A 52-year-old man with advanced metastatic melanoma, a deadly form of skin cancer, had a complete remission after being infused with billions of clones of his own CD4+ T tumor killer cells that had been cultured outside his body and “programmed” to attack a specific type of melanoma cancer cell. Experts are cautiously optimistic that breakthroughs like this are bringing us closer to the day when we regard cancer like diabetes, not curable, but controllable.
The US study was published online today, 19th June, in the New England Journal of Medicine (NEJM) and is the work of lead researcher Dr Cassian Yee, an associate member of the Clinical Research Division at Fred Hutchinson Cancer Research Center, Seattle, Washington, and colleagues.
Using a patient’s own immune system to fight cancer is a growing field called immunotherapy, where treatments don’t have the toxic side effects of standard chemotherapy and radiation therapy.
For this study, the researchers took some of the man’s own cancer-fighting immune system cells, in this case a group of white blood cells called CD4+ T cells, made about 5 billions clones of them in the lab, and then infused them back into his body. Two years later, his symptoms had vanished. Other scientists have tried to extract and clone immune cells but failed, wrote Yee and colleagues.
Some experts have reacted with caution, saying that further research needs to be done to confirm these findings, while others have hailed this as a breakthrough that demonstrates how the body’s own defences might be harnessed to fight cancer.
The human immune system already has mechanisms for fighting cancer by killing tumor cells, but sometimes these fail. And many experts believe there are ways to repair or boost these natural processes as alternatives or adjuncts to chemotherapy and radiation therapy.
The patient, a 52 year old man, who had been diagnosed with recurrent melanoma, the deadliest form of skin cancer, enrolled in a clinical research trial at Fred Hutchinson Cancer Research Center because his cancer had not responded to conventional treatments.
By the time the cloned cells were infused back into his body, the patient’s melanoma was in an advanced metastatic state, it had reached Stage 4 and spread to a lymph node in his groin and a lung.
60 days after the infusion, a procedure that took 2 hours, all his symptoms had vanished.
The man received no additional therapies, for instance treatment with growth factor or cytokines. 12 months after treatment, PET and CT scans showed no tumors present, and the patient remained disease free for a further two years, which is the last time he was examined.
In a statement Yee told the press that:
“We were surprised by the anti-tumor effect of these CD4 T cells and its duration of response.”
However, while delighted with the result, he also expressed caution, saying that the findings need to be confirmed with a larger study before the method can be said to be effective.
The patient in this study had tumor cells expressing an antigen that had a highly specific effect on his immune system.
If the approach proves to be effective in other patients, Yee estimated it might be successful in as many as 25 per cent of patients with late stage melanomas with the same type of immune system and tumor antigen.
The man on whom the treatment was sucessful was one of nine patients with metastatic melanoma who had enrolled on the trial to test the effect of using their own cloned CD4+ T cells at different doses.
Yee had already tried using CD8+ T cells in previous studies, but these cancer fighting cells don’t last as long without support from other cells, such as CD4+ T cells or growth factors such as interleukin 2. So Yee and his colleagues wondered if they might get better results with a massive dose of CD4+ T cells, because they last longer and make their own growth factor, interleukin 2, and they increase the anti-tumor power of existing CD8+ T cells.
But they had to wait until a suitable method for extracting CD4+ T cells was available, which they modified for this study. This enabled them successfully to extract the patient’s CD4+ T cells, and then clone them to be specific to the NY-ESO-1 melanoma antigen that this patient’s tumor was expressing.
The infused cloned cells lasted for at least 80 days in the patient’s body. But was more surprising, was that even though the cloned cells could only address 50 to 75 per cent of the tumor cells (because only this proportion expressed the NY-ESO-1 antigen the cloned cells were programmed for), the whole tumor shrank.
Yee and colleagues wondered if perhaps the infused cells, although only specific to one type of antigen, caused a generalized response in the immune system so that it could also target tumor cells that were expressing other types of antigen.
This idea was proved in that follow up tests revealed that the immune system’s T cells were responding to two additional tumor antigens, MAGE-3 and MART-1.
A cancer expert at Imperial College in London, Professor Karol Sikora, told BBC News that he was very excited by the study’s findings. He said one day, because of research like this, cancer will be like diabetes, we will have learned how to suppress it, if not actually cure it:
“Patients will live with their cancer, and die with their cancer, but not of their cancer,” said Sikora.
Chief surgeon at the National Cancer Institute in the US, Dr Steven Rosenberg, told the Wall Street Journal that he saw studies like this heralding the arrival of:
“The ultimate personalized medicine, because literally we create a new drug for every patient out of their own cells.”
Rosenberg, who has been working in this area for some time and has sldo published a number of papers on immunotherapy, said the drawback was that this kind of treatment was labour intensive and “doesn’t lend itself well to commercial development”.
Rosenberg presented findings of a similar project at a conference in Boston earlier this month, where 52 patients out of 93 that had been treated showed a positive response, with four of them experiencing complete remission. However, the complete results are not yet available.
“Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1.”
Hunder, Naomi N., Wallen, Herschel, Cao, Jianhong, Hendricks, Deborah W., Reilly, John Z., Rodmyre, Rebecca, Jungbluth, Achim, Gnjatic, Sacha, Thompson, John A., Yee, Cassian
N Engl J Med, Volume 358, Number 25, pages 2698-2703.
Published online on 19 June 2008.
Sources: NEJM abstract, Fred Hutchinson Cancer Research Center, BBC News, Wall Street Journal.
Written by: Catharine Paddock, PhD