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Recent experiments exploring the use of patients’ own genetically reprogrammed immune cells toward the treatment of chronic diseases such as HIV and cancer have had encouraging and sometimes high-profile results. Yet, these studies have only been conducted in a limited number of individuals, and outcomes have been inconsistent, ranging from complete remission to complete inefficacy.
Now, two teams of researchers have demonstrated a method of using patients’ cells to create long-lived immune cells that target specific HIV and cancer antigens, and appear to resist degradation over time. Their work was published today in two separate papers in Cell Stem Cell.
“Our method has realized the functional rejuvenation and unlimited production of mature cytotoxic T cells with desired antigen-specificity for the first time in vitro,” says Shin Kaneko a stem cell biologist at Kyoto University in Japan and a co-author of the HIV-related study.
Difficulties in previous attempts to extract and reengineer T cells from patients are thought to be due in part to a phenomenon known as ‘cellular senescence’, a type of aging process. Naïve, quiescent T cells can survive for decades in the body. But active T cells, particularly those expanded outside the body in the laboratory, can gradually lose the ability to proliferate and be effective. This can lead to insufficient numbers of active immune cells to combat disease.
“Replicative senescence is likely to be a major issue for adoptive cell therapy,” says Carl June, an immunologist at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. “[These papers] address this issue and are exciting demonstrations of the progress in cell and developmental biology.”
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Are 'turbocharged' immune cells key to cancer cure?
Friday January 4 2013
"Immune system 'booster' may hit cancer," BBC News reports.
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| Modified immune cells could fight both cancer and infections |
These cells, known as cytotoxic T lymphocytes (CTLs), are produced by the immune system and are able to recognise specific markers on the surface of various tumour cells, causing them to launch an attack to kill the tumour cells.
But the problem is that immune cells such as CTLs are only produced in small numbers naturally and have a short lifespan. This means these cells are not normally effective in curing the cancer completely.
In this study, researchers attemped to bypass this problem by using stem cells to "mass-produce" CTLs in laboratory conditions. This involved three-stages:
- isolating a specific type of CTL that recognises a marker on melanoma skin cancer cells
- "reprogramming" these CTLs to turn them into stem cells that could divide and develop into any type of cell in the body
- growing the stem cells under specific conditions in order to make them produce large numbers of "cloned" CTLs that would similarly attack melanoma skin cancer cells
The concept of stimulating the immune system to attack cells in the body is known as immunotherapy.
This research could be an important step in paving the way towards future immunotherapy treatment for some cancers, but it is at a very early stage.
Where did the story come from?
The news stories cover two research papers that used similar techniques published in the peer-reviewed scientific journal Cell Stem Cell.
The first study, which was focused on white blood cells that targeted cancer cells, was carried out by researchers from the RIKEN Research Center for Allergy and Immunology, Yokohama and Chiba University, Japan, and was funded by the Japan Science and Technology Agency, CREST.
The second study, on white blood cells taken from an HIV-positive individual, was carried out by researchers from the University of Tokyo and Kyoto University, among other research institutions in Japan. This research was supported by a grant-in-aid by the Global Center of Excellence Program of the Japanese Science and Technology Ministry, by a grant-in-aid from the Japan Society for the Promotion of Science, and by grants for AIDS research from the Japanese Ministry of Health, Labor and Welfare.
Immunotherapy: a cure for HIV?
In a related study, another group of researchers carried out similar research
using CTLs that were able to target HIV-infected cells from an HIV-positive
individual.
Again, the research demonstrated that they were first able to produce stem cells from these cells, and from the stem cells produce clones of CTLs that recognised the same HIV marker as the original cells.
While this is an exciting development, the same caveats apply and it is far too soon to tell if it would be either safe or effective in humans.
Again, the research demonstrated that they were first able to produce stem cells from these cells, and from the stem cells produce clones of CTLs that recognised the same HIV marker as the original cells.
While this is an exciting development, the same caveats apply and it is far too soon to tell if it would be either safe or effective in humans.
The UK media reporting of this research is accurate and well balanced. All news sources provide an appropriate tone of optimism that this research is an impressive breakthrough, but a long way from leading to a viable and safe treatment. The reporting also includes a number of useful quotes from the researchers and other experts commenting on the early stage of the research, and stressing the fact that further work is needed.
What kind of research was this?
The focus of this Behind the Headlines analysis is on the study on cancer, as opposed to the companion study on HIV. This was laboratory research which centred upon developing a method of using stem cells to clone and produce large numbers of a specialised type of white blood cell called cytotoxic T lymphocytes (CTLs). CTLs are cells naturally produced by the body that are tumour-specific, meaning that different CTLs are able to recognise specific markers on the surfaces of different tumour cells, and so launch an attack to kill the tumour cell.
Although CTLs have some effectiveness in killing tumour cells, mostly this is not enough to completely cure the patient of the tumour, because these CTL cells are only present in small numbers and have quite a short life span.
The focus of the current research was therefore to use stem cell methods to produce large numbers of tumour-specific CTLs that might pave the way towards future cancer treatments.
