In the fight against cancer, we have many weapons – some are chemicals like those used in chemotherapy, while others target specific molecules that inhibit the cancer’s growth. Both these methods are aimed at targeting and killing cancer cells, but they have limitations.
Now, a new weapon is emerging – the cell – which many believe can transform how we treat cancers. Chemotherapy and radiation therapy, the most common treatments for cancer today, lack the precision that cell therapies have. To get around this, we are now trying to use a person’s cells to fight their own cancer.
The leading example of this is CAR-T cell therapy, where an individual’s own immune cells are fitted with a specialised receptor – chimeric antigen receptor (CAR) – capable of locating and targeting the cancer. While this therapy is promising it comes with a costly price tag, encouraging researchers to look at other members of the immune system.
One of the most promising targets emerging in this area is natural killer cells (NK).
Problems with CAR-T cell therapy
“The cells, which normally initially respond to infection are the macrophages and NK cells, and these form a component of the [immune] system which is called the innate immune system,” says Dr Mahendra Rao, the Chief Development Officer of Vita Therapeutics, a cell engineering company based in Baltimore, Washington DC.
He further explains that the adaptive immune system, one which learns how to fight off an infection after it has previously encountered, involves T and B cells. “T and B cells became very attractive (to treat cancer) because of the work that was done to show that if you activate the T cells correctly, it becomes an effective method to kill cancer cells”, adds Rao.
Thus came the use of CAR-T cell therapy, which has shown to be a viable immunotherapy for blood cancers especially. The therapy involves the collection of T cells from an individual, and re-engineering them to produce proteins on their cell surface to recognise and bind to the proteins found on cancer cells.
But there remain two big problems with T cells, says Rao. CAR-T therapy is autologous (use cells obtained from the same individual) because of the immune response that it kicks off in the body if donor cells are taken. Hence the only option left is to take cells from someone who is already sick instead of someone who is healthy adds Dr Rao.
Another well-known side effect of CAR-T cell therapy is something known as the ‘cytokine storm’. When genetically modified T cells encounter cancer cells, they get highly activated and release large number of cytokines leading to symptoms of high fever, severe inflammation, low blood pressure, and in some cases, organ dysfunction. The only way to prevent this is to administer immunosuppressive medication.
“Unless you do something to bypass the immune system which is always hard to do as it affects the cells, it can cause a lot of problems” says Dr Rao.
The other problem with CAR-T cell therapies is that they can be extremely expensive to make. “It is a custom therapy, because you have to make it for each person individually,” says Dr Rao. For people in countries like India this therapy can run into multiple lakhs of Rupees.
Therefore, we turn to other players in the immune system, ones that can work just as effectively as CAR-T cells and are cheaper to manufacture. And that is how NK cells became an attractive option to look at.
The NK Alternative
Since NK cells are part of the innate immune system, these cells can quickly identify and eliminate abnormal cells, including cancer cells. NK cells bypass both problems that plague CAR T-cells: they do not cause the harmful side effects associated with CAR-T cells and are a more cost-effective option to manufacture.
“NK cells also have this advantage that you could use them against all cancers, which means one product for many cancers,” says Rao, pointing towards the fact that CAR-T cells now are used mainly against blood cancers and not solid tumours.
However, the use of NK cells to treat malignancies are few and far in between. Dr. Armand Keating, a clinician scientist at the Princess Margaret Cancer Centre in Toronto was among the first to work with NK cells. Drawing on his experience with bone marrow transplants for cancers, he saw first-hand the side effects that come with the treatment.
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“It occurred to me that cell therapy with specific cell populations could be the next sort of transplant strategy,” says Dr Keating. This prompted him to start a phase 1 clinical trial which had a total of 12 participants, all of whom has a relapse in their cancer and were undergoing some amount of palliative care. The trial used irradiated NK cells (NK92) to treat their cancer.
“Three patients out of twelve had achieved a complete remission with this NK92 line,” says Dr Keating. Although this was very early days into NK cell research it set the bar for the future use of these cells.
Dr Armand says that preliminary data from trials show that NK cells seem safe but long term follow up of participants is needed. “Within five years, we could have this [NK cell therapy] as standard of care possibly even for the treatment of some solid tumours.”
The next generation
Currently NK cell therapy lies predominantly in the research phase with several clinical trials underway. The goal is to see if NK cells can be an effective treatment for both blood cancers and solid tumours.
One such promising venture lies in the development of CAR-NK cells where NK cells can be fitted with the CAR, like what has been done in CAR-T cell therapy.
“My sense is that the next step will be to not just focus on one type of target but use a CAR-NK which will be directed against maybe two or more targets. And some of those, could be directed against the microenvironmental cells, which themselves are not malignant, but protect the tumour,” says Dr Keating.
If the strategies that are being investigated for treating solid tumours with NK cells bear out, I think it could be a major advance he adds.
Currently, CAR-NK cells have been preclinically tested in multiple solid tumours including breast cancer, ovarian cancer, pancreatic cancer, colon cancer, glioblastoma, etc.
CAR-NK cells could be promising alternative to engineered CAR-T cells, and one of the advantages is that NK cells can be sourced from the blood of unrelated donors or from umbilical cord blood that has been previously frozen. This helps avoid the use of one’s own NK cells which are not as potent.
Unlike T cells from volunteers, NK cells from others does not cause serious reactions and can provide more speedy off-the-shelf therapy says Dr Keating.
Future Potential
“The next step includes the use donors or volunteers who give blood that contains NK cells” says Dr Rao. Other approaches could include taking NK cells from cord blood or more recently from pluripotent stem cells adds Dr Rao.
As these challenges are being tackled, it signifies the addition of a valuable new weapon in our fight against cancer.
Researchers were also investigating the use of NK cell therapy in combination with other immunotherapies, such as checkpoint inhibitors and monoclonal antibodies. “The combination of anti-cancer antibodies along with NK cells is a very new exciting field that is coming along,” says Dr Rao.
