Diane F. Hale

Prone Positioning Improves Oxygenation in Adult Burn Patients with Severe Acute Respiratory Distress Syndrome

BACKGROUND Prone positioning (PP) improves oxygenation and may provide a benefit in patients with acute respiratory distress syndrome (ARDS). This approach adds significant challenges to patients in intensive care by limiting access to the endotracheal or tracheostomy tube and vascular access. PP also significantly complicates burn care by making skin protection and wound care more difficult. We hypothesize that PP improves oxygenation and can be performed safely in burn patients with ARDS. METHODS PP was implemented in a burn intensive care unit for 18 patients with severe refractory ARDS. The characteristics of these patients were retrospectively reviewed to evaluate the impact of PP on Pao2:FiO2 ratio (PFR) during the first 48 hours of therapy. Each patient was considered his or her own control before initiation of PP, and trends in PFR were evaluated with one-way analysis of variance. Secondary measures of complications and mortality were also evaluated. RESULTS Mean PFR before PP was 87 (±38) with a mean sequential organ failure assessment score of 11 (±4). PFR improved during 48 hours in 12 of 14 survivors (p < 0.05). Mean PFR was 133 (±77) immediately after PP, 165 (±118) at 6 hours, 170 (±115) at 12 hours, 214 (±126) at 24 hours, 236 (±137) at 36 hours, and 210 (±97) at 48 hours. At each measured time interval except the last, PFR significantly improved. There were no unintended extubations. Facial pressure ulcers developed in four patients (22%). Overall, 14 survived 48 hours (78%), 12 survived 28 days (67%), and six survived to hospital discharge (33%). CONCLUSIONS PP improves oxygenation in burn patients with severe ARDS and was safely implemented in a burn intensive care unit. Mortality in this population remains high, warranting investigation into additional complementary rescue therapies. LEVEL OF EVIDENCE Therapeutic study, level IV.

Cancer vaccines: should we be targeting patients with less aggressive disease?

There is enthusiasm for using vaccines to stimulate the immune system to treat cancer. In this article, the authors review the evolution of vaccines evaluated in clinical trials, starting with Phase III trials in metastatic disease and progressing to trials in the adjuvant setting. Data from these trials suggest that cancer vaccines may be more effective in patients with lower volume disease, and data from the E75 peptide vaccine trials suggest that vaccines may be most effective in less aggressive disease.

Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide AE37 vaccine in breast cancer patients to prevent recurrence

BACKGROUND AE37 is the Ii-Key hybrid of the MHC class II peptide, AE36 (HER2 aa:776-790). Phase I studies showed AE37 administered with granulocyte macrophage colony-stimulating factor (GM-CSF) to be safe and highly immunogenic. A prospective, randomized, multicenter phase II adjuvant trial was conducted to evaluate the vaccines efficacy. METHODS Clinically disease-free node-positive and high-risk node-negative breast cancer patients with tumors expressing any degree of HER2 [immunohistochemistry (IHC) 1-3+] were enrolled. Patients were randomized to AE37 + GM-CSF versus GM-CSF alone. Toxicity was monitored. Clinical recurrences were documented and disease-free survival (DFS) analyzed. RESULTS The trial enrolled 298 patients; 153 received AE37 + GM-CSF and 145 received GM-CSF alone. The groups were well matched for clinicopathologic characteristics. Toxicities have been minimal. At the time of the primary analysis, the recurrence rate in the vaccinated group was 12.4% versus 13.8% in the control group [relative risk reduction 12%, HR 0.885, 95% confidence interval (CI) 0.472-1.659, P = 0.70]. The Kaplan-Meier estimated 5-year DFS rate was 80.8% in vaccinated versus 79.5% in control patients. In planned subset analyses of patients with IHC 1+/2+ HER2-expressing tumors, 5-year DFS was 77.2% in vaccinated patients (n = 76) versus 65.7% in control patients (n = 78) (P = 0.21). In patients with triple-negative breast cancer (HER2 IHC 1+/2+ and hormone receptor negative) DFS was 77.7% in vaccinated patients (n = 25) versus 49.0% in control patients (n = 25) (P = 0.12). CONCLUSION The overall intention-to-treat analysis demonstrates no benefit to vaccination. However, the results confirm that the vaccine is safe and suggest that vaccination may have clinical benefit in patients with low HER2-expressing tumors, specifically TNBC. Further evaluation in a randomized trial enrolling TNBC patients is warranted.

Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide GP2 vaccine in breast cancer patients to prevent recurrence

GP2 is a HER2-derived, HLA-A2+ restricted peptide. Phase I studies showed GP2 administered with GM-CSF to be safe and immunogenic. Here we report the primary analysis of a prospective, randomized, multicenter phase II adjuvant trial conducted to determine the vaccines efficacy. The trial enrolled HLA-A2+, clinically disease-free, node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2 (immunohistochemistry[IHC] 1+-3+). Patients were randomized to GP2+GM-CSF versus GM-CSF alone. Disease-free survival (DFS) was analyzed in intention-to-treat (ITT) and per-treatment cohorts; pre-specified subgroup analyses were performed for patients with IHC 3+ or FISH+ disease. The trial enrolled 180 patients; 89 received GP2+GM-CSF and 91 received GM-CSF alone. The groups were well-matched for clinicopathologic characteristics. Toxicities have been minimal. The Kaplan-Meier estimated 5-year DFS rate in the ITT analyses was 88% (95% CI:78-94%) in vaccinated vs. 81% (95% CI:69-89%) (P = 0.43) in control patients after a 34 month median follow-up. In the per-treatment analysis, the estimated 5-year DFS rates were 94% (95% CI:83-98%) and 85% (73-92%) (P = 0.17). In IHC 3+/FISH+ patients, the estimated 5-year DFS rate was 94% (82-98%) in vaccinated patients (n = 51) vs. 89% (71-96%) in control patients (n = 50), (P = 0.86) in the ITT analyses and 100% vs. 89% (71-96%) in vaccinated vs. control patients in the per-treatment analyses (P = 0.08). While the overall ITT analysis did not demonstrate benefit to vaccination, this trial confirmed that the GP2 vaccine is safe and suggests that vaccination may have clinical activity, particularly in patients with HER2 overexpression who received the full vaccine series (ie per-treatment group).

Primary analysis of the prospective, randomized, phase II trial of GP2+GM-CSF vaccine versus GM-CSF alone administered in the adjuvant setting to high-risk breast cancer patients.

134 Background: GP2 is a HER2 derived, HLA-A2+-restricted immunogenic peptide designed to stimulate CD8+T cells to recognize tumor cells with any level of HER2 expression (IHC 1-3+). Accrual to a prospective, randomized, multi-center, phase II trial of the GP2 vaccine for prevention of breast cancer recurrence has completed. Here, the planned primary analysis of disease-free survival (DFS) is presented. METHODS HLA-A2+ node positive or high-risk node negative breast cancer patients (pts) with any level of HER2 expression rendered disease-free by standard of care therapy (to include trastuzumab where appropriate) were randomized to receive GP2+GM-CSF (VG) or GM-CSF (CG) alone. Pts received 6 monthly inoculations (primary vaccine series = PVS) followed by 4 boosters administered every 6 months. The Kaplan Meier method was used for statistical analysis. The intention-to-treat (ITT) population is defined as the entire randomly assigned population. The per-treatment (PT) group excluded pts who recurred during the PVS or developed a second malignancy. A pre-specified subgroup analysis was performed based on HER2 expression level. HER2 overexpression (OE) is defined as IHC 3+or FISH >2.2. RESULTS With 89 VG and 91 CG pts enrolled and vaccinated, there are no differences between groups with respect to age, node positivity, tumor size, grade, ER/PR status, and HER2 expression (p>0.05). The vaccine has been well tolerated with toxicities comparable between the VG and CG. Only one grade 3 local and systemic toxicity reaction has been reported in the VG. At 34 (1-60) month median follow-up, DFS was compared in the ITT (85% VG v 81% CG, p = 0.57) and PT (94% VG v 85% CG, p = 0.17) populations. In OE patients (51 VG and 50 CG) DFS was 94% VG v 89% CG, p = 0.86 (ITT) and 100% VG v 89% CG, p = 0.08 (PT). CONCLUSIONS GP2+GM-CSF is a novel vaccine that is safe and well tolerated. This phase II trial demonstrates potentially greater benefit in pts with HER2 OE tumors, in whom there have been no recurrences in the PT group. This may be due to synergism with trastuzumab therapy, thus justifying a phase III trial evaluating GP2 administered in the adjuvant setting to a HER2 OE population. CLINICAL TRIAL INFORMATION NCT00524277.

