They may kill cancer cells directly, or have the immune system attack the cells.
  • Using viruses to make the immune system do a better job of attacking the sarcoma cell.  In some cases, the immune system cells that attack cancer cells remain in the body only a short time, thus cancer can recur.  Tying the immune response to a viral infection seems to keep these immune cells around far longer, thus preventing tumor recurrence.
  •  Developing drugs that attack cancer cells the same way that viruses attack cells.  These drugs mimic the ways that viruses kill cells, and thus may be able to be very specific for types of cancers, as well as “recognizing” mutated tumor cells.

Published studies using viruses in a laboratory setting, both in vitro and in vivo (in these cases, mouse models), show some positive results. Below is a brief overview of some of these most recent studies:
  • The measles vaccine virus has been studied and shown some promise in treating various subtypes of sarcoma.[i][ii]
  • The vaccina virus (similar to cowpox, used in the vaccine for smallpox) has also been studied in advanced extremity sarcoma, which reported some positive results.[iii]
  • Vesicular stomatitis virus was studied in metastatic Ewing's sarcoma mouse models, and was shown to have “selectively infected and killed EWS" and delayed tumor growth.”[iv]

Due to the nature of drug development and the potential for differing results as studies continue, it’s impossible to say whether any of these studies will lead to treatments, but we will continue to monitor these and other early developments in oncolytic virotherapies.

In addition to laboratory studies, a few clinical trials using oncolytic virotherapies for sarcoma have been completed or are underway. Below is a brief overview of some of the most recent studies:
  • A handful of clinical trials of Reovirus (Reolysin) have taken place, both for pediatric and adult sarcomas.[v][vi]While previous laboratory studies showed that Reolysin may be effective therapy in sarcomas,[vii] these clinical trials had mixed results. 
  • A trial looking at varicella zoster virus (chicken pox) in combination with immunotherapy is currently open for osteosarcoma patients who meet certain criteria.  For more information about this trial visit: https://www.clinicaltrials.gov/ct2/show/NCT01953900?term=sarcoma+virus&recr=Open&rank=8
  • A Phase II clinical trial that just opened in March testing pembrolizumab in both soft tissue sarcoma and bone sarcoma patients who meet certain criteria. While not a virotherapy, Pembrolizumab (Keytruda) is a promising drug that works similarly to virotherapies, and is already approved to treat melanoma.   For more information about this trial visit: https://clinicaltrials.gov/ct2/show/NCT02301039?term=pd1+and+sarcoma&rank=1

In summary, while some studies have shown promise, it is still unclear what the future holds for treating sarcomas with oncolytic virotherapies. We will continue to follow these and other potential treatments for this rare disease.