A woman who had breast cancer for 23 years, and who had gone through 12 different lines of therapy, has shown a dramatic response to a novel cancer vaccine in a clinical trial.
A recent 6-month follow-up showed no evidence of new or recurrent disease, and scans showed regression of a distant bulky left adrenal metastasis, as well as at other sites.
A small site of residual hypermetabolism remains in the sternum, but this is thought to be related to scar tissue.
The patient, Stephanie Gangi, told Medscape Medical News that, before she entered into the trial for the novel cancer vaccine, she was “mentally and physically exhausted.” She had benefited from being diagnosed with hormone-positive breast cancer just as its treatment was evolving and progressing, which meant that, every time a treatment failed, “there was the next thing to try, which was great and kept me going.”
“But I will admit that, by age 66, and more than 20 years of cancer treatments, I was exhausted.”
Gangi, a New York City-based poet, essayist, and fiction writer, said she was “cautiously optimistic” about the cancer vaccine, but the “overriding thought was I wanted to avoid chemotherapy.”
“I was not really signing on for great outcomes, I was signing on for something that might keep chemo at bay. The biggest impact so far for me has been that, for the first time in more than a decade, I am not on any medication. That’s really amazing…and that means no side effects,” she said.
Gangi stopped the vaccine treatment this past July, and just over 3 months later, she is still “wrapping her head around” the fact that her cancer has regressed. “I’ve had breast cancer a long time,” she said, “and you can’t just snap your fingers and be fine.”
Although the two scans that she has had since the trial ended have been “astonishing,” she underlined that this is not about a ‘cure,’ but rather “clearing tumors for the first time in many years.”
“Cancer is sneaky and sinister, and it figures out how to circumvent all kinds of treatments,” she said, adding nevertheless that she is “happy and hopeful, and my family is thrilled, of course.”
Gangi was classed as having had a partial response to the cancer vaccine, one of a few in a small phase 1/2 trial at the Icahn School of Medicine at Mount Sinai in New York City. One other patient also had a partial response, and one patient had a complete response.
However, six patients have progressive disease, and one has stable disease.
These results come from an interim analysis of 10 patients from the trial, and show a 30% response rate. They were presented at the Society for Immunotherapy of Cancer 37th annual meeting (SITC 2022) on November 10.
The vaccine that was being tested combines local low-dose radiation, intramural Flt3L, which stimulates dendritic cells, and intravenous poly-ICLC, an immune stimulating factor, with the PD-1 inhibitor pembrolizumab (Keytruda).
The result is that, instead of making a vaccine in a laboratory and administering it, “we’re actually formulating it within the body,” lead author Thomas Marron, MD, PhD, professor of medicine (hematology and medical oncology) at Mount Sinai, told Medscape Medical News.
“What people don’t realize,” he said, is that bulky tumor sites contain “a lot of dead tumor, because they grow so fast and in a haphazard way.” This means that the immune system can be recruited to recognize the dead tumor and “gobble up the dead stuff that’s already there,” he added.
The hope is that that the immune system will then kill not only “the tumor you are injecting into, but also tumors elsewhere in the body,” Marron said. “So you’re basically using your body’s own immune system and on and off switches to vaccinate the patient against their cancer.”
Another patient in the trial who had a complete response to the vaccine was William Morrison, with non-Hodgkin lymphoma (NHL).
Morrison was diagnosed in 2017, at which time he was enrolled onto a phase 1 trial of an earlier version of this novel vaccine treatment regimen. “Basically, they didn’t get the results they were hoping for, and I still had the lymphoma,” he said. In 2018, his indolent follicular lymphoma transformed into an aggressive diffuse large B-cell lymphoma, for which Morrison was given six cycles of chemotherapy. This put him into remission and cleared his lymphoma.
“But the remission lasted for maybe a little over a year,” he said.
The cancer came back, and at that point he was given the opportunity to enroll in the Mount Sinai trial. At the end of the treatment, “everything was clear.”
“I’ve been for PET scans every 6 months, and I just had a scan done the other week, and everything has been fine…I’ve been pretty excited. I was pretty lucky.”
“This recent one really has worked wonders,” he said, “When they gave me the good news the other day. I felt like a big weight had been lifted.”
Morrison also said that he did not experience any serious adverse events while being treated with the vaccine. “Other than a few minor things, I tolerated it pretty well,” he said.
In contrast, Gangi said she experienced “intense” flu-like symptoms that started in the first few days after the treatment and lasted for a couple of days.
Need to Improve Response Rate
The current trial achieved responses in 30% of patients, which “is great, [but] we want to be at 100%,” said Marron.
“What we’re doing in the laboratory right now is using this as an opportunity to study what it is that’s special about those three people who responded and what’s not happening in the other seven people, and we have some initial data that we’re analyzing,” he said.