Gaining ground on a cure through synergy: combining checkpoint inhibitors with cancer vaccines

ABSTRACT Introduction: The approval of multiple checkpoint inhibitors (CPIs) for the treatment of advanced malignancies has sparked an explosion of research in the field of cancer immunotherapy. Despite the success of these medications, a large number of patients with advanced malignancy do not benefit from therapy. Early research indicates that a therapeutic combination of cancer vaccines with checkpoint inhibitors may lead to synergistic effects and higher response rates than monotherapy. Areas covered: This paper summarizes the previously completed and ongoing research on this exciting combination, including the use of the tumor lysate, particle-loaded dendritic cell (TLPLDC) vaccine combined with checkpoint inhibitors in advanced melanoma. Expert commentary: Increasing experience with CPIs has led to improved understanding of which patients may benefit and it is increasingly clear that the presence of a pre-existing immune response to the tumor, along with tumor-infiltrating lymphocytes, is key to the success of CPIs. One exciting possibility for the future is the addition of a cancer vaccine to CPI therapy, eliciting these crucial T cells, which can then be augmented and protected by the CPI. A number of current and future studies are addressing this very exciting combination therapy.

Cancer vaccines in colon and rectal cancer over the last decade: lessons learned and future directions

ABSTRACT Introduction: Great advances have been made in screening for and treatment of colorectal cancer (CRC), but recurrence rates remain high and additional therapies are needed. There is great excitement around the field of immunotherapy and many attempts have been made to bring immunotherapy to CRC through a cancer vaccine. Areas covered: This is a detailed review of the last decade’s significant CRC vaccine trials. Expert commentary: Monotherapy with a CRC vaccine is likely best suited for adjuvant therapy in disease free patients. Vaccine therapy elicits crucial tumor infiltrating lymphocytes, which are lacking in microsatellite-stable tumors, and therefore may be better suited for these patients. The combination of CRC vaccines with checkpoint inhibitors may unlock the potential of immunotherapy for a much broader range of patients. Future studies should focus on vaccine monotherapy in correctly selected patients and combination therapy in more advanced disease.

Early efficacy analysis of the AE37 vaccine in patients with HER2 low-expressing and triple-negative breast cancer.

109 Background: Peptide vaccines comprised of HLA class II epitopes, which elicit CD4+ T cell responses, play a critical role in potentiating immune responses. We are conducting a randomized phase II trial of AE37, a hybrid peptide created by the addition of the Ii-Key moiety (LRMK) to the HER2 helper epitope, AE36 (HER2 aa776-790). Here, we present efficacy data focusing on outcomes in patients with low HER2 (IHC 1+ or 2+) expression and triple negative breast cancer (TNBC). METHODS The trial is enrolling node positive or high risk node negative breast cancer patients with any degree of HER2 expression (IHC 1+, 2+ or 3+ or FISH > 1.2) rendered disease-free following standard of care therapy. Patients are randomized to receive either AE37+GM-CSF or GM-CSF alone in 6 monthly intradermal inoculations followed by booster inoculations administered every 6 months. RESULTS The trial has enrolled 254 patients; 105 in the vaccine group (VG) and 149 in the control group (CG). After a median follow-up of 22.3 months, the disease-free survival (DFS) rate in the VG is 90.3% vs 81.1% in the CG (p=.46), a 49% risk reduction. Evaluating patients with low HER2 expression (IHC 1+ or 2+), there are 53 VG patients and 77 CG patients. The groups are well-matched with respect to the percentage of patients with high grade tumors, tumors > 2cm, the rate of node positivity and ER/PR status (all p>.5). The DFS rate in the VG of low HER2 expressers is 89.8% vs 68.2% in the CG (p=.12), a 68% risk reduction. When limiting analyses to patients with TNBC (ER/PR negative, HER2 1+ or 2+), there are 13 VG patients and 23 CG patients. The groups are again well-matched with the exception of control patients having a larger percentage of tumors > 2 cm (70% vs 31%; p=.02). The DFS rate in the VG of TNBC patients is 83.3% vs 47.6% in the CG (p=.23), a 68% risk reduction. CONCLUSIONS Early analyses suggest clinical benefit to vaccination with AE37, particularly in patients with low HER2-expressing tumors. Importantly, the benefit appears to persist in TNBC patients. Patients will continue to be followed per protocol for 5 years; however, these data suggest that a subsequent phase III trial should evaluate the vaccine in patients with low HER2-expressing disease to include TNBC.