As this research has so far only been carried out in the laboratory, many more research steps are needed to investigate the effectiveness and safety of using these cells as treatments for tumours.
In the related study, another group of Japanese researchers carried out similar research, this time using CTLs that are able to target HIV-infected cells from an HIV-positive individual, and then seeing whether they were able to generate large numbers of these cells in the laboratory.
What did the research involve?
First the researchers started with a specific type of CTL (CD8+) which is able to recognise a certain marker (MART-1) on melanoma skin cancer cells.
In order to try to produce clones from this cell, they first needed to "reprogramme" the cell and turn it into a kind of pluripotent stem cell (iPSC), which has the potential to develop into any other type of body cell. To do this they infected the CD8+ cells with a particular virus that carries four genes previously shown to be able to reprogramme a normal body cell into an iPSC.
They then looked at the cell colonies that were produced about a month later. When they found that the cell colonies produced did have the characteristics of iPSCs, they then investigated whether these iPSCs could produce new CTLs that recognised the MART-1 marker. To do this, the researchers cultured these iPSCs with other cells which can help them to develop into T cells ("supporting cells"), and then with an antibody that stimulates them to develop specifically into CTLs.
In the related study, the other group of researchers also aimed to "reprogramme" the CD8+ cells taken from the HIV-positive individual to see if they could produce iPSCs from these, and then generate new clones of CD8+ cells that specifically targeted HIV.
What were the basic results?
The researchers found that after 40 days of being cultured with the "supporting cells", the iPSCs generated cells that expressed certain characteristic proteins produced by T cells, and about 70% produced a receptor that specifically recognised the MART-1 marker on melanoma skin cancer cells.
Stimulation of these cells with an antibody then produced a large number of CTL-like cells, and more than 90% of these cells specifically recognised the MART-1 tumour marker. When these cells were then presented with cells displaying this marker, they began to release a protein involved in "recruiting" other cells of the immune system to form an attack against the MART-1 cell.
This demonstrated that the cells produced from the iPSCs were functional, active CTL-like cells.
In the HIV study, the researchers found that they were also able to successfully reprogramme the HIV marker-recognising CTL cells to produce iPSCs, and from these stem cells they were then able to produce large numbers of CTL-like cells that recognised the same marker.
How did the researchers interpret the results?
The researchers say that starting with a specific type of melanoma-targeting cytotoxic T-lymphocyte (CTL), they were able to produce induced pluripotent stem cells (iPSCs). They were then able to use these stem cells to produce large numbers of functional melanoma-targeting cells identical to the original CTL cells.
These types of cells might one day have the potential to be considered as treatments for melanoma or other cancers, according to the researchers. The related study demonstrated that this approach could also possibly have potential for use in the field of cellular treatments for people with infectious diseases.
Conclusion
These two Japanese studies are valuable research, demonstrating that it is possible to take specialised immune cells and "turn" them into stem cells. These stem cells can then be used to generate a larger number of specialised immune cells.
Importantly, these cells were shown to have the ability to target the same specific cellular markers as their "parent" immune cells, which means they would be expected to be similarly effective in targeting abnormal cells in humans (either melanoma skin cancers or HIV-infected cells in the respective studies) and triggering an immune response to attack and kill them.
However, this research has so far only been conducted in the laboratory and has focused on developing a way to generate large numbers of CTL immune cells, rather than testing how effective they are at combating tumours or infections.
It also only involved two specific types of CTL which are only able to recognise certain markers on melanoma skin cancer cells or HIV-infected cells, and has not been investigated for other cancer types or other infectious diseases. It is also unclear how safe this approach to treating cancers or infection would be.
The next step is likely to be testing the effects of CTLs generated in this way on animals with these types of tumours or infections.
Much more work will be needed to examine the effectiveness and safety of any possible treatments in animals and humans before they could be widely used.
Overall these are promising findings, but it is still very early days.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.
Links to the headlines
Immune system 'booster' may hit cancer. BBC
News, January 3 2013
World first as scientists create cancer-killing cells that can be injected into patients. Daily Mail, January 3 2013
New Jab 'To Hunt Down Cancer Cells'. Daily Express, January 3 2013
Links to the science
Vizcardo R, Masuda K, Yamada D, et al. Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cell. Cell Stem Cell. Published online January 3 2013
Further reading
Nishimura T, Kaneko S, Kawana-Tachikawa A. et al. Generation of Rejuvenated Antigen-Specific T Cells by Reprogramming to Pluripotency and Redifferentiation. Cell Stem Cell. Published online January 3 2013
World first as scientists create cancer-killing cells that can be injected into patients. Daily Mail, January 3 2013
New Jab 'To Hunt Down Cancer Cells'. Daily Express, January 3 2013
Links to the science
Vizcardo R, Masuda K, Yamada D, et al. Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cell. Cell Stem Cell. Published online January 3 2013
Further reading
Nishimura T, Kaneko S, Kawana-Tachikawa A. et al. Generation of Rejuvenated Antigen-Specific T Cells by Reprogramming to Pluripotency and Redifferentiation. Cell Stem Cell. Published online January 3 2013
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