|New Method of Gene Therapy Alters Immune Cells for Treatment
of Advanced Melanoma; Technique May Also Apply to Other Common Cancers
A team of researchers at the National Cancer Institute (NCI), part of the National
Institutes of Health, has demonstrated sustained regression of advanced melanoma
in a study of 17 patients by genetically engineering patients’ own white blood
cells to recognize and attack cancer cells. The study appears in the online edition
of the journal Science on August 31, 2006*.
“These results represent the first time gene therapy has been used successfully
to treat cancer. Moreover, we hope it will be applicable not only to melanoma,
but also for a broad range of common cancers, such as breast and lung cancer,” said
NIH Director Elias A. Zerhouni, M.D.
Autologous lymphocytes — a person’s own white blood cells — have previously
been used to treat metastatic melanoma. In a process called adoptive cell transfer,
lymphocytes are first removed from patients with advanced melanoma. Next, the
most aggressive tumor-killing cells are isolated, multiplied in the lab, and
then reintroduced to patients who have been depleted of all remaining lymphocytes.
While reasonably successful, this method can only be used for melanoma patients
and only for those who already have a population of specialized lymphocytes that
recognize tumors as abnormal cells.
Thus, NCI researchers, led by Steven A. Rosenberg, M.D., Ph.D., sought an effective
way to convert normal lymphocytes in the lab into cancer-fighting cells. To do
this, they drew a small sample of blood that contained normal lymphocytes from
individual patients and infected the cells with a retrovirus in the laboratory.
The retrovirus acts like a carrier pigeon to deliver genes that encode specific
proteins, called T cell receptors (TCRs), into cells. When the genes are turned
on, TCRs are made and these receptor proteins decorate the outer surface of the
lymphocytes. The TCRs act as homing devices in that they recognize and bind to
certain molecules found on the surface of tumor cells. The TCRs then activate
the lymphocytes to destroy the cancer cells.
In this study, newly engineered lymphocytes were infused into 17 patients with
advanced metastatic melanoma. There were three groups of patients in this study.
The first group consisted of three patients who showed no delay in the progression
of their disease. As the study evolved, the researchers improved the treatment
of lymphocytes in the lab so that the cells could be administered in their most
active growth phase. In the remaining two groups, patients received the improved
treatments. Two patients experienced cancer regression, had sustained high levels
of genetically altered lymphocytes, and remained disease-free over one year.
One month after receiving gene therapy, all patients in the last two groups still
had 9 percent to 56 percent of their TCR-expressing lymphocytes. There were no
toxic side effects attributed to the genetically modified cells in any patient.
Approaches to increase the function of the engineered TCRs — including the
development of TCRs that can bind to tumor cells more tightly — and to further
optimize delivery methods using retroviruses are under investigation. In addition,
the researchers believe it may be beneficial to further modify lymphocytes by
inserting molecules that assist in directing lymphocytes to cancerous tissues.
Clinical trials are being conducted to enhance treatment effectiveness using
total body radiation therapy to deplete a patient’s supply of non-altered lymphocytes
before replacing them with purely engineered cells. The researchers also have
isolated TCRs that recognize common cancers other than melanoma.
“We are currently treating advanced melanoma patients using adoptive transfer
of genetically altered lymphocytes, and we have now expressed other lymphocyte
receptors that recognize breast, lung, and other cancers,” said Rosenberg.
“These very exciting successes in treating advanced melanoma bring hope that
this type of gene therapy, altering lymphocytes, could be used in many types
of common cancers and could be achievable in the near future,” said NCI Director
John E. Niederhuber, M.D. He acknowledged Rosenberg for his persistent and visionary
study of the role of the immune system in the treatment of cancer. “He is one
of the leaders we all look to for moving us forward,” Niederhuber said.
Skin cancer is the most common of all cancers. According to the American Cancer
Society, melanoma accounts for about 4 percent of skin cancer cases, but it is
also the most serious and most aggressive type. In the United States, an estimated
62,190 new cases of melanoma will be diagnosed and approximately 7,910 people
will die of the disease in 2006.
For a Q&A on gene therapy techniques similar to those used in this study, go
For more information on Dr. Rosenberg’s research, go to http://ccr.cancer.gov/staff/staff.asp?profileid=5757.
For more information about cancer, please visit the NCI Web site at http://www.cancer.gov,
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.