Prospects of off-label (OL) drug use in oncology: Identifying predicting variables for registration and universal healthcare reimbursement.

e18842 Background: Many cancer drugs used OL, eventually complete clinical development and are registered and reimbursed, while others are not. We aimed to describe OL indications' registration and reimbursement prospects in a universal healthcare system and identify groups of treatments that remain OL longer. Methods: We studied 612 OL oncology prescription requests for 115 unique indications and 29 drugs. All requests were approved by the Institutional Drug Committee in Rabin Medical Center, a tertiary center in Israel, between January 2016 and December 2018. OL indications were not registered by the Israeli Ministry of Health (MOH) and were not included in the Israeli National List of Health Services (NLHS) for reimbursement at the time of prescription. Additionally, 459 requests for 100 indications were not approved by the FDA at the time of prescription. We explored the subsequent regulatory and reimbursement milestones in the timeline following each prescription. We identified three temporal events: FDA indication approval, MOH indication registration, and NLHS indication inclusion of reimbursement. We then defined three time-to-event variables from the OL prescription to each of the three milestones. We applied Kaplan-Meier analysis and multivariable Cox regression to identify drug and indication properties, which are predictors for registration and reimbursement. Results: With a median follow-up of 34.5 months, 10.4% of indications were eventually registered in Israel, and 6% were included in the NLHS. 7% of non-FDA approved indications were subsequently approved. For MOH registration, positive predictors were immunotherapy, sufficient evidence (ESMO-MCBS A-B, 5-4), and a patient access program at the time of prescription (HR = 21.99; p< .0005, HR = 3.4; p= .02 and HR = 2.73; p< .0005, respectively). Negative predictors were metastatic setting and lung and gastrointestinal (GI) cancers (HR = 0.42; p= .002, HR = 0.17; p= .001, and HR = 0.24; p= .043, respectively). For NLHS inclusion, positive predictors were immunotherapy, sufficient evidence, and an access program (HR = 9.03, HR = 6.24, and HR = 2.56, respectively, all p< .0005). Negative predictors were lung and GI cancers and orphan disease designation (HR = 0.07; p= .002, HR = 0.14; p= .021, and HR = 0.13; p= .009, respectively). For FDA approval, positive predictors were immunotherapy, sufficient evidence, and a patient access program (HR = 12.11; p< .0005, HR = 4.34; p= .002, and HR = 2.25; p= .001, respectively). Negative predictors were metastatic setting, lung cancer, and orphan disease (HR = 0.43; p= .003, HR = 0.25; p= .006, and HR = 0.08; p= .018, respectively). Conclusions: Few OL indications are subsequently approved and reimbursed, usually due to clinical futility and insufficient evidence. However, we identified factors related to lack of initiative for further clinical development and registration.

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Factors associated with off-label (OL) drug use in oncology: The role of cost and financing in a universal healthcare system.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18825 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18825-e18825

Author(s):

Noa Gordon ◽

Daniel A Goldstein ◽

Boaz Tadmor ◽

Salomon M. Stemmer ◽

Dan Greenberg

Keyword(s):

