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Biotech / Medical : MEDX ... anybody following? -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (676)	6/5/2003 6:12:21 AM
From: Icebrg	Read Replies (1) \| Respond to of 2240

Phase I trial of antibody to CTLA-4 (MDX-010) with melanoma peptides/Ifa for resected stages III/IV melanoma Year: 2003 Printable Version Abstract No: 2853 Author(s): J. S. Weber, J. Snively, S. Sian, R. Lau, P. Lee, R. Scotland, T. Davis; Univ of Southern California, Los Angeles, CA; Stanford University School of Medicine, Palo Alto, CA; Medarex Inc., Annandale, NJ Abstract: MDX-010 is a human antibody that blocks CTLA-4 on activated T cells, increasing antigen-specific T-cell activity. CTLA-4 blockade with MDX-010 induced clinical regressions in patients with stage IV melanoma and prostate carcinoma after a single dose. Nineteen patients with resected stages III/IV melanoma received escalating doses of anti-CTLA-4 intravenously with each injection of a gp100/tyrosinase/MART-1 peptide vaccine with incomplete Freund's adjuvant (IFA). Cohorts received antibody at 0.3, 1 and 3 mg/kg. Tyrosinase 368-376 (370D), MART-1 26-35 (27L) and gp100 209-217 (210M) peptides were modified to increase HLA binding, and were administered eight times over twelve months at 1 mg/dose/peptide. Median age was 50, with 10 men and 9 women. 17 patients had stage IV, and 2 had stage III resected disease. Toxicity and immune response (IR) to the vaccine were the principal endpoints, IR was measured by DTH skin testing with peptides, ELISPOT and peptide-tetramer assays. Time to relapse and overall survival were also assessed. Rapidly reversible dose limiting toxicity was seen at the highest antibody dose of 3 mg/kg. Three patients experienced self-limited grade III diarrhea or abdominal pain associated with CT evidence of rapidly reversible acute ileitis. Two patients had significant rash. Anti-CTLA-4 had a prolonged half-life and saturating levels (>1mcg/ml) were sustained for at least a month after each dose in all patients. Leukocyte subset data showed that total WBC counts increased modestly from 6250/mm3 to 7785/mm3 after one month of treatment in the highest cohorts. There were no consistent effects on activated CD8, CD4 or NK cells, and no difference in CD4/8 ratios with treatment. DTH testing indicated that 4/9 patients responded to gp100, and 2/9 to MART-1. ELISPOT assays showed immune responses in 4/16 patients using fresh CD8 T cells. All patients are alive, but 5/19 have relapsed, three alive with disease, and two in remission after further surgery. Correlations of IR, toxicity and outcome with dose are ongoing. MDX-010 is immunologically active and alters tolerance. Further characterization of its clinical potential is ongoing.

To: Icebrg who wrote (676)	6/7/2003 5:13:25 PM
From: Icebrg	Read Replies (1) \| Respond to of 2240

From my earlier post: >>Results: Three patients had objective cancer regression, including one with a complete response with resolution of two subcutaneous masses, 31 lung nodules and one brain metastasis.>> We have now got some scans to show. Interesting stuff, really. This is metastatic melanoma. It is a very serious condition and normally only possible to treat with IL-2. Few respond and no one will like the treatment. IL-2 is pretty bad. Results seen with the patient who had a complete response. Lugn metastasis before and after. images.visualwebcaster.com Brain metastasis before and after. images.visualwebcaster.com Quite impressive even if only seen in one patient out of 14. But I don't think IL-2 does much better. This result was discussed at the Y! Medarex board, which from time to time (but not always) can be quite useful. How is it possible that MDX-010, which is a mAb can influence a metastasis inside the brain? One would expect that the BBB would stop all efforts to influence the disease mAb-wise. Surfson8 provides what appears to be the correct answer: High affinity T cells by: surfson8 06/07/03 03:37 pm Msg: 75166 of 75169 One of the most interesting points made by Allison during the webcast was that CTLA-4 particularly targets the high affinity T cells and that 010 therefore elevates high affinity T cells. These cytotoxic T lymphocytes (CTL) should be qualitatively superior to those produced ordinarily. Another exciting point was that CTL can be generated by 010 even when CD4 T cells are missing. This is part of the rationale for testing 010 in HIV patients. As to the brain activity, 010 enhances T cell activation during a process called antigen presentation whereby specific T cells are produced. This process is thought to occur primarily in lymph nodes draining a tissue and not in the tissue itself. Once the antigen specific T cells are generated, they can migrate into the brain. The antibody therefore only has to have access to the lymph nodes. Since large quantities of blood perfuse lymph nodes, and their vessels are leaky, access is not a problem. This is of course extremely positive. Being able to influence brain metastases without having to introduce the mAb inside the BBB. And it works (according to my "calculations") not only for the problems of getting access to the CNS. mAbs also have a hard time getting access inside solid tumors. Problems with access, high internal pressure etc. But we have the same situation for these tumors. It is not necessary at all for MDX-010 to gain access inside the tumor. The T-cells will take care of that. And they will even be extra potent. The other side of the coin is however that this type of treatment will generate negative side-effects. In most patients auto-immune responses were seen. But they seem to be possible to manage. All in all, a very interesting development. I don't think MDX-010 got the recognition in media, that it deserved. But it is possible to stay ahead. Listen to the webcast available from Medarex's side and from which presentation the above slides were pulled. Erik