Results of a small trial published online on 5 March in the Proceedings of the National Academy of Sciences, where patients with progressive metastatic melanoma were treated with billions of lab-grown clones of the their own anti-tumor cells, are raising hopes that a treatment can be developed to knock back the advanced form of this most dangerous skin cancer.
Melanoma is a type of cancer that develops in the pigment-producing cells of the skin. Metastatic melanoma is melanoma that has spread to other parts of the body, such as the tissue that lies beneath the skin, the lymph nodes, or to organs like the lungs, liver, brain and bones.
The small, early-phase trial involved 11 patients, and was led Dr Cassian Yee of the Clinical Research Divison of Fred Hutchinson Cancer Research Center in Seattle in the US.
The aim of the trial was to find the most suitable environment in which to infuse 15 to 20 billion tumor-fighting CD8+ T cells so they could last as long as possible in the body to fight cancer cells.
Yee and colleagues extracted CD8+ T cells from 11 patients with progressive metastatic melanoma that was no longer responding to conventional treatment and multiplied them in the lab before re-infusing them back into their bloodstream.
CD8+ T cells are a type of white blood cell in the body’s immune system that attacks a protein associated with the cancer.
Yee, an expert in T cell therapy for patients with cancer, and a researcher in the Hutchinson Center’s immunotherapy program, told the press:
“Our results confirm that if we can develop methods to grow these kinds of cells in the lab, then we can give these high-proliferating, helper-independent T cells to all patients for T-cell therapy.”
“Fortunately, we have been able to achieve this goal and are in the process of treating patients in an ongoing study with these helper-independent T cells,” he added.
The results showed that one of the 11 patients experienced complete remission that has lasted for at least three years.
Four other patients experienced a temporary halt in cancer growth.
Before they received their T cell infusions, all the patients were treated with high doses of cyclophosphamide, a chemotherapy drug usually given to treat lymphomas. But in this case, it was to eliminate all the patients’ lymphocytes or white blood cells. Doing this stimulates the body to release growth factors that help produce more T cells.
After receiving their infusions, 8 of the 11 patients also received low doses of interleukin-2 (IL-2) growth factor, to further encourage T cell growth.
The patient who experienced complete remission, and the four who experienced temporary non-progression of the disease, were among the 8 who received low doses of IL-2.
The remaining three of the 11 patients received high doses of IL-2, and while two of them also experienced temporary non-progression of the disease, this dose showed more toxic side effects.
In all cases, except for the patient who experienced complete remission, disease progression resumed 12 to 19 weeks after the T cell infusion.
Speculating on why some patients responded to treatment better than others, Yee said while individual differences among the patients had something to do with it, the main reason is the persistence of the infused T cells in the body.
This trial shows “we certainly have a way to go,” said Yee, but it does contribute two key findings about how to produce the best environment in which to use “adoptively transferred” tumor-specific T cells.
The first key finding is that high-dose cyclophosphamide alone is safe and results in T cells lasting much longer in the body than with other chemotherapy drugs, or none at all, as demonstrated in other studies.
The other key finding is that the CD8+ T cell clones infused into the patients persist. Yee and colleagues believe this is because they are derived from “central memory T cells”, which can fight cancer and infections:
“When we infused them as clones, they reverted back to an earlier memory type of T cell, ” said Yee.
“This is important because these cell types have a high potential to proliferate in the patient,” he added.
Yee and colleagues also found that two of the patients showed signs of upregulation in the receptor for IL-7 growth factor, and for CD28. Both these are important for promoting T cell growth. For instance, CD28 codes for a protein that helps T cells multiply and survive.
This suggests the cloned cells are “helper independent”, since they showed signs of not requiring help from any other growth agents.
Yee said in the future, studies may use other versions of interleukin growth factor, and even vaccines, to boost the body’s response to the infused T cells.
Funds from the National Institutes of Health and the National Cancer Institute, together with a grant from the Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund, helped pay for the trial.
Written by Catharine Paddock PhD