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GP2 and AE37 HER-2/neu Peptide Vaccines Show Promise in Phase I Studies

2009; Wolters Kluwer; Volume: 31; Issue: 4 Linguagem: Inglês

10.1097/01.cot.0000346858.07736.75

1548-4688

Brande Victorian,

Cancer Immunotherapy and Biomarkers

NEW YORK CITY—HER-2/neu GP2 and AE37 peptide-based vaccines have shown comparable outcomes to E75 in results from Phase I studies reported here at the Chemotherapy Foundation Symposium. “There's been a lot of work that's gone into actually identifying these immunogenic peptides, Colonel George Peoples, MD, Chief of Surgical Oncology at Brooke Army Medical Center and Director and Principal Investigator of the Cancer Vaccine Development Program at the United States Military Cancer Center, said in his presentation.Figure: COL. GEORGE PEOPLES, MD: “Once we know what it is that the immune system actually is recognizing from the HER-2 protein, our philosophy is: use that. Don't use the whole protein, don't use a cell that expresses HER-2/neu, but use the actual immunogenic peptide. It's the simplest thing, it's purified, it doesn't require the body to do much, you can give it at industrial strengths if you so choose, and it has no biologic properties in and of itself other than being a point of recognition.”“Once we know what it is that the immune system actually is recognizing from the HER-2 protein, our philosophy is: use that. Don't use the whole protein, don't use a cell that expresses HER-2/neu, but use the actual immunogenic peptide. It's the simplest thing, it's purified, it doesn't require the body to do much, you can give it at industrial strengths if you so choose, and it has no biologic properties in and of itself other than being a point of recognition.” The first of these vaccines to be explored in the adjuvant setting was E75 (OT 6/25/08). In the largest of the E75 trials, which Dr. Peoples reported on at the meeting, approximately 180 node-positive and high-risk, node-negative women maximally treated and disease-free entered the Phase II study. A total of 101 HLA-typed A2-positive patients were vaccinated and 79 A2-negative patients were followed prospectively as controls. One of the drawbacks of using a peptide-based vaccine, Dr. Peoples explained, is that it is HLA-restricted and therefore only useful in HLA-A2 positive patients. That strategy, however, was chosen specifically because HLA-A2 positive patients make up about half of the HER-2/neu breast cancer population. Locally, 82% of patients experienced Grade 1 toxicities and 18% had Grade 2 toxicities, while systemic toxicity was mild, at 15.5% for Grade 0; 69%, Grade 1; 13%, Grade 2; and 2%, Grade 3. Local reactions can be fairly intense, Dr. Peoples noted. “We split our injection into two sites. You will see a lot of erythema and some induration. These are the type of reactions you can get and they only make up a minority.” In the E75 trial about 20% of the local reactions reached this level, which prompted a reduction in the need for granulocyte macrophage colony-stimulating factor with the same dose of the peptide. About 80% of vaccine recipients had a delayed type hypersensitivity (DTH) response, a significant number, Dr. Peoples noted. About 2% of all circulating tumor cells also recognized the E75 peptide, which is also a significant number considering the number of antigens the body has to respond to on a regular basis, Dr. Peoples said. That number does drop, though, after vaccinations have stopped, and even more so six months after completion of the vaccine series. Similar Safety Profiles Two other peptides, GP2 and AE37, were also studied in Phase I trials modeled after the early studies of E75 and showed similar safety profiles. GP2 is close in relationship to E75, being a short peptide that stimulates CD8 killer cells and a CPI epitope. However the peptide is found in another portion of the protein and there are different characteristics associated with GP2 in terms of its binding, potentially for the subsets of T cells it stimulates. AE37, on the other hand, is a longer peptide and stimulates CD4 helper cells.Figure: SEYMOUR M. COHEN, MD: “The numbers in the study are small, but it spiked interest, it's certainly worth pursuing, and I'd like to see further work done on this.”In comparison with E75, a larger percentage of patients reacted locally to GP2, 39% for Grade 1 and 61% for Grade 2, suggesting that there may be more immunogenicity associated with GP2, Dr. Peoples noted. Immunologic response was split between women who had preexisting ex vivo immune response (10 patients) and those who did not (8 patients). The responses for those with preexisting levels were about 0.8% pre-vaccine, 1.5% at the maximum dosage, 0.6% post-vaccine, and 0.9% in the long-term. For those women without preexisting responses, the rate was 0.06% pre-vaccine, 1.4% at the maximum, 0.5% post-vaccine and 0.9% long-term. The results were also split between those with a preexisting in vivo immune response and those without. The rates pre-vaccination were 2% for those with previous response and 3% for those without. Post-vaccination, the rates were 28% in those with preexisting response and 44% for those without. The larger response in those not receiving the vaccine suggests that there is a level of tolerance involved, Dr. Peoples said. Similarly, local toxicities for AE37 were 40% for Grade 1 and 60% for Grade 2. Systemic toxicities were 13%, Grade 0; 73%, Grade 1; and 13%, Grade 2. Regarding CD4 cell reaction, the immunologic response levels were 34 pre-vaccine; 6,427 post-vaccine; and 9,159 in the long-term. “One of the differences here is you don't get that lag effect that we see with the CTL [cytotoxic T lymphocyte] epitopes, but it appears that the helper T cells are stimulated long-term,” Dr. Peoples said A significant DTH response was also associated with the peptide, with an increase from about 4% pre-vaccine to 6% after vaccination. ‘Certainly Worth Pursuing’ Asked for his opinion for this article, one of the moderators of the breast cancer session at which Dr. Peoples spoke, Seymour M. Cohen, MD, Associate Clinical Professor of Medicine, Hematology, and Medical Oncology and Oncological Sciences at Mount Sinai School of Medicine in New York City, called the trial very interesting and said, “What I like is that very often trials are done in people with far advanced disease, who are really very sick and may not respond to anything, but when you give something a chance upfront, you may find real efficacy. “You can't go much further because the numbers in the study are small, but it spiked interest, it's certainly worth pursuing, and I'd like to see further work done on this. The others [GP2 and AE37] may be interesting also.” Phase III Trial Planned Dr. Peoples said that a Phase III trial is planned for E75, which will include only HLA-A2 node-positive high-risk, node-negative patients using boosters. “We know that we can do better with the E75 patients, because the majority were not optimally dosed and the majority of those patients were not boosted after their primary vaccine series,” he said. GP2 and AE37 are currently undergoing Phase II testing in low and intermediate HER-2/neu expressers to see whether they also provide a clinical benefit, he noted. His team has also begun to use all of the peptides in combination with trastuzumab to see if that will also increase the effectiveness of both agents, and the peptides have been used together in combination to form a multi-epitope vaccination.