Ehrlich II –2nd World Conference on Magic Bullets



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Biopharmaceuticals in plants; toward the next century of medicine.'
HEFFERON KL
Cornell Research Foundation, Cornell University, Ithaca, NY, 14850
Plants present a novel means by which large quantities of vaccine and therapeutic proteins can be produced in a safe and cost-effective manner. Biopharmaceuticals produced in plants are easy to store, require fewer timely and expensive purification steps, and lack the containment risks associated with proteins produced in animal or bacterial expression systems. Over the past decade, much progress has been made with respect to the development of vaccines, antibodies and other therapeutic proteins. This presentation outlines the steps involved in the generation of transgenic plants, the engineering of plant virus expression vectors for transient expression of vaccine proteins and other therapeutics in plant tissue, and the advantages of this technology over the use of conventional transgenic plants. An investigation into the basis of mucosal immunity using plant-based oral vaccines is addressed. The scale-up of plant-derived vaccine proteins in entire crops or in large batch cell suspension cultures is covered, as is the development of clinical trials utilizing plant-derived biopharmaceutical proteins. Risks involved and biosafety concerns regarding plant-derived biopharmaceuticals are investigated. The presentation will conclude with a discussion of the future of plant-based vaccines and other therapeutic proteins in human and veterinary medicine with respect to commercial viability and as a tool to improve global public health.


EGFRvIII-targeted vaccine (CDX-110) induces immune responses and prolongs survival when given with temozolomide in GBM patients
HEIMBERGER AB3, ARCHER GE1,2, BIGNER DD2, DAVIS T4, FRIEDMAN HS1,2, KELER T4, MITCHELL DA1, REARDON D1, SAWAYA R3, SAMPSON JH1,2
1Departments of Neurosurgery, 2Pathology, Duke University Medical Center, Durham, North Carolina; 3Department of Neurosurgery, University of Texas, M. D. Anderson Cancer Center, Houston, Texas; 4Celldex Therapeutics, Philipsburg, New Jersey
Background: Conventional therapies for GBM fail to target tumor cells exclusively. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent and immunogenic mutation that is not expressed in any normal tissues, but is widely expressed in GBMs and other neoplasms making it an attractive target for active immunotherapy.

Methods: A phase II multi-center clinical trial was undertaken to assess the immunogenicity and efficacy of an EGFRvIII-specific peptide vaccine in patients with newly-diagnosed, EGFRvIII+ GBM in combination with simultaneous standard or continuous temozolomide (TMZ). After gross-total resection and radiation/TMZ (75mg/m2/d), consecutive cohorts received monthly cycles of 200 mg/m2 (N=13) or continuous 100 mg/m2 (N=8) TMZ simultaneous with intradermal vaccinations with an EGFRvIII-specific peptide (PEPvIII) conjugated to keyhole limpet hemocyanin (KLH) until tumor progression or death.

Results: 21 patients were enrolled. There were no significant differences in vaccine immunogenicity (P>0.999; binomial proportions), PFS (P=0.7979; logrank), or OS (P=0.7728; logrank) between TMZ regimens. Although TMZ induced Grade II lymphopenia in 53.8% of patients, the co-administration of TMZ with the EGFRvIII vaccine (CDX-110) results in strong sustained immune responses to EGFRvIII in 100% (CI95: 0.72, 1.00) of evaluated patients. Median PFS was 16.6 months (CI95: 9.1, 22.7) and median survival was 33.1 months (CI95: 18.2, infinity). The survival of the vaccinated patients exceeded a matched historical control group (14.3 months; CI95: 13.0, 16.2)(P<0.0001) and a subgroup treated with TMZ (15.2; CI95: 13.9, 20.5)(P=0.0078) and is equivalent to the results seen in patients vaccinated without simultaneous temozolomide (P=0.4108).

Conclusion: CDX-110 peptide vaccination with standard of care temozolomide in patients with GBM appears very promising and is under investigation in a phase III, randomized clinical trial.


Matching the Individual Patient to the Results of Large Clinical Trials and Testing the Null Hypothesis Using Fuzzy Theory
HELGASON CM1, JOBE TH2
1,2Univ. Illinois College of Medicine @Chicago, Chicago, IL., USA
Background: Translation of results of large clinical trials to the individual patient who always is to some degree and in many ways unlike any patient in that trial is imprecise.