Logistic Regression ◽

Healthcare System ◽

Treatment Initiation ◽

Sufficient Evidence ◽

Supporting Evidence ◽

Universal Healthcare ◽

Multivariable Logistic Regression ◽

Metastatic Setting ◽

Tertiary Center ◽

Universal Healthcare System

e18825 Background: In recent years, OL use in oncology has become widespread, with estimates ranging up to 50-75% of all prescriptions. Most OL use is not publicly reimbursed within universal healthcare systems. We aimed to characterize the financing sources of OL use and to identify predictors for forgoing such treatment. Methods: We studied 708 oncology OL prescription requests submitted for approval to the Institutional Drug Committee in Rabin Medical Center, a large tertiary center in Israel, between January 2016 and December 2018. We included only requests for patients that were alive for more than 60 days following prescription approval. For each indication we extracted the level of supporting evidence at the time of prescription (sufficient, limited, inadequate). We also examined patients’ disease and sociodemographic properties, treatment costs, and financing sources. We used univariable logistic regression to ascertain these variables’ effects on actual OL drug initiation. We then used multivariable logistic regression to explore predicting factors for drug initiation. Results: The median monthly cost of a planned OL treatment was ILS39,928 (approximately US$ 11,500). Approximately one third (31%) of the treatments did not have a financing source at the time of request approval. The primary financing sources were patient access plans (30%) and private health insurance (25%). Of 708 approved OL requests, only 583 (82.3%) treatments were initiated. The proportion of requests that were eventually initiated was higher in the metastatic versus adjuvant setting (84.9% vs. 76.5%; p= .008). The estimated median OS for metastatic patients was 9.9 months, significantly higher in patients that did initiate treatment versus patients that did not (10.4 vs. 7.2 months; p= .048). Although not significant, median costs of initiated treatments were higher compared to treatments that were not (ILS41,686 vs. ILS24,670). Prescriptions for the metastatic setting and immunotherapy as well as ones with sufficient evidence had higher odds for treatment initiation (OR = 1.73; p= .007, OR = 1.69; p= .013 and OR = 1.62; p= .016). Prescriptions with limited supporting evidence and with no planned financing source had lower odds for treatment initiation (OR = 0.59; p= .012, OR = 0.37; p< .0005). A multivariable logistic regression showed that if no financing plan was in place at the time of request, there was a 2.5 times higher likelihood of not initiating the treatment (OR = 2.5; p< .0005). Conclusions: While OL recommendation is widespread and institutional approval is granted, a substantial proportion of treatments are not initiated. Although cost was not associated with treatment initiation, having a planned financing source was a strong predictor for OL treatment initiation. This study elucidates the financing sources of OL treatments in a universal healthcare system and identifies access barriers.

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Mortality in patients with atrial fibrillation with or without heart failure following hospital discharge

European Heart Journal ◽

10.1093/ehjci/ehaa946.0362 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A Kartas ◽

A Samaras ◽

D Vasdeki ◽

G Dividis ◽

G Fotos ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Primary Endpoint ◽

Cox Regression ◽

Cross Sectional ◽

Tertiary Center ◽

All Cause Mortality ◽

Endpoint Event ◽

Secondary Endpoints ◽

Sectional Analysis

Abstract Background The association of heart failure (HF) with the prognosis of atrial fibrillation (AF) remains unclear. OBJECTIVES To assess all-cause mortality in patients following hospitalization with comorbid AF in relation to the presence of HF. Methods We performed a cross-sectional analysis of data from 977 patients discharged from the cardiology ward of a single tertiary center between 2015 and 2018 and followed for a median of 2 years. The association between HF and the primary endpoint of death from any cause was assessed using multivariable Cox regression. Results HF was documented in 505 (51.7%) of AF cases at discharge, including HFrEF (17.9%), HFmrEF (16.5%) and HFpEF (25.2%). A primary endpoint event occurred in 212 patients (42%) in the AF-HF group and in 86 patients (18.2%) in the AF-no HF group (adjusted hazard ratio [aHR] 2.27; 95% confidence interval [CI], 1.65 to 3.13; P<0.001). HF was associated with a higher risk of the composite secondary endpoint of death from any cause, AF or HF-specific hospitalization (aHR 1.69; 95% CI 1.32 to 2.16 p<0.001). The associations of HF with the primary and secondary endpoints were significant and similar for AF-HFrEF, AF-HFmrEF, AF-HFpEF. Conclusions HF was present in half of the patients discharged from the hospital with comorbid AF. The presence of HF on top of AF was independently associated with a significantly higher risk of all-cause mortality than did absence of HF, irrespective of HF subtype. Funding Acknowledgement Type of funding source: None

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Long-term success of flexible endoscopic septal division with the stag beetle knife for Zenker’s diverticulum: a tertiary center study

Diseases of the Esophagus ◽

10.1093/dote/doaa019 ◽

2020 ◽

Vol 33 (11) ◽

Author(s):

Sauid Ishaq ◽

Keith Siau ◽

Minhong Lee ◽

Haleema Sultan ◽

Shalmani H Mohaghegh ◽

...

