Solid Tumors - We have found the pretreating solid tumors on mice with chemotherapy greatly increases their response to immuntoxins. Using mesothelian expressing tumors as a model we have developed a new method to measure the amount of immunotoxin taken up by tumors in mice by labeling SS1P with alexa 488. We used this method to show the number of cells in a tumor that accumulate SS1P are greatly increased after effective chemotherapy. We will use this method to study other tumor types and immunotoxins. Pancreatic cancers are poorly responsive to chemotherapy and immunotoxins. Using several different cell lines we are analyzing the bases of the resistance. Hemotopoetic Tumors: We have produced a mutant form of immunotoxin HA22 that is pretease resistant by removing catlepsin sensitive sites in domain 11 of the toxin. Unexpectedly this new immunotoxin (HA22-LR) has very low toxicity in mice and has increased cytotoxic activity against cells from patients with CLL making in a candidate for a new generation of immunotoxins. We are developing a method of measuring the cytotoxic activity of immunotoxin HA22 on cells from patients with ALL to determine if we can predict which patients will respond to HA22 and to use these cells to study me of resistance to immunotoxins and cytotoxic drugs. We have continued to try and produce immunotoxins with decreased immunogenicity by identifying and removing B cell epitopes. We have initiated a new program to identify and remove T cell epitopes. We are also continuing our efforts to increase the affinity of immunotoxins against CD22 and mesothelin. <p>We have developed an immunotoxin SS1P that targets ovarian cancers, mesotheliomas and pancreatic cancers that is currently in clinical trials. We are carrying out laboratory experiments to produce improved forms of SS1P that are less immunogenic so that several treatment cycles can be given. We have also investigated how to improve the activity of SS1P against solid tumors and found that if chemotherapy is give before SS1P there is profound synergy. We are investigating the mechanism of this synergy.</p><p>We have studied mesothelin expression in lung cancer and demonstrated lung cancer cells are good targets for SS1P therapy.</P><p>We have produced less immunogenic immunotoxins by mutating amino acids on the surface of PE38 to alenine or glycine. We are determining the pathway that toxins use to induce apoptosis.</p>
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