Vaccine for triple-negative breast cancer produces ‘exciting’ results in early testing
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Preliminary results of a phase 1 trial for a novel vaccine that could eventually prevent triple-negative breast cancer exceeded expectations, based on data presented at San Antonio Breast Cancer Symposium.
Researchers at Cleveland Clinic tested the vaccine on 16 women and 75% showed an immunologic response to the drug, which is based on the “retired protein hypothesis” developed by Vincent Tuohy, PhD, immunologist at Cleveland Clinic’s Lerner Research Institute, who died in January.
Study investigators also determined a safe dose of the vaccine with no adverse reactions but have reopened the trial to test new dosing levels to potentially increase its effectiveness.
“There was no guarantee we would get any type of immune response in these women, and our other fear was, what if we could only get an immune response at an unacceptably toxic dose? Then you wouldn’t be able to use it,” Justin M. Johnson, PhD, program manager at Cleveland Clinic, told Healio. “The great news is we have a dose that gives a good immune response and is well tolerated, and we’re working on fine-tuning that to be even better.”
The vaccine targets alpha-lactalbumin, a protein in both human and cow milk, that is expressed in 70% of triple-negative breast cancer tumors, according to background research provided by the researchers. Patients in this portion of the trial had been diagnosed with triple-negative breast cancer, treated within the previous 3 years and developed residual disease.
Johnson spoke with Healio about the phase 1 results, potential concerns, the future of the trial and more.
Healio: How would you summarize the results from this portion of the trial?
Johnson: The toxicity at the current dose level we plan to use is acceptable and it’s mild and well tolerated (10 µg of the alpha-lactoalbumin dose, 10 µg zymosan, which helps start the immune reaction). Second, the T-cell profile in the majority of the women tested so far has been significant. The third takeaway is that we still don’t necessarily have the optimal dose, so we’re currently testing those intermediate doses.
Healio: Why are you continuing your evaluation of the dosage?
Johnson: We thought we’d have to go much higher than 10 mg to get a response, but we are seeing a response at 10 µg. Dose level 2 was too high — the 100 µg alpha-lactalbumin proved to be a problem in only one of the six subjects tested but — per protocol — that is considered unacceptable. Now we’re looking at alpha-lactalbumin levels between 10 and 100 µg, and we’re also going to explore elevating the zymosan. We know 100 µg zymosan is too much and 10 µg works, but there might be a dose in between that’s better. For our intermediate doses, we’re going to not only raise the alpha-lactalbumin, but we may raise the zymosan as well.
Healio: How did the research team react to the results?
Johnson: I would say most of us would feel this is a better-than-expected outcome because this drug has never been tested in humans. We remained hopeful that we could get an immune response to alpha-lactalbumin in humans but, going into this, we didn’t know whether this would occur. That’s why we’re doing the trial, and the fact that roughly three-quarters of the women in our study had an immune response to the vaccine is really exciting.
Healio: Did you have concerns about irritation at the injection sites, the adverse reaction reported in the results?
Johnson: The irritation at the injection sites was expected because of the nature of this drug. It’s designed not to be immediately absorbed by the body, but rather to stay at the site of injection for several weeks, and that is intentional because that’s what really gets the immune system to notice it and to get it revved up. Hopefully, in the future, as we develop this drug even more, we’d like to be able to get rid of that side effect entirely, but for right now it’s considered a grade 1 adverse event. I’d love for the adverse events grade to go from 1 to 0; I don’t know if that’s possible. There’s nothing disappointing so far — we’re keeping our fingers crossed.
Healio: Can you describe the other cohorts in phase 1 of this trial?
Johnson: Our phase 1B trial is immunizing healthy women now that we’ve established a safe toxicity profile. These are women who have family history or genetic risk markers for breast cancer, so they have a high chance of developing triple-negative breast cancer, and they’re so concerned about it they’ve already made the decision to go to Cleveland Clinic and get a prophylactic mastectomy because of this risk. Phase 1B is designed so that we immunize the women before their surgery and then during their surgery, we take a sample of the mammary tissue. First, this makes the trial extra safe for these women because even if there were an adverse reaction in mammary tissue that we didn’t anticipate, that mammary tissue is coming out anyway. Second, it gives us a unique opportunity to look at healthy mammary tissue from women who’ve had the vaccine again to see if there’s any unusual toxicity that we didn’t anticipate.
The phase 1C portion of the trial, which we’ve also just started, came about because there was a change in the standard of care. When we designed and started this trial in 2020 and 2021, pembrolizumab (Keytruda, Merck) was not part of the routine treatment of these patients, and now it is. We have to consider what the combination of that drug and our vaccine might be. In the 1C cohort, we’re treating patients who are being treated with pembrolizumab concurrently.
Healio: Do you have any other concerns?
Johnson: We’re looking into ways to produce the drug in a more practical way. Right now, the drug is essentially made to order. It’s made in the pharmacy, and its stability is fairly short. We have to administer it within 2 hours, so we’re looking to improve that for phase 2 and beyond. To come up with a more stable formulation — one that we could put in a bottle and ship out to all of our future phase 2 testing sites and can sit on the shelf a couple of weeks and then be administered — is one of the challenges we’re dealing with right now.
I guess one disappointing thing about phase 1 is that despite the enormous interest and the number of women who want to get into the trial, accrual to phase 1B has been challenging because of the specific requirements. There’s a limited population of women who are coming in to get a prophylactic mastectomy, they must do that at Cleveland Clinic, and on top of that they have to consent to the trial. The biggest challenge is having to time these immunizations, which have to occur within a certain window before their surgery. It took us a long time to get women into that cohort after we opened it — almost a year — but I’m happy to report that we already have one woman in phase 1B and another one who will be coming on study soon. We hope to keep recruiting as many of those women as we can.
Healio: Is there anything else you’d like to say?
Johnson: I would like to mention my mentor, Dr. Tuohy, who passed away. We’re carrying on his work and his legacy. His retired protein hypothesis — which is the foundation of the work that we’re talking about — he felt was applicable to other cancer vaccines. This idea of using a protein that’s no longer normally made in the body, but is made in tumors, provides a perfect opportunity to make a potentially safe and effective vaccine. We’re developing an ovarian cancer vaccine based on this same technology, and next year we’re going to start a program where we’re looking at additional cancers — other types of cancers of the breast and ovary and also cancers in other organs.
Reference:
- Johnson JM, et al. Poster P02-17-12. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
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