John L. Marshall, MD

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Novel Vaccines for the Treatment of Gastrointestinal Cancers

November 1st 2005

Continuing advances in immunology and molecular biology duringthe past several decades have provided optimism that immunomodulatorystrategies may be clinically useful in patients with cancer.Key advances have included: (1) recognition of the critical role of theantigen-presenting cell and greatly improved understanding of antigenprocessing and presentation, including the molecular interactionsbetween HLA molecules and antigenic epitopes on the antigen-processingcell and the receptors on T cells, and (2) the roles ofcostimulatory molecules such as B7.1, ICAM-1, and LFA-3 in the inductionand maintenance of an immune response. In addition, newtechniques have allowed us to identify immunogenic antigenic determinants,alter their binding affinities, and evaluate the overall successof the intervention through both in vivo and in vitro assays.Carcinoembryonic antigen (CEA) is overexpressed in a large numberof gastrointestinal, lung, and breast cancers. Clinical trials have establishedtreatment protocols using viral vectors to immunize patients toCEA without producing deleterious autoimmune phenomena. By combiningvarious vectors to include MUC-1 and/or CEA plus costimulatorymolecules in a prime-and-boost regimen, we are beginning to see signsthat this intervention can not only produce changes in immune functionbut also potentially improve clinical outcomes. Phase III studies totest these hypotheses are under way.

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Improving the Toxicity of Irinotecan/5-FU/ Leucovorin: A 21-Day Schedule

September 1st 2003

Irinotecan (CPT-11, Camptosar) is one of the new generation ofchemotherapeutic agents that has activity in advanced colorectal cancer.It has antitumor efficacy as a single agent, and also has beencombined with fluorouracil (5-FU) and leucovorin (IFL) to treat thesepatients. Randomized studies have confirmed the superiority of IFL to5-FU and leucovorin alone with regard to patient survival, time toprogression, and tumor response rate. The optimal schedule for combiningthese agents remains uncertain, but in the United States, theschedule of IFL weekly for 4 consecutive weeks repeated every 6 weeks,according to the schedule reported by Saltz et al, has been widely used,although with some toxicity (especially myelosuppression and diarrhea).In an attempt to improve the tolerability of IFL, some haveadvocated modifying the schedule of IFL to weekly for 2 weeks, withrepeated cycles every 21 days. Twenty-three patients with advancedcolorectal cancer have been treated on this schedule at a single institution.Therapy was well tolerated, with 35% of patients experiencinggrade 3/4 neutropenia, two of whom had episodes of febrile neutropenia,and 9% with grade 3/4 diarrhea. The median relative dose intensityof irinotecan administered in the first 18 patients treated with thisregimen was 94%. These data support the hypothesis that modifying theschedule of administration of IFL improves the tolerability and abilityto deliver the regimen, but must be confirmed by randomized prospectivestudies, which may also attempt to evaluate the role of bolus 5-FUin the treatment of advanced colorectal cancer.