V. E. Herrin

A pilot clinical trial testing mutant von Hippel- Lindau peptide as a novel immune therapy in metastatic Renal Cell Carcinoma

BackgroundDue 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.MethodsSix 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.ResultsFour 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.ConclusionsThe 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

Chemotherapy for ovarian cancer: current concepts.

Ovarian cancer is the most common gynecologic cancer and has the highest case-fatality rate of all gynecologic malignancies: over one-half of all women diagnosed with ovarian cancer die of their disease. Chemotherapy for epithelial ovarian carcinoma has evolved rapidly during the last 15 years. Demonstrations that combination chemotherapy was superior to single-agent therapy began to improve outcome among women with this disease. By 1990, the advent of the platinum compounds had improved response rate, and the new standard of care combined platinum with alkylating agents. Recently, more significant progress has been made with utilization of the taxanes, which demonstrate not only improved response rates, but significantly prolonged survival as well. The most current clinical trials have established that taxane/platinum combination chemotherapy should be the standard of care for epithelial ovarian cancer. Recent and ongoing studies also address such issues as relative efficacy of different doses of taxanes and platinum, length of infusion for the taxanes, and interchangeability of the platinum compounds. This broad overview of the development of current standards of treatment also will address unresolved issues in this field, including intraperitoneal administration of chemotherapy and dose intensification.

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.

Abstract 2414: Comparable effect of p53 peptide vaccine in adjuvant or pulsed on dendritic cells in ovarian cancer patients: A gynecologic oncology group study

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Purpose: Peptide antigens have been administered by different approaches in 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 the wild-type (wt) p53 vaccine using two approaches. 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 subcutaneous wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells intravenously. Interleukin-2 (IL-2) was administered in both cohorts in alternative cycles. The immunologic response was assessed by ELISPOT and tetramer assays. Results: Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B had an immunologic response. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced 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 demonstrated that using either vaccination approach could generate comparable specific immune responses against the wt p53 peptide with minimal toxicity. Accordingly, our findings support the utilization of the less demanding subcutaneous method. Furthermore, as IL-2 may add toxicity and induce T regulatory cells, which can suppress the immune response, therefore, it may not be needed in future trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2414.

325 THROMBOEMBOLISM IN MULTIPLE MYELOMA PATIENTS RECEIVING THALIDOMIDE COMBINATION CHEMOTHERAPY.

Purpose To establish the incidence of thromboembolism (TBE) in multiple myeloma (MM) patients on thalidomide combination chemotherapy. Methods A retrospective review was performed on all multiple myeloma patients at our tertiary care facility from January 2000 to December 2006. Patients were assessed for baseline characteristics, including age, sex, and past medical and surgical histories. Risk factors for TBE were evaluated, including a documented hypercoagulable state, a history of prior TBE, comorbidities, cytogenetics, and concurrent medications. It was also noted whether a central venous catheter (CVC) was in place. TBE included deep vein thromboses (DVTs) and pulmonary embolism (PE). It was also noted if patients had arterial TBEs. Patient chemotherapy regimens with or without thalidomide were reviewed, and each patient was assessed for evidence of TBE. Furthermore, thalidomide doses and titration intervals were documented. If thalidomide was used, patients were evaluated for concurrent use of prophylactic anticoagulation. Types of anticoagulation included low-molecular-weight heparin, full-dose warfarin, low-dose warfarin (usually 1 mg), and aspirin. If the patient had documented TBE, the median time to TBE while on the thalidomide combination was noted. Patients on full anticoagulation following TBE were followed for continued thalidomide use and bleeding events. Results Of 118 eligible patients, there were 29 (24% of patients) occurrences of DVT or PE. Preliminary results show that 13 (11%) of the patients with TBE were on some thalidomide combination, whereas 15 (13%) were not. Seven of 13 patients with TBE on thalidomide were not on prophylactic anticoagulation. Three events occurred on low-dose warfarin, two on full-dose warfarin, and one on enoxaparin. Conclusions It has been previously reported that about 10% of MM patients develop DVT when treated with chemotherapy alone. DVT rates of 25 to 30% have been documented with the addition of thalidomide to conventional chemotherapy or dexamethasone, whereas it occurs in only 3% of those treated with dexamethasone alone. No randomized trials have been done to establish the most effective type of prophylactic anticoagulation in this patient population. We hope to identify those patients at highest risk for TBE in our population and the best regimen for TBE prophylaxis.

