Here are the abstracts:
Booster inoculations of the AE37 peptide vaccine enhance immunological responses in a phase II study. Abstract No: 3095
Author(s): Eleftheria A Anastasopoulou, Efi Pappou, Panagiotis Tzonis, Alexandros Ardavanis, Sathibalan Ponniah, Constantin N. Baxevanis, James L. Murray, Michael Papamichail, Sonia A. Perez, George Earl Peoples, Elizabeth Ann Mittendorf; Cancer Immunology and Immunotherapy Center Saint Savas Cancer Hospital, Athens, Greece; Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece; Cancer Vaccine Development Program, United States Military Cancer Institute, USUHS, Bethesda, MD; The University of Texas MD Anderson Cancer Center, Houston, TX; Cancer Immunology and Immunotherapy Center, Athens, Greece; San Antonio Military Medical Center, San Antonio, TX
Background: We are conducting a multicenter randomized phase II trial of AE37, the Ii-Key hybrid peptide of HER2 776-790 (AE36). The purpose of the study is to determine if the AE37 vaccine can prevent recurrence in disease-free conventionally treated node-positive (NP) and high-risk node-negative (NN) breast cancer patients at significant risk for recurrence. Since clinical efficacy is anticipated to occur as the result of long lasting memory immune responses induced by vaccination, repeated booster inoculations were scheduled as part of the trial. Here we present data on immune responses in patients who received boosters up to 24 months after completion of the primary vaccination series (PVS).
Methods: The trial is enrolling NP or high-risk NN patients with any degree of HER2 expression (IHC 1-3+ or FISH > 1.2) rendered disease-free following standard of care therapy. The vaccine group (VG) received AE37+GM-CSF and control group (CG) GM-CSF alone in 6 monthly i.d. inoculations followed by boosters administered every 6 months x 4. Immunologic responses were assessed in vivo by dermal reactions at the inoculation site, and in vitro, against the AE36 peptide, with proliferation and IFN-γ ELISPOT assays.
Results: 25 patients in the VG and 23 in the CG have completed their boosters. After the last booster (BRC24), 100%, 54% and 54% in the VG (vs. 9%, 18% and 27% in the CG) responded by dermal reaction, proliferation and IFN-γ ELISPOT, respectively. Mean dermal reactions (orthogonal mean in mm) in vaccinated patients was 25.9±3.13 at completion of the PVS (R6) and increased to 35.47±4.35 at BRC24 (p=0.01). VG patients increased their proliferation response (stimulation index, SI) to AE36 from 0.97±0.046 at baseline (R0) before vaccination to 2.27±0.57 at R6 (p=0.0003) which was maintained until BRC24 (SI 2.21±0,33, p<0.0001). The number of IFN-γ specific spots/106 PBMC increased from 26.88±12.36 at R0 to 40.35±17.02 (p=0.07) at R6, up to 62±16.82 (p=0.0076) at BRC24. Conclusions: Our data demonstrate that AE37 vaccine boosters enhance the immune responses against HER elicited during the PVS, thus sustaining long lasting immunity, a prerequisite for possible clinical efficacy which is currently being evaluated.
Risk factors for development of delayed urticarial reactions in the phase II trial of HER2 peptide vaccines plus GM-CSF versus GM-CSF alone in high-risk breast cancer patients to prevent recurrence Abstract No: 3097
Author(s): Alfred F Trappey, John S. Berry, Timothy J Vreeland, Diane F. Hale, Alan K. Sears, Sathibalan Ponniah, Sonia A. Perez, Guy T. Clifton, Michael Papamichail, Nathan M. Shumway, Elizabeth Ann Mittendorf, George Earl Peoples; Brooke Army Medical Center, San Antonio, TX; Cancer Vaccine Development Program, United States Military Cancer Institute, USUHS, Bethesda, MD; Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece; Cancer Immunology and Immunotherapy Center, Athens, Greece; San Antonio Military Medical Center, Fort Sam Houston, TX; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Surgery, Brooke Army Medical Center, Fort Sam Houston, TX
Background: We are monitoring the incidence of delayed urticarial reactions (DURs) in our phase II trial evaluating adjuvant HER2-specific vaccines (AE37 and GP2) for the prevention of breast cancer recurrence. Here, we characterize DURs and analyze risk factors for their development.
Methods: After completion of standard of care therapy, disease-free node-positive or high-risk node-negative patients (pts) were randomized to receive either a peptide+GM-CSF (VG) or GM-CSF (CG). Pts receive 6 monthly intradermal inoculations during the primary vaccine series (PVS) then four boosters (B) every 6 mos. Immune response is measured by delayed type hypersensitivity (DTH) pre- (R0) and post-PVS (R6) and local reaction (LR) at R1 – R6.