Methods: We hypothesized that 1) fuzzy measures of subsethood and entropy precisely match any individual patient to the average patient of any large clinical trial, and 2) that fuzzy subsethood and entropy can be used in the experimental setting to precisely measure the difference between patient states at different points in time and between groups of patients. Fuzzy entropy is the measure of the sameness or non difference between elements and is valued in the unit interval of zero to one. Elements of a fuzzy set are each valued in the unit interval. One patient can be represented by a fuzzy set of elements of biophysiological or other clinical interest. The unit interval value of any element is determined by laboratory or clinical scale measurement followed by normalization or by expert or consensus assignment. In the geometric space of fuzzy theory, the unit hypercube, one fuzzy set as point can represent a patient.

Results: Fuzzy subsethood measures the degree to which fuzzy set A belongs to fuzzy set B. The degree to which fuzzy set A belongs to B and B to A is a measure of the similarity between fuzzy sets A and B. The measure of difference between conditions, unknown or unmeasured variables, of two fuzzy sets A and B is measured by K, derived from fuzzy subsethood, and when accounted for gives a true comparison of fuzzy sets A and B. Following one patient from fuzzy state A to B that patient has changed from one point in time to another. The subsethood measure compares these states. In the experimental setting, this measure is applied to each patient of control and experimental groups. When testing the null hypothesis, the fuzzy entropy measure is the measure of “no difference” between control and experimental patient (s). A fuzzy entropy measure of 1 confirms the null hypothesis. A measure of match between a patient at the bedside and the average patient of any clinical trial is the measure of similarity of those patients accounting for the difference in their context. This measure falls within the unit interval and can be multiplied by the risk reduction, or other statistic of the trial to reach a predictive value for that unique patient.

Conclusion: Fuzzy measures allow statistical results of large clinical trials to be exactly matched to the unique individual patient at the bedside.

Aciclovir- a Nearly Atoxic Antiviral Drug with Severe Neurotoxic Side Effects- a Retrospective Review of 280 Cases and the Importance of Analysing the Aciclovir Metabolite CMMG.



HELLDÉN A
Laboratory Medicine, Stockholm, Sweden
Background: Acyclovir (ACV) and its prodrug valaciclovir (VACV) is an effective agent against herpes simplex (HSV) and varicella zoster virus (VZV) infections. It is regarded as a nearly non-toxic drug. However, acyclovir-induced neurotoxicity (AIN) has been reported, predominantly in patients with renal impairment. AIN may be difficult to distinguish from the CNS-infection itself. We have earlier shown that the metabolite of aciclovir, 9-carboxymethoxymethylguanine (CMMG), is inconsistently increased and above 10 µmol/L in serum (S) in AIN. This study elucidated if AIN and HSV encephalitis symptoms could be separated from each other and if measurement of CMMG could be a marker of AIN.

Methods: Published case reports on suspected AIN, cases reported to the Swedish adverse drug reactions database “SWEDIS”, and cases investigated at the Karolinska University Hospital were reviewed. Type and frequency of ACV side-effects, renal function at the start of (V)ACV treatment, and serum concentrations of ACV and CMMG were studied. Three published reports on herpes encephalitis and the type and frequency of the initial symptoms were also included.

Results: 280 patients with AIN were found. Sixty-five percent were treated due to VZV, 18% due to HSV and 17% due to other causes. Chronic renal failure was present in 168 (60%) and acute renal failure or increasing S-creatinine in fifty-six patients (20%). The most frequent CNS-symptoms were confusion/disorientation, hallucinations and fatigue. ACV (N=124) and CMMG (N=77) concentrations were (mean ± SD) 44.4 ± 55.0 µmol/L and 38.3 ± 38.6 µmol/L, respectively. Sixty-two of the 77 AIN patients (81%) with S-CMMG had a concentration above 10 µmol/L. Patients with HSV encephalitis (N=197) presented with altered consiousness, fever, personality changes, confusion/disorientation and seizures.

Conclusions:

  1. AIN is not uncommon and probably underdiagnosed, especially as the initial symptoms in patients with AIN or HSV (or other encephalitis) are similar and make it difficult to distinguish between the two states.

  2. The majority of patients with AIN had acute or chronic renal failure.

  3. Measurement of CMMG might be the first effective tool to distinguish between CNS symptoms from herpes encephalitis or AIN. The method is already in use in several Swedish hospitals with promising results.




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