Immunotherapy innovation: Moon Shots effort aims natural killer cells at
Clayton Boldt, Ph. D.
MD Anderson’s adoptive cell therapy (ACT) platform is advancing the next generation of cell-based immune therapies to bring innovative approaches to our patients quickly, safely and effectively. The platform is one of the research engines driving MD Anderson’s Moon Shots Program®, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
By working closely with several of the disease-focused Moon Shots®, the ACT platform has pioneered the use of chimeric antigen receptor (CAR)-modified natural killer (NK) cells for treating cancer. This cutting-edge CAR NK-cell platform was the focus of a recent licensing agreement and research agreement between MD Anderson and Takeda, who will now collaborate to bring this innovative cell therapy forward.
Q: Can you describe the normal function of NK cells and why you’re interested in using them as a new cell-based cancer therapy?
A: NK cells are cells of the immune system, and their function is to distinguish between normal cells and abnormal cells, such as those that have become cancerous or infected by a virus. NK cells continuously patrol the body to look for these abnormal cells and destroy them.
NK cells can actually recognize cancer cells as soon as they start to acquire mutations, destroying those cells quickly and then preventing cancer from developing further. However, sometimes NK cells find it difficult to recognize certain types of cancer.
What we’re trying to do is use the inherent ability of NK cells to recognize cancer and build on that by giving them the ability to seek and destroy cancer cells that have made themselves invisible. It’s akin to arming a fighter jet with a heat-seeking missile.
Q: How would CAR NK-cell therapy work?
A: We isolate NK cells from umbilical cord blood stored in our cord blood bank and genetically engineer them to introduce a CAR, which recognizes a target on the surface of cancer cells. These CAR NK cells are then manufactured and given to patients.
CAR NK cells are given to a patient in two phases. First, we give conditioning chemotherapy for three days to prepare the patient’s body for the cell infusion. After two days, we infuse the CAR NK cells in just the same manner that we would give a blood transfusion. Then, we wait for the cells to do their job.
Because of the impressive safety profile, CAR NK cells can actually be given in an outpatient procedure, and we follow them as an outpatient for 30 days.
Q: What are the advantages of CAR NK-cell therapy compared to CAR T-cell therapy?
A: Perhaps the biggest advantage of CAR NK cells is that they do not cause graft versus host disease (GVHD), a devastating condition caused by donor T cells attacking healthy cells in the recipient. Because NK cells don’t cause GVHD, they can be given from a donor to a recipient without any requirement for matching. That means from one donor you can make multiple doses of CAR NK cells to treat multiple patients.
In fact, we have shown that we can manufacture hundreds of doses of CAR NK cells from a single unit of cord blood. Ultimately, our plan is to freeze and store these CAR NK cells in a cell bank so that when a patient comes to the clinic, we can take those CAR NK cells immediately from the bank to treat the patients, making this a truly off-the-shelf-product. So, the time from diagnosis to cancer treatment is significantly shorter.
So far, we’ve treated a small number of patients and, while our follow up is relatively short, we have learned that the side effects related to this therapy are minimal, if any. We do see some side effects related to the conditioning chemotherapy, but those are very easily manageable and resolve within 1-2 weeks. Thus far, we have not observed any long-term side effects, and it does not appear to be impacting our patients’ quality of life.
CAR NK cells also appear to work very rapidly, such that when we assess patients for response at 30 days post-therapy, we have seen very impressive clinical responses. Additionally, in all patients we’ve studied so far, we can find the CAR NK cells in their blood as far out as one year after the infusion.
Q: How is the ACT platform working to advance CAR NK cells into the clinic for our patients?
A: The ACT platform is working in collaboration with several Moon Shots to translate the cell therapies that we have developed in the research lab to the clinic.
For instance, the CAR against CD19, which is what’s currently in the clinic for the treatment of patients with chronic lymphocytic leukemia (CLL), Non-Hodgkin's Lymphoma and acute lymphocytic leukemia (ALL), was initially developed in collaboration with the CLL Moon Shot and the B-Cell Lymphoma Moon Shot, together with the support and expertise from the ACT platform.
This support enabled us to translate the preclinical work from my lab to develop the procedure for CD19 CAR NK cells in the GMP facility, which allowed us then to take them into the Phase 1/2 clinical trial we’re now conducting.
Q: What are your future plans for this work?
A: In the lab we are continuously striving to innovate. For us, going after CD19 was in fact a proof of principle. We wanted to show that the CD19 CAR NK cells are going to be at least as effective as CD19 CAR T cells in terms of efficacy. We've shown that they are as effective and that the safety profile is even better than what we have observed with CAR T cells. Obviously, with the added advantage that the cells can now be generated as an off-the-shelf product.
We are of course very interested in targeting other types of cancer in collaboration with multiple Moon Shot teams and other investigators at MD Anderson. We've now developed CARs against 10 different types of cancer that we are testing and validating pre-clinically, with the ultimate goal of translating these to the clinic. The next generation CAR NK cells are around the corner, and we hope that we will be able to get those to the clinic to benefit many more patients.
Q: How has your work been enabled by the infrastructure and support of the Moon Shots Program?
A: The Moon Shots Program supported the CAR NK concept from birth. Early on, we couldn't get grant funding from any of the funding agencies because they believed that this approach was too risky and unlikely to work. The Moon Shots Program supported it from its preclinical development all the way to the current clinical trials.
Of course, with the success of the CAR NK-cell therapy, we've now succeeded in raising funding from outside agencies. But, had it not been for the support of the Moon Shots Program, I honestly can say that we never would have been able to develop this therapy for our patients.
Katy Rezvani, M.D., Ph.D., equips innate immune system natural killer
cells with a chimeric antigen receptor that targets B cell malignancies,
an approach that’s yielded results in early clinical trials. Her lab is
developing CAR NK cells against other cancers.