Combination of dendritic cell (DC) vaccination with CTLA4 blockade in patients (pts) with metastatic melanoma: a phase 1 clinical trial
Abstract Number: 2537
Monday, Apr 14, 2008, 1:10 PM - 1:25 PM
Antoni Ribas, Begonya Comin-Anduix, Jason Jalil, Pilar De la Rocha, Elisabeth Seja, Arturo Villanueva, Bradley R. Straatsma, Alistair J. Cochran, James S. Economou, John A. Glaspy, Jesus Gomez-Navarro. UCLA Medical Ctr., Los Angeles, CA, Pfizer Global Research and Development, New London, CT
Background.
Tumor antigen-loaded DC vaccines activate antitumor immunity by stimulating T cells, and cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-blocking monoclonal antibodies (mAbs) release a key negative regulatory pathway on T cells. We tested the hypothesis that CTLA4 blockade with the fully human anti-CTLA4 mAb tremelimumab (formerly CP-675,206) may enhance T cell responses stimulated by tumor antigen peptide-pulsed DC, leading to antitumor activity in pts with melanoma.
Methods.
Autologous DCs were differentiated from adherent monocytes in granulocyte-macrophage colony-stimulating factor and interleukin-4 for 8 days, then pulsed with the MART-1(26-35) melanoma peptide (MART-1/DC). HLA-A*0201+ pts with MART-1+ melanoma, stage IIIc or IV, received a fixed dose of 10 million MART-1/DC together with a dose escalation of tremelimumab at 3, 6, or 10 mg/kg monthly (qm) and 10 or 15 mg/kg quarterly (q3m). Primary endpoints were safety and immune effects; secondary endpoint was clinical efficacy per RECIST criteria.
Results.
16 pts were accrued to 5 dose levels. Dose-limiting toxicities (DLTs) of G3 diarrhea and G2 hypophysitis developed in 2 out of 3 pts receiving tremelimumab at 10 mg/kg qm together with 10 million MART-1/DC. Two cohorts then enrolled pts at decreased exposure to tremelimumab (10 and 15 mg/kg q3m), with no further DLT. Using the major histocompatibility complex (MHC) tetramer assay, in 6 pts (including 2 responders) MART-1-specific T cells expanded in peripheral blood beyond the assay variability when assessed with the reference change value at the 99% significance level. 1 pt at 3 mg/kg qm has a partial response (PR) in bulky lung metastasis and is disease-free at 42+ mo. 1 pt at 10 mg/kg qm has an ongoing PR in lung metastasis at 25+ mo. 2 pts at 15 mg/kg q3m have ongoing responses at 9+ mo, 1 CR in in-transit metastasis and 1 PR in nodal metastasis.
Conclusions.
The combination of MART-1 peptide-pulsed DC and tremelimumab at 15 mg/kg q3m warrants further study based on the results of a phase I clinical trial with 4 long-lasting objective responses among 16 pts (25% objective response rate) with advanced, surgically-incurable malignant melanoma. Immune monitoring in peripheral blood had limited ability to discern clinical responders to this combination. |