Keyword(s):

Cox Regression ◽

Multivariable Analysis ◽

Zenker’S Diverticulum ◽

Long Term Outcome ◽

Zenker's Diverticulum ◽

Tertiary Center ◽

Symptom Remission ◽

Treatment Naïve ◽

Symptom Recurrence

Summary Objectives Flexible endoscopic septum division is an established treatment for Zenker’s diverticulum (ZD); however, long-term outcome data are lacking. We aimed to evaluate the long-term efficacy of flexible endoscopic septal division (FESD) using the stag beetle knife for ZD and identify predictors of symptom recurrence. Methods Patients undergoing the procedure between 2013 and 2018 were prospectively enrolled. Procedures were performed by a single operator. Symptom severity pre- and postprocedure was recorded using the dysphagia, regurgitation, and complications scale. Symptom recurrence was defined as a total score > 1 after the index procedure. Time-to-event analyses were performed using Kaplan–Meier plots, with multivariable analyses performed using Cox regression models. Results Altogether, 65 patients (mean age 74.0 years, 60% male) were included. Previous stapling had been performed in 44.6% of patients. Over the mean posttreatment follow-up period of 19 months, 5.6% of the treatment naïve group and 34.5% of the recurrent group underwent repeated FESD (P = 0.003), with rates of symptom remission and improvement of 75.4% and 92.7%, respectively. Recurrence at 48 months was higher in patients with recurrent ZD (84.7%) than in treatment-naïve patients (10.7%). On multivariable analysis, recurrent disease (hazard ratio [HR] 20.8, P = 0.005) and younger age (HR 0.96/year, P = 0.047) were associated with symptom recurrence. Conclusions In patients with treatment-naïve ZD, flexible endoscopic septal division is safe and provides durable symptom remission. However, in patients with poststapling recurrence, the risk of recurrence is high and time-dependent.

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Real-world analysis of disease progression after CDK 4/6 inhibitor (CDKi) therapy in patients with hormone receptor positive (HR+)/HER2- metastatic breast cancer (MBC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e13030 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e13030-e13030

Author(s):

Malinda West ◽

Andy Kaempf ◽

Shaun Goodyear ◽

Thomas Kartika ◽

Jessica Ribkoff ◽

...

Keyword(s):

