Calling a halt: CD4 T-cell therapy can control advanced melanoma

August 1, 2008

A proof-of-concept study has shown, for the first time, that it is possible to control and perhaps eradicate advanced melanoma using only a patient's cloned CD4 T cells.

Key Points

National report - A proof-of-concept study has shown, for the first time, that it is possible to control and perhaps eradicate advanced melanoma using only a patient's cloned CD4 T cells.

One of 10 select patients has been able to live cancer-free for two years following completion of the procedure; response among the other patients varied.

The therapeutic approach focused on NY-ESO-1, a marker peptide found on the surface of about 50 percent to 75 percent of melanoma cells. It can be recognized by a particular T cell subset of the immune system that is produced by the HLA-DPB1*0401 allele.

The patient's T cells were collected through leukapheresis; the key subset was isolated and expanded in vitro over the course of several weeks, and 5 billion cells were infused. There was no additional conditioning of the cells or the patient. He experienced transient flu-like symptoms for three days, lead researcher Cassian Yee, M.D., tells Dermatology Times.

NY-ESO-1-specific T cells ordinarily are very rare, and in this patient, they were not detectable in his blood at baseline, even though they could be culled and expanded from that sample.

By day three post infusion, they constituted almost 2 percent of all peripheral blood mononuclear cells, and that fluctuated between 0.7 percent and 3.0 percent of PBMCs for as long as they were measured.

Results

Follow-up CT scanning of the patient two months after infusion showed complete resolution of the melanoma, including tumor metastasis in the lungs and lymph nodes. The patient has remained cancer-free for two years.

The study was conducted at the Fred Hutchinson Cancer Research Center and the University of Washington, and appeared in the June 19 issue of the New England Journal of Medicine.

Dr. Yee says this is "a proof-of-principle study that demonstrates that these CD4 T cells alone, if given in sufficient numbers, have an antitumor effect. They persist long term in patients, and in this case, appear to lead to sustained remission."

He says the approach was made possible by recent advances in methodologies for isolating and expanding the T cell subset that recognizes NY-ESO-1.

Dr. Yee believes the infused CD4 T cells persisted for at least 80 days, because they generate the cytokine interleukin-2 (IL-2) that is necessary for their survival.

CD8 T cells used in earlier studies "don't last for more than a few weeks," probably because they do not produce the necessary IL-2.

Surprisingly, the intervention also seems to have stimulated a broader immune response that includes T cells that recognize MAGE-3 (tumor markers melanoma antigen-3) and MART-1 (melanoma antigen recognized by T cells).

Dr. Yee says that may help to explain what appears to be the complete eradication of the melanoma, even though a substantial portion of the tumor cells did not express NY-ESO-1.

Additional patients enrolled

The patient was one of nine enrolled in the ongoing study. All had advanced, progressive disease that was refractory to therapy.

The paper dealt only with the single patient, but Dr. Yee was willing to speak about the other nine patients in the study.

While the specificity of the T cells is important, he says, so too are their numbers. Some patients did not respond at all to the intervention, while others showed a dose response; the higher number of CD4 T cells infused, the more likely patients were to have a favorable response and stable disease.

Patients who showed little or no response to a low dose often showed a stronger response when infused a second time with a high dose of T cells.

Dr. Yee hopes that a combination of CD4 T cells with other agents, such as CD8 T cells, might increase both the proportion of patients who respond to the therapy and the persistence of that response.

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