Khloe Frank Honors Biology 396 Dr.

Lara Shamieh 10/19/11 Paper Summary: Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1 Hunder et al. 2008 The researchers for this study were investigating if CD4+ T cells can be taken from a patients blood, grown in vitro with selection for an antigen-specific response, and then reintroduced into the patients body in order to treat a cancerous tumor. This is important and interesting because successful results would have huge implications for future cancer treatments and perhaps even for use in treating other diseases. For this study, the researchers tested one patient who had a metastatic melanoma tumor containing multiple antigens (mostly NY-ESO-1, MART-1, and MAGE-3), and whose condition had not improved during previous cancer treatments. The researchers took CD4+ T cells from the patients body and cloned them in culture, then selected for the cells that recognized the NYESO-1 epitope and acted against the antigen by yielding interleukin-2 and interferon-y. In this study, the patient did not receive any conditioning or treatment prior to the introduction of about 5 billion antigen-specific CD4+ T cell clones into his body. The researchers modeled their procedure for cloning CD4+ T cells on the previously established one for cloning CD8+ T cells, but grew the CD4+ cells specifically to respond to NY-ESO-1 by treating them with an NY-ESO-1 peptide, interleukin-2, and interleukin-7. The researchers then selected one of the four resulting antigen-specific CD4+ clones to further cultivate and introduce into the patient with the objective of causing his tumor to regress. After the clone cells were introduced into the patient, the researchers completed assays to show which antigens the clone cells responded to and to determine for which antigens the patients body had produced antibodies. These assays confirmed that the cells they had cloned responded to the NY-ESO-1 antigen. During the period after the clone cells were introduced into the patients body, the researchers used quantitative PCR to measure the number of CD4+ clone T cells in the present in patient at various times. PCR measurements showed no perceptible clone cells in patient before infusion, but measured them to be 2.0% of total peripheral-blood mononuclear cells three days after treatment and remain at 0.7-3.0% for at least 80 days after treatment. At 2, 22, and 26 months after clone cell treatment, scan evaluations showed that the cancerous tumor had been repressed and remained imperceptible in the patient. No other treatments were needed besides the original clone cell infusion, and there were neither extraordinary side effects (besides the usual for cytokine infusion) nor noticeable detrimental long-term consequences as a result of this procedure. A key observation from this study was that the NY-ESO-1 antigen-specific clone cell treatment induced other T cells that were specific to other antigens present in the patients tumor (MART-1 and MAGE-3) to become more active and prevalent as well. The authors of the paper suggest that tumor cells killed by NY-ESO-1 CD4+ T cell clones may have contained the other

Khloe Frank Honors Biology 396 Dr. Lara Shamieh 10/19/11 antigens and thus, upon their death, triggered the activation of T cells specific to those antigens in a response called antigen spreading. They also considered the possibility that regression of the tumor created an environment in which other antigen-specific T cells could develop. The clone cell treatment did not cause an increase of T cells specific to antigens that were not prominent in tumor. This antigen spreading effect is important because it shows that only one type of antigen-specific T cell clone is necessary in order to cause an entire tumor to regress, which makes this treatment very efficient and effective. Overall, this study supports the hypothesis that CD4+ T cells from a patient can be cultured with selection for an antigen-specific response and then reintroduced into the patients body in order to treat a cancerous tumor. The side effects of such treatment are minimal, the treatment works quickly and for a long period of time (relative to surgical removal, treatment with CD8+ T cells, and some drug treatments), and the treatment is effective in causing tumor regression. The costs were not mentioned in this article, but should also be taken into account when considering the outlook for future use of this treatment. Overall, the results of this study demonstrate that this procedure has great potential as a cancer treatment and should continue to be researched and modified.