Breast Cancer ◽

Cox Regression ◽

Metastatic Breast ◽

Molecular Characteristics ◽

Rapid Progression ◽

Hormone Receptor Positive ◽

Her2 Breast Cancer ◽

Metastatic Setting ◽

Increased Risk ◽

Visceral Disease

e13030 Background: CDKi with endocrine therapy (ET) is approved treatment of metastatic HR+/HER2- breast cancer based on PFS benefit vs ET alone. Outcomes data following CDKi discontinuation (dc) is limited, with trials ongoing in this setting. The reported phenomenon of rapid progression within 4 months of CDKi dc raises concern over CDKi impact on HR+/HER2- MBC biology. This study aims to define outcomes after CDKi dc and identify predictors of progression. Methods: This is a retrospective review of women ≥18 years with HR+/HER2- MBC who received CDKi between 4/1/14 and 12/1/19. Patient and tumor characteristics, pre and post CDKi tx, and reason for CDKi dc were collected. Time to event outcomes from date of CDKi dc (primary = PFS, secondary = Overall Survival, OS) were analyzed with Kaplan Meier estimators and Cox regression. Results: Analysis included 140 patients (median age 65 years), with most MBC (84%) arising from earlier stage disease. 51% of MBCs had visceral disease, and 66% received tx prior to CDKi. The most common CDKi was palbociclib (93%); and most common ET were letrozole (52%) and fulvestrant (40%). Median CDKi tx duration was 9 months (3.5 – 17.4) with 80% dc due to progression. Post CDKi txs included chemotherapy (44%), ET (24%), targeted tx (21%), no further tx (7%) and CDKi tx (4%). Median follow up was 12 months. mPFS post CDKi dc were 6.5 months (95% CI: 5.0 – 7.9) and 11.3 months (95% CI: 4.6 – 23.7) in patients who dc CDKi due to progression or other reasons, respectively (HR 1.77, 95%CI: 1.10-2.85). Among 112 patients who progressed on CDKi, estimated 4-month incidence of post CDKi progression or death was 31% (Table ). mOS post CDKi dc was 15.4 months (95%CI: 13.3-19.0) and mOS post CDKi initiation was 26.5 months (95% CI: 23.3 – 34.3). Visceral disease (HR 1.45, 95%CI: 1.01-2.08) and progression as reason for CDKi dc (HR 1.77, 95%CI: 1.1-2.85) were predictors of PFS (p < 0.05). Receiving fulvestrant with CDKi (HR 1.42, 95%CI: 0.96-1.0), prior chemotherapy in the metastatic setting (HR = 1.39, 95% CI: 0.90 – 2.14), and shorter CDKi duration were associated with non-significant increased risk of PFS. Conclusions: Rapid progression or death at 4 months occurred in 31% of MBCs following CDKi dc due to progression. Ongoing studies to define clinical and molecular characteristics of rapidly progressing tumors are underway to develop targeted tx approaches and improve outcomes.[Table: see text]

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Improvement of survival in VA patients with gall bladder cancer given chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4132 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4132-4132 ◽

Cited By ~ 1

Author(s):

M. Atiq ◽

M. M. Safa ◽

R. S. Komrokji ◽

A. R. Jazieh ◽

A. F. Muhleman ◽

...

Keyword(s):

Bladder Cancer ◽

Adjuvant Chemotherapy ◽

Gall Bladder ◽

Median Survival ◽

Bladder Carcinoma ◽

Cox Regression ◽

Gall Bladder Cancer ◽

P Value ◽

Gall Bladder Carcinoma ◽

Metastatic Setting

4132 Background: Gallbladder carcinoma, though rare, has very poor prognosis. Most of patients with gall bladder carcinoma present with either unresectable disease or metastasis. Median survival in gall bladder carcinoma has been documented to be 6 months in SEER data. There is no data available on the outcome of Veterans’ Affair (VA) patients with gall bladder carcinoma. Impact of chemotherapy in adjuvant and metastatic setting is not well-studied. Methods: We used the VA Central Cancer Registry (VACCR) to analyze VA patients with Gall Bladder cancer diagnosed between 1995 and 2005. The reference date for data collection and reporting is January 1, 1995. This site aggregates the data collected by the medical centers’ cancer registries. Data was entered and analyzed using bio-statistical software SPSS. Results: There were a total of 232 patients. Of these, 185 (79.7%) were whites and 37 (15.9%) were blacks. The mean age was 71 years. Pathology was adenocarcinoma in 198 (85.3%), non-specified carcinoma in 29 (12.5%) and small cell carcinoma in 5 (2.2%) cases. Overall median survival was 5.27 months. Surgery was performed in 119 patients (51%). Only 19 (16%) patients received adjuvant chemotherapy. The baseline characteristics were similar between patients who received adjuvant chemotherapy and no adjuvant chemotherapy. Also, the median survival was similar (8.3 months vs. 8.7 months) (P-value 0.37). In patients who did not undergo surgery, the median survival for patients who received chemotherapy was 8.0 months vs 1.7 months for patients who did not receive chemotherapy (p-value 0.013). Eighty-nine (38.5%) patients were diagnosed with stage IV disease. Amongst these patients chemotherapy improved the median survival (2 months vs. 6.97 months; p-value 0.04). In a Cox regression model stage, surgical margins, surgery, chemotherapy were independent predictors of patient survival. Conclusions: Gall bladder carcinoma in VA patients has similar survival compared to other reports. Our data is one of the largest retrospective cohorts in gall bladder cancer and suggests that chemotherapy improves survival in advanced gall bladder cancer patients. No significant financial relationships to disclose.