Absence of clinical findings reliably excludes unstable cervical spine injuries in children 5 years or younger

BACKGROUND Increased accessibility and rapidity of computed tomography (CT) have led to increased use and radiation exposure to pediatric trauma patients. The thyroid is radiosensitive and therefore at risk for developing malignancy from radiation exposure during cervical spine CT. This analysis aimed to determine which preelementary trauma patients warrant cervical spine CT by defining incidence and clinical characteristics of preelementary cervical spine injury. METHODS This was a retrospective review of pre-elementary trauma patients from 1998 to 2010 with cervical spine injury admitted to a Level I trauma center. Patients were identified from the trauma registry using DRG International Classification of Diseases—9th Rev. codes and reviewed for demographics, mechanism of injury, clinical presentation, injury location, injury type, treatment, and outcome. RESULTS A total of 2,972 preelementary trauma patients were identified. Twenty-two (0.74%) had confirmed cervical spine injuries. Eleven (50%) were boys, and the mean (SD) age was 3 (1.7) years. The most common mechanism of injury was motor vehicle collision (n = 16, 73%). The majority (59%) were in extremis, and 12 (55%) arrived intubated. The median Glasgow Coma Scale (GCS) score was 3 (interquartile range, 3–10); the median Injury Severity Score (ISS) was 33 (interquartile range, 17–56). Nineteen injuries (76%) were at the level of C4 level and higher. The mortality rate was 50%. All patients had clinical findings suggestive of or diagnostic for cervical spine injury; 18 (82%) had abnormal neurologic examination result, 2 (9%) had torticollis, and 2 (9%) had neck pain. CONCLUSION The incidence of cervical spine injury in preelementary patients was consistent with previous reports. Missing a cervical spine injury in asymptomatic preelementary patients is extremely low. Reserving cervical spine CT to symptomatic preelementary patients would decrease unnecessary radiation exposure to the thyroid. LEVEL OF EVIDENCE Therapeutic study, level IV.

Abstract P5-16-02: Final Results of the Phase I/II Trials of the E75 Adjuvant Breast Cancer Vaccine

Background: We have completed phase I/II clinical trials vaccinating breast cancer patients (pts) with E75, a HLA-A2/A3-restricted HER2/neu (HER2) peptide vaccine. The vaccine was administered in the adjuvant setting to prevent recurrences in high risk patients rendered disease-free with standard of care therapy. We have previously reported preliminary results indicating that the vaccine (including booster inoculations) is safe and effective in stimulating an anti-tumor immune response. Here, we report the final 5 year results from these trials. Methods: The phase I/II trials were performed as dose-escalation/schedule-optimization trials enrolling node positive and high-risk, node negative breast cancer patients with tumors expressing any level of HER2. HLA-A2/A3+ pts were enrolled into the vaccine group (VG) while HLA-A2/A3- pts were followed prospectively as the untreated control group (CG). The VG pts were given 4–6 monthly intradermal inoculations of E75 with GM-CSF during the primary vaccine series (PVS). In addition, a voluntary booster program was initiated during the trial, with booster inoculations being offered every 6 months after completion of the PVS. Patients were monitored for local and systemic toxicity (graded by NCI Common Terminology Criteria for Adverse Events). In vivo immune response was assessed in the VG by delayed type hypersensitivity (DTH) reactions to both E75 and saline, pre- and post-PVS. VG and CG pts were followed for 60 months (mo) and recurrences were documented. Demographic differences were compared with the Fisher9s exact test and disease-free survival was determined using the Kaplan-Meier method and compared by log-rank test. Results: 195 pts were enrolled, 6 withdrew (2 from VG, 4 from CG), 1 was lost to follow-up prior to vaccination, and 1 was found to be ineligible, leaving 187 evaluable pts; 108 in the VG and 79 in the CG. 53 pts volunteered for the booster program and received at least one booster inoculation. The VG and CG were well-matched with the only statistically significant difference being ER−/PR- status (31.1% in VG vs 17.7% in CG, p = 0.04). Vaccination was well tolerated (maximum local toxicity: 73.1% Grade 1, 26.9% Grade 2, 0% Grade 3; maximum systemic toxicity: 72.2% Grade 1, 15.7% Grade 2, and 2.8% Grade 3). In the VG, pre- to post-PVS E75 DTH significantly increased (mean 3.8 ±1.0 vs 14.8±1.4, p Conclusions: The E75 breast cancer vaccine is safe and well–tolerated. It elicits strong immune responses in vaccinated patients. At the end of the 5 year follow-up period, the E75 vaccine shows a strong trend toward preventing breast cancer recurrence in vaccinated patients. To investigate this vaccine (now known as NeuVax) further, the PRESENT trial, a prospective, randomized, double-blind, placebo-controlled, multi-center phase III registration trial has been initiated and is actively enrolling. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-16-02.