BiotechTracker - MDX-010 Enhances Both Positive and Negative Immune Responses
June 26, 2003 Mixed results from Medarex’s (NASDAQ: MEDX) MDX-010 (MDX-CTLA4) developmental program were published online in the Proceedings of the National Academy of Sciences. The preliminary, phase II data suggest that although major hurdles remain for this drug, its development will accelerate understanding of the role of CTLA-4 in modulating the immune response to tumors. Such understanding will benefit MDX-010 and related drugs.  This small translational and clinical trial is important for several reasons, (1) it demonstrates a role for CTLA-4 blockade in cancer immunotherapy, (2) it establishes a clinically important role for CTLA-4 in the maintenance of tolerance against self antigens in humans, (3) it begs for continued study of MDX-010 alone and in combination with tumor vaccines. Such study is likely to elucidate the relationship between autoimmune effects against normal tissues and against tumors, which will lead to better understanding of clinically relevant means to dissociate normal from anti-tumor immune response.  In advance of this work, anti-CTLA-4 animal model data and preliminary human data suggested that MDX-010 improves cancer immunotherapy efficacy. In the current study, 14 patients with metastatic melanoma were treated with serial intravenous MDX-010 and a subcutaneous tumor vaccine. The vaccine consisted of two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). All of the study subjects had undergone surgical intervention for their primary lesion, and received MDX-010 3.0 mg/kg once every three weeks in this regimen.  The resultant CTLA-4 blockade by MDX-010 induced grade III/IV autoimmune manifestations in six patients (43%). Dermatitis, enterocolitis, hepatitis, and hypophysitis were observed. Objective cancer regression was observed for three patients (21%). 2 complete responses and 1 partial response were seen. Half of the individuals experiencing autoimmune adversities also experienced an anti-tumor response. Conversely, no patient experienced an anti-tumor response without experiencing autoimmune adversity. Thus, modification of the anti-tumor immune response appears intimately associated with modification of normal immune function, at least without further refinement of the protocol.  One responder experienced complete resolution of a 0.5 cm brain lesion, two subcutaneous nodules, and 31 lung metastases. The second complete response was of an abdominal subcutaneous nodule and a solitary lung lesion. The partial response saw tumor shrinkage of a solitary lung lesion, lasting over 10 months after two treatment cycles.  MDX-010 is in multiple phase II trials in melanoma and prostate cancer, and it is also being tested in a phase I anti-HIV protocol. An ongoing phase II trial in melanoma is expected to enroll up to 55 patients.
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