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Germline BRCA1and BRCA2 mutations in patients with HER2-negative metastatic breast cancer (mBC) treated with first-line chemotherapy: Data from the German PRAEGNANT registry.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1048 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1048-1048

Author(s):

Peter A. Fasching ◽

Chunling Hu ◽

Steven Hart ◽

Andreas D. Hartkopf ◽

Florin A Taran ◽

...

Keyword(s):

Regression Models ◽

Cox Regression ◽

Brca Mutation ◽

Statistical Significance ◽

Brca2 Mutation ◽

Metastatic Breast ◽

Progression Free Survival ◽

Parp Inhibitors ◽

First Line ◽

Metastatic Setting

1048 Background: Germline BRCA1/2 ( gBRCA) mutations (mt) are some of the few actionable alterations in mBC patients. The PARP inhibitors olaparib/talazoparib are more effective than chemotherapy (ctx) in patients with a gBRCAmt and HER2 negative(-) mBC. In mBC patients the TNT-study suggested a better progression-free survival (PFS) for g BRCA-mt compared to patients with a gBRCA1/2 wildtype (wt) when treated with platinum and not with a taxane. Otherwise little is known about the prognostic effect of g BRCA1/2mt in mBC patients. Methods: PRAEGNANT (NCT02338167) is a prospective mBC registry with a focus on molecular biomarkers. Patients were eligible for this analysis if their mBC was HER2- and treated with ctx for the first time (referred to as first-line ctx). Hormone receptor (HR) positive patients had to have all hormone therapies exhausted. Mutation frequencies and their association with patient and tumor characteristics were analyzed. Multivariable Cox regression models were built with commonly established prognostic factors and g BRCA mutation status as predictors of PFS and overall survival (OS) from first-line ctx. Results: Out of 2932 PRAEGNANT patients, 576 were HER2- and received first-line ctx. Of those 529 patients with g BRCA genotype results and follow up information could be analyzed. 24 patients (4.5%) had a g BRCAmt (11 BRCA1, 13 BRCA2). Mutation rate in HR positive patients was 3.9% (17/432) and 7.2% (7/97) in HR negative patients. Most patients received ctx either as the first treatment in the metastatic setting or after one line of hormone therapy (n=382; 72.2%). Multivariable Cox regression models showed an adjusted hazard ratio for gBRCAmt vs. gBRCAwt patients of 0.70 (95% CI: 0.43-1.15) for PFS and of 0.41 (95% CI: 0.18-0.93) for OS. Most frequent ctx treatments were taxane (52%) or capecitabine based (21%). Additionally, the prevalence of somatic BRCA1/2 mutations in this population will be presented. Conclusions: In this HER2- mBC population under ctx g BRCA mutation rates were within the expected range of about 5%. Within the analyzed population patients with a g BRCA mutation seemed to have a better OS than patients without a mutation. PFS results pointed in the same direction without statistical significance. However, with only 24 mutations replication of these results in additional cohorts is warranted. Clinical trial information: NCT02338167.

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Patterns of metastasis and second primary malignancies (SPM) in colorectal cancer: A perspective from Peru.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15068 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15068-e15068

Author(s):

Jorge Leon ◽

Fernando Namuche ◽

Paola Catherine Montenegro ◽

Claudio J. Flores

Keyword(s):

