In the past few months, we’ve seen major fundraises and partnerships from European biotechs that develop cancer cell therapies based on a type of immune cell called natural killer cells. This continuing progress could one day result in off-the-shelf cell therapies for cancer.
T-cell immunotherapies like CAR T-cell therapy have revolutionized cancer treatment in recent times. However, they have a significant disadvantage. The patient needs to get their immune T cells extracted, engineered to target the tumor, and infused again. This approach is costly and takes weeks — a luxury that many cancer patients can’t afford. Also, the cells extracted are often of variable quality, making it harder to produce an effective cell therapy.
Natural killer cells — a key part of the innate immune system — could provide an answer to many of the disadvantages of current cancer immunotherapies.
Like T cells, natural killer cells can be engineered to better recognize a specific tumor. But they have a couple of advantages. One is that they can detect more chemical signals of tumors than T cells. Another is that they are less prone to attacking healthy tissue than T cells are. This means it’s possible to give patients natural killer cell therapies derived from healthy donors with less risk of the foreign cells attacking the patient’s body.
“The key to unlocking the true potential of CAR therapy is off-the-shelf treatments,” said Chris Nowers, CEO of the Irish startup ONK Therapeutics.
The most advanced natural killer cell therapies are currently being tested in phase II trials to treat solid tumors and blood cancers. Some of the most prominent biotechs in the field include Bellicum Pharmaceuticals and NantKwest in the US, XNK Therapeutics in Sweden, and Kiadis Pharma in the Netherlands, which closed a €875M licensing deal with Sanofi in July. Small European companies have also been busy in the last several months bringing their own versions of these cell therapies to the fore.
Earlier this month, ONK Therapeutics raised €6.8M ($8M) to develop an off-the-shelf natural killer cell therapy for blood cancer. The firm engineers natural killer cells to present two types of cancer-busting proteins on their surface. One type is CAR proteins, the same used in CAR-T cell therapy to direct the cells against a specific target. The other is TRAIL proteins, which cause cancer cells to commit suicide.
Equipping natural killer cells with both CAR and TRAIL proteins allows them to attack cancer on two fronts, stopping tumor cells from escaping the therapy by mutating their surface proteins.
Michael O’Dwyer, CSO and founder of ONK Therapeutics, explained that the action of TRAIL proteins against cancer has been known for the last 20 years, but initial treatment experiments yielded disappointing results. The problem was getting the natural killer cells to cluster sufficiently around tumor cells to activate cell death.
“We are expressing TRAIL in its natural form, in the membrane of the cell,” O’Dwyer told me. He added that the boosted expression of TRAIL could make the immune cells better at killing multiple tumor cells than normal.
Natural killer cells have shown great potential for treating blood cancer, but their applications might not stop there. “One of the biggest challenges moving forward is how to build on the developments in the field and harness natural killer cell therapies for the treatment of solid cancers,” Anders Holm, COO & Head of Business Development of Oslo-based Zelluna Immunotherapy, told me.
In June, the Norwegian biotech raised €7.5M to tackle solid tumors using natural killer cells. To do this, the company is blending these cells with another emerging technology based on T cell receptors (TCRs), which can detect cancer proteins that are normally hidden within the tumor cell.
“TCRs are a well-validated solid tumor-targeting mechanism. When coupled with the killing capacity of natural killer cells, we believe this approach could be a highly effective and safe treatment option,” Holm explained.
Just this month, Heidelberg-based company Affimed launched a transatlantic partnership with the natural killer cell therapy developer NKMax America to make cell therapies better at killing solid tumors. Affimed develops specific antibodies that activate these cells against tumors, which could turbocharge NKMax’s cells.
Their approach aims to activate both the innate and the adaptive immune system. “By enabling a patient to develop a full immune response, we can create newer approaches to treatment that could eventually lead to a cure,” Adi Hoess, CEO of Affimed, told me.
One of the main bottlenecks in natural killer cell therapies is understanding the interactions between these innate immune cells and the target cancer cell. These interactions can determine the effectiveness of the treatment, as well as any potential undesired effects such as life-threatening levels of inflammation. Studying these interactions often takes a few days. However, Amsterdam-based LUMICKS offers a solution to shorten this time to 15 minutes.
“Our technology is based on applying acoustic forces at the single-cell level to probe the interaction strength between natural killer cells and their target cells, which are commonly tumor cells,” Rogier Reijmers, Principal Scientist at LUMICKS, told me. He added that performing these tests in a high-throughput manner was impossible in the past, “but this barrier has now been breached.”
In July, LUMICKS announced a collaboration with the Dutch biotech Glycostem to improve the screening of natural killer cells and make it easier to select the best cells for developing into cell therapies.
Overall, natural killer cell therapies display an increasing enthusiasm from researchers and investors, which has translated into significant investments. Going forward, one of the main directions of companies in the field is to expand these cell therapies to more tumor types.
“In the last few years, basic biology, in vivo data, and further clinical experience shows the ability of natural killer cells to home to tumors, harbor memory-like features and persist in patients for much longer than expected. These intriguing data open up an untapped dimension of natural killer cells”, Holm noted. “The likelihood that natural killer cells will be used as allogeneic, off-the-shelf products is currently bigger than it is for T cells, or at least they are catching up rapidly,” Reijmers added.
Image from Elena Resko and ©ONK Therapeutics