Results: Twenty-four (6.1%) of 393 initiated patients report a DUR; 13 VG (vDUR), and 11 CG (cDUR); vDUR - 9 AE37, 4 GP2. Time to onset of symptoms is 9±5 days (d) and is similar in vDUR/cDUR (p = 0.27). DURs manifest as hives/pruritis in all patients. Average duration of symptoms is 32.6 d ± 8.8 d (no difference in vDUR/cDUR [p = 0.23]). Episodes have resolved with antihistamines or IV/oral steroids. Ten (4 cDUR, 6 vDUR) patients have had recurrent episodes that have resolved similarly. 75% of first episodes occur between R6-B3. For DUR patients v. those who have not had a DUR (noDUR), there are no differences in demographics. DTH response is similar in vDUR pts v. noDUR VG pts (R0- p = 0.34; R6- p=0.40). cDUR pts had a greater DTH response v. CG noDUR pts at R6 (13.2 v 4.7 mm, p=0.01). LRs are greater in DUR pts compared to noDUR pts after the second vaccination (R2 – 66.2 v 48.2 mm, p=0.02). LR for DUR pts decrease and are less than noDUR at R6 (45.4 v 57.4 mm, p=0.09). Relative risk for developing DUR for LR > 100 mm at R2 is 3.49 (1.58-7.68, 95% CI [p=0.004]). At 29.9 months median follow-up, there have been no recurrences in VG and CG DUR v. 75.9% DFS for noDUR (p=0.05).
Conclusions: DURs occur infrequently and without long-term sequelae. Pts at risk for developing DUR are identified early in the vaccine series using LR. Robust immune response in DUR may explain the survival benefit demonstrated here.
The following is the publish only abstract:
Effect of immunization with Ii-key modified HER2 (776-790) peptide vaccine (AE37) on immunologic responses in prostate cancer patients.
Author(s): Sonia A. Perez, Eleftheria Anastasopoulou, Efi Pappou, Panagiotis Tzonis, Stratos Bisias, Anastasios Thanos, Eric von Hofe, Michael Papamichail, Constantin N. Baxevanis; Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece; Antigen Express, Worcester, MA
Background: We have shown that the AE37 vaccine (Ii-Key modified HER2(776-790) peptide) is safe and induces HER2/neu–specific cellular immune responses in patients with prostate cancer (Perez SA et al Clin. Cancer Res. 2010, 16:3495). We now present data from 4-year immunological assessments of prostate cancer patients who received AE37.
Methods: Seventeen patients in a phase I study were given 6 doses of AE37 at monthly intervals and one additional dose a year after initiating treatment. Immunological testing to assess active versus suppressive immunity was conducted one month (intermediate-term immunomonitoring [ITI]) and 3 years (long-term immunomonitoring [LTI]) after the final dose of AE37. ELISPOT and proliferation assays were conducted to assess cytokine secretion and mitogenic response to antigen. DTH reactions were measured to assess in vivo immune response to antigen. All assays were conducted using native HER2(776-790) peptide (AE36). The percent Treg cells and ng/ml TGFβ were determined as markers for immune suppression.
Results: Neither ELISPOT nor proliferation assays were statistically different at LTI compared to ITI. While clearly above pre-vaccine responses, the drop in DTH was statistically significant (p < 0.05). Similarly, the increase in Treg cells and circulating TGFβ was also statistically significant. An increase of >200 % in PSA-doubling time at any point during the study was observed in 6/17 patients, with 3 retaining this effect to 5 years.
Conclusions: AE37 generates immunological memory associated with possible clinical efficacy in spite of Tregs and TGF-β levels returning at 4 years after being decreased for up to 6 months after initial AE37 vaccination. These results support further randomized testing of the AE37 vaccine.
The publish only abstract is interesting. We know from an earlier publication (see here) that nine of the subjects who completed the vaccine series were stage IV metastatic (later stage) patients with bone metastases. In that earlier publication, the researchers noted,
The maximum increase of specific IFN-γ–producing T cells in response to vaccination with AE37, detected by ELISPOT and expressed as mean fold increase from baseline levels, was higher in stage II-III and castrate-sensitive patients compared with stage IV and castrate-resistant patients, respectively, although this difference was not statistically significant. Similarly, DTH responses to the vaccine, determined as the difference of post vac minus baseline DTH, were statistically significantly lower in stage IV patients.
In that report, the researchers conclude that,
In conclusion, the use of the AE37 immunotherapeutic vaccine is a novel strategy for managing patients with prostate cancer. This clinical trial shows that the vaccine is safe and immunologically active. However, proof of clinical benefit will require a phase II trial in a homogeneous group of patients with less extensive disease, including disease-free patients at high risk of recurrence.
Therefore, it appears reasonable to assume that results for the Phase I study would be even more positive if the appropriate traget population had been identified, with booster innoculations to prolong the effectiveness of the vaccine. The incease of >200 % in PSA-doubling time at any point during the study for 6/17 patients is remarkable, and since this earlier Phaser I study was initiated Antigen Express has learned much about the vaccine. Booster series have been added to the breast cancer Phase II, with a targeting of lower HER2 expressing early stage subjects.
As we can see with the first ASCO abtract, titled "Booster inoculations of the AE37 peptide vaccine enhance immunological responses in a phase II study", Antigen Express is on the right tract in developing AE37. The prostate cancer Phase I illustrates that AE37 stimulates long lasting memory, and the new booster program can help add to the desired effect. The second ASCO abstract,titled "Risk factors for development of delayed urticarial reactions in the phase II trial of HER2 peptide vaccines plus GM-CSF versus GM-CSF alone in high-risk breast cancer patients to prevent recurrence", highlights the strong safety profile of AE37/GM-CSF + booster, so all appears on track, even if these abstracts don't yet outline final results of the ongoing Phase II study in early stage HER2 breast cancer patients, which may be needed to lift GNBT's dreadful stock. Those final results may come later this year.
Click on the abstract titles to view the content at ASCO's 3013 Annual Meeting website.