Colorectal Cancer ◽

Metastatic Disease ◽

Biological Therapy ◽

Cox Regression ◽

Univariate Analysis ◽

Rank Test ◽

Second Primary ◽

Primary Tumor Site ◽

Metastatic Setting ◽

Second Primary Malignancies

e15068 Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. Approximately 20% of patients with CRC already have metastases at diagnosis, and this figure has been stable over the last two decades. The lack of data makes it more difficult to manage our patients. The metastatic setting and patients with second primary malignancies are complicated scenarios. The objective of our study was to explore and describe the metastasis patterns and the second primary malignancies’ frequency in CRC patients. Methods: We retrospectively reviewed the electronic medical records of 609 patients with CRC from one specialized Peruvian cancer center between 2006 and 2016. For the evaluation of the metastasis pattern, we selected 198 patients with metastasis at debut and the patients who had relapse of the disease. Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. We evaluated the metastasis pattern according to primary tumour sidedness, age, CEA, histological grade, histological type. A survival analysis was performed with Kaplan Meier method, comparing the curves with Log Rank test for metastasectomy, biological therapy and number of sites with metastatic disease. A multivariate analysis was performed using the Cox regression model with the statistically significant variables found in the univariate analysis. Results: At the time of diagnosis, stage IV disease accounted for 15.3% (93) of all CRC cases. 105 (stage I-III) pts had relapse disease. Regardless of the primary tumor site, the most common site for metastatic spread was the liver (42.9%), lung (12.6%), carcinomatosis (18.2%). Pts who underwent metastasectomy presented a better OS [HR, 0.284; 95% CI, 0.123-0.657; p < 0.05], as well as pts who received biologic therapy [HR, 0.641; 95% CI, 0.416-0.990; p < 0.05] and a greater number of sites with metastatic disease had worst OS [HR, 1.878; 95% CI, 1.181-2.985; p < 0.05] The incidence of SPM following CRC was 48/609 (7.8%), the more frequent localizations were: breast, prostate and lung with 14.6% each, then kidney 10.4%, bladder 8.3%. Conclusions: In mCRC metastasectomy, biological therapy and number of sites with metastatic disease play an important role in OS. The more frequent localizations with SPM were breast, prostate and lung.

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Clinical outcome of pancreatic cancer patients with indeterminate pulmonary nodules.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.220 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 220-220

Author(s):

Austin G Kazarian ◽

Sarah L Mott ◽

Carlos Hou Fai Chan

Keyword(s):

Pancreatic Cancer ◽

Clinical Outcome ◽

Cancer Patients ◽

Tumor Size ◽

Cox Regression ◽

Pulmonary Nodules ◽

Metastatic Recurrence ◽

Kaplan Meier ◽

Metastatic Setting ◽

Isolated Lung

220 Background: Indeterminate pulmonary nodules (IPNs) are often found on staging CT scans for pancreatic cancer and pose a treatment conundrum since resection is contraindicated in metastatic setting. Here we aim to determine the clinical outcome of pancreatic cancer patients with IPNs undergoing curative resection. Methods: Retrospective analysis of 1,182 pancreatic cancer patients in the institutional Oncology Registry between 2007 and 2017 was conducted. Survival probabilities were estimated using the Kaplan-Meier method. Time was calculated from diagnosis to death for overall survival (OS), and from operation to recurrence for recurrence-free survival (RFS). Cox regression models were used to assess the effects of demographic, clinicopathologic, and treatment variables on OS and RFS. Results: IPNs were found in 50 patients undergoing surgery (43 pancreatoduodenectomy, 7 distal pancreatectomy). Negative margins were obtained in 82% of patients. Six and 44 patients had stage 0/I and stage II disease, respectively. Twelve and 35 patients received neoadjuvant and adjuvant therapy, respectively. Over a median follow-up of 20 months from the time of diagnosis, 37 patients (74%) developed local recurrence or distant metastasis in liver (38%), lung (32%), peritoneum (8%), or other sites (8%). Median RFS was 14 months and median OS was 23 months. Tumor size (HR 1.56, CI 1.23-1.98, p < 0.01) and elevated pre-operative CA19-9 (HR 2.51, 1.22 – 5.15, p = 0.01) were associated with lower RFS. Tumor size (HR 1.43, CI 1.10-1.86, p < 0.01) and diabetes (HR 2.05, CI 1.02-4.11, p = 0.04) were associated with lower OS. Patients with lung only recurrence tended to have superior OS relative to other single sites (HR 2.05, CI 0.66-6.33, p = 0.21) or multiple sites (HR 2.30, 0.75-7.50, p = 0.15). Patients with lung only recurrence had a median survival after recurrence of 17.9 months compared to 6.5 months for other single sites or 4.3 months for multiple sites. Conclusions: Only a portion of IPNs develop into true lung metastasis and that isolated lung metastatic recurrence may confer a better survival over metastasis of other sites. Ongoing efforts will identify serum biomarkers to predict recurrence in the hopes of guiding future clinical practice.

