Natural Killer Cells Plus Immunotherapy for Triple-Negative Breast Cancer
Between 10% and 15% of all breast cancer cases are triple negative, meaning the cancer cells lack estrogen or progesterone receptors and make very little of the protein HER2.
Triple-negative breast cancer (TNBC) is the fastest growing of all types of invasive breast cancer, and it is associated with limited treatment options and poor prognosis. It is more common among women under the age of 40 years, black women and women with a BRCA1 mutation.
QUILT-3.067 is a phase 1b/phase 2 study to evaluate the safety and efficacy of metronomic combination therapy among patients with TNBC who progressed on or after standard-of-care chemotherapy.
Researchers administered a combination of agents, including a TNBC vaccine, in this trial. Study treatment was given in two phases: an induction phase and a maintenance phase. Patients received induction treatment for up to 1 year and, if tolerated, could remain in the maintenance phase of the study for up to 1 year.
Cell Therapy Next spoke with trial investigator Chaitali Nangia, MD, MBBS, co-director of medical oncology at Chan Soon-Shiong Institute for Medicine LA and Newport Beach, who provided an update on the progress of patients with TNBC in the trial, results of which were presented at the 2019 San Antonio Breast Cancer Symposium.
Q: What is your rationale for conducting this trial?
Once you have crossed into the first two lines of therapy for metastatic TNBC, historically, PFS is approximately 2 or 3 months. There is a lack of good standard-of-care options beyond second-line therapy for TNBC. The overall outcome of these patients remains poor, so that’s an unmet need and potential for developing newer treatment paradigms and therapies.
Our hypothesis is that with complex cancer tumorigenesis and pathways and interplay with various immunogenic cellular processes, multiple agents are required to get results. It is rather oversimplistic to think that one treatment modality can overcome all pathways. There are so many escape mechanisms. The therapies we used were added on very strategically. For example, we have agents that mitigate immune suppression in the tumor microenvironment, and then we brought in things like cisplatin for inducing and coordinating the immune checkpoint signals. Then we have the yeast vaccine to condition the dendritic cells and the T cells. We added tumor-targeting natural killer (haNK, NantKwest) cells to enhance innate immune response and an IL-15 superagonist (N-083, ImmunityBio) to maintain the response and help over come immune resistance. You need help from different chemotherapies, radiation and immunotherapies to put it all together.
Q: What makes this treatment method novel compared with the current standard of care for TNBC?
The standard of care therapy in second line and above right now would be a single-agent chemotherapy, with an expected PFS of a couple months.
Q: How would you characterize the effectiveness of current treatments for TNBC?
The current treatment options are, at best, OK. With each line of therapy, toxicity accrues in a way that causes more immunosuppression, affecting bone marrow function and, depending on the agent you use, causing more neuropathy. Patients would typically progress in 3 to 5 months, but now they have extra baggage of toxicities to carry and must change to a different type of therapy. It’s not the most effective solution. Thus, novel study designs like ours are required to address this unmet need.
Q: Can you describe the high-affinity natural killer (NK) cell portion of this treatment?
These are off-the-shelf NK cell lines. They have been very effective in their natural functioning and worked synergistically with the other therapies we’ve given. What’s useful about these NK cells is that there has been no sign of cytokine release syndrome when given to patients. We’ve managed to provide these therapies in an outpatient setting, and we’ve observed no grade 4 or grade 5 adverse events. These NK cells are tolerable, and they work.
Q: What makes these NK cells an attractive weapon in treating TNBC?
NK cells are of paramount importance for enhancing innate immune responses, and perform a pivotal role in cell lysis with the release of cytolytic granules and are key in immune surveillance, as well as in recognition despite the loss of MHC1. They can also be transported to different places and given in an outpatient setting. You don’t need super-high-skilled staff to provide this cell therapy. It is easy to administer, it is not very complex and it works.
Q: How many patients have you enrolled so far?
Q: What are the key takeaways from the results you presented at last year’s San Antonio Breast Cancer Symposium?
The biggest takeaway is a median PFS of 13.7, with an overall response rate of 67%. Our disease control rate, which included stable disease, was 78% and our complete response rate was 22% (n = 2). Not only did we get a decent response, the response was durable. Seven of the nine patients are still alive, and four remain under study.
Q: Your experimental protocol was given as third-line treatment, is that correct?
Most patients were on their third line of treatment, but inclusion criteria were beyond first-line standard of care.
Q: What, if any, treatment-related adverse events have you seen thus far?
Eight of the nine patients had primary chemotherapy-related neutropenia or anemia, but all cases were low grade. There was one grade 3 haNK-related adverse event with fever and fatigue, but no patient withdrew due to a serious adverse event or experienced cytokine release syndrome.
Q: What do you envision for this type of treatment in the future? Could it be moved into earlier lines of therapy?
Absolutely. This was a proof-of-principle study to show that multiagent chemotherapy and chemoradiation therapy are needed, and we can do these things safely for our patients without cytokine release syndrome. I think the next step would be to keep the key component, that being NK cells. If we had newer versions of NK cells, which are PD-1-type NK cells, they might override the need for adding a checkpoint inhibitor to the regimen. There may be a way to simplify it, but key elements will remain.
Q: Is there anything else clinicians should know about your research in this area?
Immunotherapy is not a yes-or-no proposition. We are at the frontier of combinatorial approaches with chemo-immuno-radiotherapy. – by Drew Amorosi
Disclosures: Nangia reports no relevant financial disclosures.