“We are seeing that the patients who responded have a much more robust response to the Ft3L in particular…and that could suggest that maybe we need a better Ft3L, or we could think about other ways to potentially manipulate this vaccine.
“Most of the patients who are referred to me are people who have run out of options…and that usually means they’ve had many different types of chemotherapy,” Marron commented. For example, Gangi had already been through 12 different chemotherapy regimens.
Chemotherapy suppresses the immune system, but it’s not only that — also having an effect are all the other treatments aimed at reducing nausea and allergic reactions to the anti-cancer therapy, Marron explained.
“By the time that I see a patient,” Marron said, “oftentimes their immune system is not optimal. So another way in which we would hope to see better responses is by moving this vaccine earlier in the treatment paradigm, and administering it to patients as their first or second treatment.”
Senior author Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Mount Sinai’s Tisch Cancer Institute, added that it “might be easy” to incorporate the vaccine into earlier lines of therapy.
He told Medscape Medical News that both immunotherapy and radiation therapy are “standard” treatments, and the key is “adding multiple ingredients together that don’t have cumulative toxicity.”
“You can’t just chemo one plus chemo two, because they have some of the same toxicities, but the delightful thing here is this therapy had been quite safe.
“So in theory it would be fairly easy to incorporate this into earlier lines of therapy, once we can get a bit more proof of principle,” Brody said.
Approached for comment, Ann W. Silk, MD, said that the results are “particularly impressive because we know anti-PD-1 plus radiation therapy does not work in hormone-positive breast cancer or lymphoma”.
Silk, an oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, told Medscape Medical News that one advantage of this vaccine is that it “is not restricted to a certain number of antigens and does not rely on an algorithm.”
“I would love to see more data in hormone-positive metastatic breast cancer patients,” she added. “I would use this approach after the hormonal treatments stop working, but before chemotherapy.”
Silk also said that the safety profile “looks quite good, and I imagine this approach would result in a much better quality of life for patients as compared to chemotherapy.”
Details of the Trial and Results
The Mount Sinai researchers had previously developed a personalized genomic cancer vaccine, PGV-001, which showed promise in a phase 1 trial in 13 patients with solid tumors or multiple myeloma and a high risk of recurrence after surgery or autologous stem cell transplant.
Next, they worked to develop the concept further to turn the tumor into its own vaccine, which involved inducing anti-tumor responses in indolent NHL, which typically responds poorly to checkpoint blockade, by combining Ft3L, low-dose irradiation, and poly-ICLC.
The next phase 1 trial showed that this approach was feasible, but preclinical modeling suggested that the addition of PD-1 blockade could improve the cure rates. The researchers therefore conducted the current trial, recruiting 10 patients with indolent NHL, metastatic breast cancer, or head and neck squamous cell carcinoma (HNSCC).
Patients were given local radiation therapy on days 1 and 2, and intramural Ft3L to the same tumor on day 9, followed by eight intravenous injections of poly-ICLC over 6 weeks. On day 23, they received their first of eight doses of pembrolizumab.
Marron explained that the radiotherapy increases the amount of dead material for the immune system to work on by “killing some of the tumor cells,” adding: “We’re not trying to kill the whole tumor with the radiation…it just starts the process of releasing some more of that dead stuff.”
He explained that Ft3L is a human growth factor that simulates dendritic cells, “which I always say are the professor cells of the immune system,” as they tell the body “what’s good and what’s bad.”
The poly-ICLC is “basically like a fake virus,” Marron said, as it “turns on those immune cells that have taken up the tumor antigen in the neighborhood” of the tumor, so they “teach the immune system that there is something bad”.
Finally, the pembrolizumab is there to “take the foot off the brake of the immune system” and “grease the wheels a bit more”, he added, even though it does not work in all patients, or in all tumor types, including indolent NHL.
The trial was planned in two phases. In the first part, six patients were enrolled to assess the safety of the approach; the phase 2 stage of the trial followed a Simon’s Two-Stage design, with the aim of recruiting seven patients of each tumor type, followed by a further 12 patients if they showed a response.
The current interim analysis that was presented at the SITC meeting focused on the first 10 patients in the phase 2 part, who were enrolled between April 2019 and July 2022. This included six patients with metastatic breast cancer, three with indolent NHL, and one with HNSCC, all of whom completed their first disease response assessment.
All patients experienced treatment-related adverse events, largely comprising low-grade injection site reactions and flu-like symptoms linked to the poly-ICLC injections.
One patient experienced grade 3 pembrolizumab-related colitis, while another had self-resolving grade 3 fever following poly-ICLC injection.
The study was sponsored by Icahn School of Medicine at Mount Sinai and conducted in collaboration with Merck Sharp & Dohme LLC and Celldex Therapeutics. No relevant financial relationships were reported.
Society for Immunotherapy of Cancer 37th Annual Meeting: Abstract 595. Presented November 10, 2022.
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