Polarized DC as Melanoma Vaccine: Phase 1 Evaluation
Principal Investigator: Pawel Kalinski
Abstract: Th1-, CTL-, and NK cell-driven cell-mediated immunity is the most effective form of response against cancer. Based on the novel paradigm of polarization of dendritic cells (DCs), and on our recent observations that the presence of IFNalpha allows for the generation of type-1 polarized DCs (DC1s) in serum-free conditions, we have recently developed the first clinically-applicable protocol to generate DC1s. Such alphaDC1s are the first clinically-applicable type of DCs that combine all 3 properties important for their in vivo activity as inducers of anti-cancer immunity. These are: 1) fully mature status; 2) high migratory responsiveness to CCR7 ligation; and 3) high IL-12p70-producing function. alphaDC1s show selectively enhanced ability to induce type-1 anti-cancer responses, when compared to the current "gold standard" of clinically-used DCs. Peptide-pulsed alphaDC1s induce up to 40-fold higher numbers of CTLs against MART- 1, tyrosinase, and gp100, during in vitro sensitization of peripheral blood T cells from melanoma patients. They also induce strong antitumor activity of CD4+ Th1 cells and NK cells. We hypothesize that alphaDC1-based vaccines administered by intralymphatic route will be safe and will act as superior inducers of tumor-specific responses in alphaDC1- treated melanoma patients in a novel phase I clinical trial. We will pursue one Specific Aim: Specific Aim 1. Demonstrate the safety and immunologic effectiveness of alphaDC1-based vaccines in patients with stage III/IV melanoma. We will perform a randomized phase I clinical trial (UPCI 03-118; IND#: 11,754) involving 28 patients, comparing the safety and the immunologic (and potentially clinical) efficacy of intralymphatic vaccination with aDC1s versus standard (IL-1beta/TNFalpha/IL-6/PGE2-matured) DCs. The immunomonitoring performed as a part of this aim will allow us to analyze the vaccination induced immunologic changes of melanoma-specific responses in circulation and DTH biopsies. The positive outcome of this study will allow us to obtain a proof of principle for the in vivo immunologic effectiveness of vaccines utilizing the phenomenon of DC polarization, and will help us to design an extended follow-up study of the immunologic and clinical effectiveness of alphaDC1-based vaccines. Verification of the in vivo efficacy of alphaDC1s, will also lead to follow-up studies of the mechanism of high activity of these cells in the induction of type-1 anticancer immunity and the prospective identification of the key mediators involved.
Funding Period: 2005-05-01 - 2009-04-30
more information: NIH RePORT
- Immunotherapy of cancer in 2012John M Kirkwood
Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA
CA Cancer J Clin 62:309-35. 2012....
- Dendritic cells in cancer immunotherapy: vaccines or autologous transplants?Pawel Kalinski
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 1863, USA
Immunol Res 50:235-47. 2011....
- Helper activity of natural killer cells during the dendritic cell-mediated induction of melanoma-specific cytotoxic T cellsJeffrey L Wong
Department of Surgery, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 1863, USA
J Immunother 34:270-8. 2011..These results indicate that the helper function of NK cells can be used in clinical settings to improve the effectiveness of DC-based cancer vaccines...
- Type-1 polarized dendritic cells loaded with apoptotic prostate cancer cells are potent inducers of CD8(+) T cells against prostate cancer cells and defined prostate cancer-specific epitopesEva Wieckowski
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Prostate 71:125-33. 2011....
- Polarized dendritic cells as cancer vaccines: directing effector-type T cells to tumorsPawel Kalinski
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, United States
Semin Immunol 22:173-82. 2010..These developments allow for selective induction of tumor-specific T cells with desirable effector functions and tumor-relevant homing properties and to direct the desirable types of immune cells to tumors...
- Independent regulation of chemokine responsiveness and cytolytic function versus CD8+ T cell expansion by dendritic cellsPayal B Watchmaker
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
J Immunol 184:591-7. 2010....
- Generation of stable Th1/CTL-, Th2-, and Th17-inducing human dendritic cellsPawel Kalinski
Department of Surgery, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
Methods Mol Biol 595:117-33. 2010....
- Dendritic cells in immunotherapy of established cancer: Roles of signals 1, 2, 3 and 4Pawel Kalinski
University of Pittsburgh, Department of Surgery, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Suite 1 46, Pittsburgh, PA 15213, USA
Curr Opin Investig Drugs 10:526-35. 2009....
- Dendritic cell-based therapeutic cancer vaccines: what we have and what we needPawel Kalinski
Department of Surgery, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Res Pavilion, Suite 1 46, 5117 Center Avenue, PA 15213 1863, USA
Future Oncol 5:379-90. 2009..Furthermore, recent studies also identify the tools to counteract such phenomena, in order to assure the desirable induction of Th1-cytotoxic T lymphocytes, NK-mediated type-1 immunity and appropriate homing of effector cells to tumors...
- Ability of mature dendritic cells to interact with regulatory T cells is imprinted during maturationRavikumar Muthuswamy
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
Cancer Res 68:5972-8. 2008....
- Type 1-polarized dendritic cells loaded with autologous tumor are a potent immunogen against chronic lymphocytic leukemiaJe Jung Lee
Department of Surgery and Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, 1 46 Hillman Cancer Ctr, 5117 Centre Ave, Pittsburgh, PA 15213, USA
J Leukoc Biol 84:319-25. 2008..4-38 times) of functional CD8+ T cells against CLL cells. The current demonstration that autologous tumor-loaded alphaDC1 are potent inducers of CLL-specific T cells helps to develop improved immunotherapies of CLL...