Adoptive Cell Transfer Shows Dramatic Results in Refractory Melanoma
A study in the April 2005 Journal of Clinical Oncology, from the lab of Dr. Steven Rosenberg, chief of National Cancer Institute's (NCI) Surgery Branch, reports promising results of adoptive cell transfer (ACT) immunotherapy among 35 patients with metastatic melanoma. ACT is an innovative biological therapy developed by NCI researchers which has been shown to shrink solid tumors that have resisted other treatments. Of that cohort, 3 experienced a complete response and 15 had a partial response lasting from 2 months to 2 years - a response rate of 51 percent. Thirteen of the 18 who responded had cancers resistant to chemotherapy and 34 of the 35 patients had been resistant to high-dose interleukin-2 (IL-2) therapy. The study provides clinical confirmation of Dr. Rosenberg's previous cancer immunotherapy study published in Science in 2002. That study showed an effect from treatment on tumors in 6 out of 13 patients - a response rate of 43 percent.
These and other studies are laying the foundation for biological therapies that use the body's immune system, directly or indirectly, to fight cancer or to lessen the side effects of other treatments. Dr. Rosenberg says the field was jump-started 20 years ago by the discovery that IL-2 cytokines - which can also be made in the lab - could shrink established, metastatic solid tumors. Since then, researchers have identified dozens of antigens on the surface of certain cancer cells that the body's immune system recognizes and attacks as intruders. Immunotherapeutic vaccines are being studied that would use these features to target exclusively the cancer cells for elimination. "Although cancer vaccines have yet to prove effective," Dr. Rosenberg said, "much work on that front is ongoing."
The ACT trials illustrate many of the principles of biological immunotherapy. Dr. Rosenberg's team first identified the specific T cells that each patient's immune system generated in response to his or her cancer. The researchers removed a sample of these cells from the tumor site and put them through an ex vivo enhancement process to create tumor-infiltrating lymphocytes (TILs). "These cells exist in the body and can specifically recognize the tumor; most are ineffective in their native state," explains Dr. Rosenberg. His team selected the most aggressive T cells from among those that had infiltrated the tumors, testing them ex vivo against tumor samples from that patient. The most potent cells were then collected and multiplied.
An important refinement on the technique was to prepare the patient's immune system to accept the engineered TIL cells. The researchers accomplished this by lymphodepletion, a chemotherapy regimen that eliminates many of the patient's resident ineffective T cells that failed to combat the cancer. Once the new multiplied TIL cells are returned to the patient's body and to the immature T cells in the biological environment of the patient's immune system, they are supplemented by high doses of IL-2 cytokines, proven immune system stimulators.
"We've learned a lot about managing such treatments and dealing with the toxicities safely," notes Dr. Rosenberg. "Treatment-related mortality in IL-2 patients is now less than 0.5 percent," and there were no treatment-related deaths in the new trial. "We saw the expected toxicities associated with lymphodepleting chemotherapy," the researchers wrote in the article, but "these were mostly transient and readily managed with standard supportive techniques."
A new era of cancer therapy is nigh. Although Dr. Rosenberg cautions against overselling early experimental results, he maintains the hope that - as his team and others continue to evolve biological approaches for their specific cancer models - "principles will crystallize and guidelines will emerge to lead us to more general immunotherapies for other types of cancer."
By Addison Greenwood