Pre-immature dendritic cells (PIDC) pulsed with HPV16 E6 or E7 peptide are capable of eliciting specific immune response in patients with advanced cervical cancer.

BACKGROUND: The protein products of the early genes E6 and E7 in high-risk HPV types 16 and 18 have been implicated in the oncogenic capability of these viruses. Therefore, these peptides represent attractive vaccine therapy targets. METHODS: Thirty-two patients with advanced cervical cancer (HPV16 or 18 positive) were treated with HPV16 E6 (18-26) (Arm A) or HPV16 E7 (12-20) peptide (Arm B) pulsed on PBMCs in order to illicit immune response against the relevant peptide on both arms. These PBMCs were cultured for a short time (48 hours only) and in the presence of GM- CSF, accordingly, they were identified as "Pre-Immature Dentritic Cells". RESULTS: 51Cr release assay and ELISPOT demonstrated evidence of specific immune response against the relevant peptide in 10/16 (63%) evaluable patients in arm A and 7/12 (58%) in arm B. HPV16 E6 was found to be homologous to HPV18 E6 in both vivo and vitro. The median overall survival (OS) and progression free survival (PFS) for the full cohort was 10.0 and 3.5 months, respectively. There were no RECIST responses in any patient. The majority of toxicities were grade I and II. CONCLUSIONS: We demonstrated the feasibility and ability of Pre-Immature Dentritic Cells pulsed with HPV16 E6 (18-26) or HPV16 E7 (12-20) to induce a specific immune response against the relevant peptide despite the advanced disease of the cervical cancer patients treated on this trial. We believe that this observation deserves further investigations.

A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients.

PURPOSE: Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine. EXPERIMENTAL DESIGN: Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer overexpressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received SC wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells IV. Interleukin-2 (IL-2) was administered to both cohorts in alternative cycles. RESULTS: Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B developed an immunologic response as determined by ELISPOT and tetramer assays. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced the expansion of T regulatory cells. The median overall survival was 40.8 and 29.6 months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7 months, respectively. CONCLUSION: We found that using either vaccination approach generates comparable specific immune responses against the p53 peptide with minimal toxicity. Accordingly, our findings suggest that the use of less demanding SC approach may be as effective. Furthermore, the use of low-dose SC IL-2 as an adjuvant might have interfered with the immune response. Therefore, it may not be needed in future trials.

A pilot clinical trial testing mutant von Hippel-Lindau peptide as a novel immune therapy in metastatic renal cell carcinoma.

BACKGROUND: Due to the lack of specific tumor antigens, the majority of tested cancer vaccines for renal cell carcinoma (RCC) are based on tumor cell lysate. The identification of the von Hippel-Lindau (VHL) gene mutations in RCC patients provided the potential for developing a novel targeted vaccine for RCC. In this pilot study, we tested the feasibility of vaccinating advanced RCC patients with the corresponding mutant VHL peptides. METHODS: Six patients with advanced RCC and mutated VHL genes were vaccinated with the relevant VHL peptides. Patients were injected with the peptide mixed with Montanide subcutaneously (SQ) every 4 weeks until disease progression or until the utilization of all available peptide stock. RESULTS: Four out of five evaluable patients (80%) generated specific immune responses against the corresponding mutant VHL peptides. The vaccine was well tolerated. No grade III or IV toxicities occurred. The median overall survival (OS) and median progression-free survival (PFS) were 30.5 and 6.5 months, respectively. CONCLUSIONS: The vaccine demonstrated safety and proved efficacy in generating specific immune response to the mutant VHL peptide. Despite the fact that the preparation of these custom-made vaccines is time consuming, the utilization of VHL as a vaccine target presents a promising approach because of the lack of other specific targets for RCC. Accordingly, developing mutant VHL peptides as vaccines for RCC warrants further investigation in larger trials. TRIAL REGISTRATION: 98C0139.

The effect of new duty hours on resident academic performance and adult resuscitation outcomes.

BACKGROUND: From July 2011, the Accreditation Council for Graduate Medical Education implemented new resident duty hours throughout the US. This study aimed to determine whether changes to call schedules due to these new duty hours achieved the intended goals of excellent patient care and improved resident learning. METHODS: We conducted a retrospective cohort study at an academic hospital. For patient outcomes, we used the hospital registry for code blues and rapid responses to compare the proportion of deaths and transfers to an intensive care unit (July 2010 to June 2011; July 2011 to June 2012). For resident learning, we compared delta percentage scores for annual in-service training examinations (2009 to 2010; 2010 to 2011; 2011 to 2012). RESULTS: We recorded 187 code blues and 469 rapid responses during the 2-year period: 48 (7.3%) deaths, 374 (57.0%) transfers to the intensive care unit, and 234 (35.7%) stabilizations on the floor. Of all transfers to the intensive care unit, those due to a code blue decreased after implementation of the new duty hours (36% [63/174] vs 25% [49/200], P = .02; adjusted odds ratio = 0.59; 95% confidence interval, 0.37-0.92). The median (interquartile range) delta percentage scores for annual in-service training examinations decreased significantly from the first time-period (2009 to 2010: 7 [4-11]) to the third time-period (2011 to 2012: 5 [2-8], P = .02). CONCLUSION: We observed a reduced proportion of transfers to the intensive care unit with a code blue after implementation of new resident duty hours. Resident academic performance experienced a small but significant decrease in in-service training examination delta percentage score. We need large, multicenter studies to corroborate these findings.

Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers.

INTRODUCTION: There is mounting evidence describing the immunosuppressive role of bulky metastatic disease, thus countering the therapeutic effects of tumor vaccine. Therefore, adjuvant immunotherapy may have a better impact on clinical outcome. In this phase II clinical trial, we aimed to test the feasibility of using a specific mutant ras peptide vaccine as an adjuvant immunotherapy in pancreatic and colorectal cancer patients. MATERIALS AND METHODS: Twelve patients with no evidence of disease (NED), five pancreatic and seven colorectal cancer patients were vaccinated subcutaneously with 13-mer mutant ras peptide, corresponding to their tumor's ras mutation. Vaccinations were given every 4 weeks, up to a total of six vaccines. RESULTS: No serious acute or delayed systemic side effects were seen. We detected specific immune responses to the relevant mutant ras peptide by measuring IFN-gamma mRNA expression by quantitative real-time PCR. Five out of eleven patients showed a positive immune response. Furthermore, the five pancreatic cancer patients have shown a mean disease-free survival (DFS) of 35.2+ months and a mean overall survival (OS) of 44.4+ months. The seven colorectal cancer patients have shown a mean disease-free survival (DFS) of 27.2+ months and a mean overall survival (OS) of 41.5+ months. CONCLUSION: In this study, we found that it is feasible to use mutant ras vaccine in the adjuvant setting. This vaccine is safe, can induce specific immune responses, and it appears to have a positive outcome in overall survival. Therefore, we believe that such an approach warrants further investigation in combination with other therapies.