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Natural killer cells as effective as, less toxic than T cells
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Natural killer cells engineered with chimeric antigen receptors demonstrated comparable efficacy as T cells but appeared less toxic, according to study results.
The findings could be significant, given the advantages that natural killer cells offer.
For example, engineered natural killer cells could be delivered safely in an off-the-shelf manner, and research so far suggests natural killer cells do not trigger the same potentially severe toxicities — such as organ damage, neurotoxicity or death — that have been associated with use of re-engineered T-cells.
The results — obtained from studies in mice — have laid the groundwork for a planned trial in humans.
“One of the main challenges of immunotherapy has been the clinical manufacture of modified cells,” Dan S. Kaufman, MD, PhD, professor of medicine in the division of regenerative medicine and director of cell therapy at UC San Diego School of Medicine, as well as a HemOnc Today Editorial Board Member, said in a press release. “We have shown that we can engineer [human-induced pluripotent stem cells] and create chimeric antigen receptor-expressing natural killer cells to better target refractory cancers that have resisted other treatments.”
HemOnc Today spoke with Kaufman about the research his team has conducted into re-engineering natural killer cells with chimeric antigen receptors, the advantages to using natural killer cells instead of T cells, the potential implications if this approach is proven effective and safe, the malignancies for which this approach may offer the greatest benefit, and the next steps in research.
Question: Can you explain the rationale for this approach?
Answer: Natural killer cells are a population of lymphocyte immune cells that are separate from T cells. They are known to be a part of the immune system and are known to kill tumor cells and virally infected cells. Clinical studies with natural killer cells have been conducted for more than 15 years, and they have shown that allogeneic natural killer cells have been effective for treating certain cancer types — primarily leukemia, and specifically acute myeloid leukemia.
Q: What have you found so far?
A: Studies from my lab during the past decade have shown that we can make these natural killer cells from human pluripotent stem cells. We did this first with human embryotic stem cells, and now we do it from induced pluripotent stem cells. Natural killer cells can be made in the lab that essentially look and act the same as natural killer cells that we get from the blood. We have been testing these cells against certain types of tumors, and results from our most recent study show we can engineer them to work better than CAR T cells. We are now able to add these CARs to enhance the natural killer cell-mediated killing of more refractory tumors.
Q: Is there any indication as to which malignancies may be the best target for this approach?
A: Similar to many experts in the field conducting work on CAR-expressing cells — whether it is natural killer cells or T cells — we are trying to figure out what the best solid tumor targets are. We have shown that, even without the CARs, natural killer cells treat AML. This cancer type will most likely be included in some of the initial trials for these cells. As far as solid tumors, the mesothelin targeting that we showed in this paper for ovarian cancer, which is expressed on many other tumor types — such as pancreatic and breast cancers — may be a good target for initial clinical trials. There are a lot of possibilities, and we are still trying to determine what the best human target is going to be.
Q: What are the potential implications if this approach is proven to be safe and effective?
A: This is a real way to improve upon CAR T-cell therapies, and we will be able to treat larger numbers of patients. Natural killer cells work as allogeneic cells, so they do not have to be matched to a specific patient. Therefore, we can now produce a targeted, off-the-shelf therapy. We can make hundreds or thousands of doses to treat large numbers of patients, and we can do this in a very standardized method.
Q: How long until a clinical trial is feasible , and what would that trial ideally look like in terms of patient population and design?
A: We hope to start a human clinical trial with collaborators by the end of this year using what we have termed the ‘unmodified’ natural killer cells in the initial trial. We hope to have these as the first cells in trials in the United States during this calendar year. Then, either in 2019 or early 2020, we hope to have these CAR-expressing natural killer cells in clinical trials. – by Jennifer Southall
Reference:
L Ye, et al. Cell Stem Cell. 2018;doi:10.1016/j.stem.2018.06.002.
For more information:
Dan S. Kaufman, MD, can be reached at University of California, San Diego, 9500 Gillman Drive, La Jolla, CA 92093; email: dskaufman@ucsd.edu.
Disclosure: Kaufman reports a consultant role with and research support from Fate Therapeutics.