220 REDUCED-INTENSITY CONDITIONING USING ALEMTUZUMAB IN ALLOGENEIC HEMATOPOIETIC TRANSPLANTATION.

Purpose Allogeneic hematopoietic transplantation after a myeloablative conditioning regimen has been shown to be an effective and potentially curative treatment for many hematologic malignancies due to the graft-versus-malignancy (GVM) effect. However, significant toxicities of such regimens have limited their use to younger, otherwise healthy patients. Reduced-intensity conditioning (RIC) transplantation has broadened eligibility to include older patients and those with comorbid conditions. RIC regimens using fludarabine and melphalan have been associated with a high risk of graft-versus-host disease (GVHD). Our institution adopted a RIC protocol that added alemtuzumab, an anti-CD52 monoclonal antibody that decreases T cells in the transplant recipient, to melphalan and fludarabine in an attempt to reduce the risk of GVHD while maintaining the GVM effect. Methods From January 2005 to June 2006, 19 patients with hematologic malignancies received an allogeneic transplant using the RIC protocol. Median patient age was 52 years (34-66). Results Acute and chronic GVHD occurred in 6 of 19 (31%) and 5 of 19 (26%), respectively, with only 17% of each being > grade II. Cytomegalovirus (CMV) reactivation occurred in 13 of 19 (68%). Seven of 19 (37%) patients experienced disease relapse or progression. One hundred-day survival was 79%. Ten of 19 (53%) have died at the time of this report. CMV infection was the probable cause of death in 3 of 10 (30%) deaths, or 16% of patients overall. Only one death was attributable to GVHD. Conclusions RIC allogeneic transplant represents a reasonable treatment option for a variety of hematologic malignancies. There was a low incidence of severe GVHD and a 100-day survival of 79%. However, the mortality rate due to toxicity of this regimen was high at 37%. CMV infection represents a large proportion of this toxicity and provides an area to be improved upon in future RIC protocols, perhaps by using lower doses of alemtuzumab.

ALEMTUZUMAB DOSING BY RECIPIENT WEIGHT IS IMPORTANT FOR REDUCED-INTENSITY CONDITIONING FOR ALLOGENEIC TRANSPLANTATION.: 329

From June 2002, to August 2006, our institution used reduced-intensity conditioning (RIC) regimens for allogeneic transplantation of 40 adult at-risk older patients or patients with comorbid conditions. Malignancies included multiple myeloma, AML, CML, NHL, MDS, CLL, and one renal cell carcinoma. Thirteen (32%) were in CR at time of transplant, whereas 27 (68%) had relapsed or refractory disease. Median age was 50 years (range 24-66) and median follow-up was 8 months (1-36 months). Degree of HLA match at A, B, and DR was 6/6 or better for 31 patients and either single antigen or allele mismatches for the others. Three RIC regimens consisted of intravenous infusions of: fludarabine 30 mg/m2 × 5 days and melphalan 140 mg/m2 × 1 day in all groups, and of Alemtuzumab 20 mg/d × 5 days (protocol 1), × 3 days (protocol 2), and × 2 days (protocol 3). Twenty-three patients received MUD products and 17 received MRD products; cell source was bone marrow (17), PBSC (19), cord blood (1), and combination products (3). All patients received an adequate CD34+ cell dose or TNC dose (cord blood transplant). GVHD prophylaxis was tacrolimus tapering after day +100 and mycophenolate mofetil tapering after day +30. Determination of the optimal dose of alemtuzumab was a goal of this study. All patients except one achieved a WBC graft. Relapse or disease progression occurred in only 37% of protocol 3, 40% of protocol 2, and 67% of protocol 1. Although alemtuzumab doses were given in a standard fashion not adjusted for body weight or surface area, it was found that a lack of consideration of patient size did not represent the intent of the given protocols. Weight-based alemtuzumab dose adjustment showed that a much broader dose range than expected had occurred. Those receiving protocol 1 were in a dose range of 1.01 to 1.90 mg/kg; for protocol 2, the range was 0.36 to 1.08 mg/kg; for protocol 3, the range was 0.36 to 0.70. The median dose of alemtuzumab for the cohort was 0.68 mg/kg. A clustering of acute GVHD grades I to II appeared below the median dose at approximately 0.55 mg/kg; only one patient had grade IV GVHD. In summary, these data indicate that using the patient9s body weight in the determination of an optimal alemtuzumab dose is a more reasonable approach to developing and standardizing RIC protocols with this drug.