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Pre-Clinical Development of a Subunit Vaccine Expressing an IE1-IE2 Fusion Protein of HCMV.

Blood ◽

10.1182/blood.v110.11.165.165 ◽

2007 ◽

Vol 110 (11) ◽

pp. 165-165

Author(s):

Zhongde Wang ◽

Wendy Zhou ◽

Tumul Srivastava ◽

Corinna La Rosa ◽

Stephen J. Forman ◽

...

Keyword(s):

T Cell ◽

Fusion Protein ◽

Dna Vaccine ◽

Rhesus Macaques ◽

Cd8 T Cell ◽

Clinical Development ◽

T Cell Subsets ◽

Sufficient Evidence ◽

Cell Transplant ◽

Hiv Patients

Abstract CMV infection is an important complication of patient recovery from transplantation, and affects a wide variety of individuals including newborns and HIV patients with advanced disease. An effective CMV vaccine for patients who have already acquired an infection has yet to successfully incorporate an antigenic repertoire capable of eliciting a cellular immune response. To address this problem, we have developed a vaccine candidate derived from modified vaccinia Ankara (MVA) that expresses three immunodominant antigens (pp65, IE1, IE2) from CMV, we have termed CMV-MVA. While other antigens are also immunologically recognized to varying degrees, the evidence for these three antigens to be involved in protective immune responses in a majority of CMV-infected patients is compelling and justifies their inclusion into a vaccine to prevent viremia and control infection. MVA has an extensive history of successful delivery into rodents, Rhesus macaques, and other non-human primates, and more recently as a clinical vaccine in cancer patients and HIV patients in a state of immunosuppression. CMV-MVA is engineered with a bacterial marker to track its purification, which can be removed by recombination, a requirement for clinical development. The novelty of this vaccine is the fusion of the two largest and adjacent protein-coding exons from the immediate-early (IE) region of CMV, their successful expression as a fusion protein in MVA, and robust immunogenicity in both primary and memory response models. The advantages of this approach include placement of all vaccine antigens in one vector, and diminishing the dose of virus needed to attain sufficient immunity simultaneously against all of the included antigens. Evaluation of the immunogenicity of the viral vaccine in transgenic HLA mouse models (A2, B7, A11) shows that it can stimulate primary immunity against all three antigens in both the CD4+ and CD8+ T cell subsets. Evaluation using human PBMC from CMV-positive donors shows robust stimulation of existing CMV-specific T cells in both the CD4+ and CD8+ T cell subset. These results extend to both healthy volunteers and patients within 6 months of receiving hematopoietic cell transplant (HCT). Evaluating PBMC from transplant recipients in all three risk categories (D+/R+,D+/R−, D−R+), we found an equivalently strong recognition of both antigens, in some cases more vigorous than in the PBMC of healthy adults. This candidate vaccine is being developed in partnership with the NCI as a therapeutic for HCT recipients. Strategies of vaccine delivery include vaccinating the transplant donor, and/or the recipient at day 90 or later, if warranted clinically and with sufficient evidence of safety. The ongoing evaluation of a DNA vaccine against CMV suggests a worthwhile strategy of combining MVA with a plasmid DNA vaccine. Our preliminary studies using DNA prime and MVA boost in Rhesus macaques show it to be a more powerful CMV vaccine regimen than either component given separately. Evidence for the capacity of CMV-MVA to modify viremia through immunologic mechanisms from both clinical and monkey studies will be presented.

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