Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally and there are essentially no effective systemic therapies for this disease. In the previous grant period, we made several novel observations about the immunobiology of this malignancy. Both the murine and human T cell repertoires can recognize alpha fetoprotein (AFP), an oncofetal protein produced by a majority of HCC. In a murine tumor model of genetic immunotherapy, AFP can serve as a tumor rejection antigen. We have performed extensive epitope mapping of hAFP and have identified 4 immunodominant and as many as 10 subdominant peptide epitopes in the context of HLA-A2.1. Finally, we have initiated an AFP peptide trial in patients with HCC and are able to detect T cell responses to these immunodominant peptide epitopes. In this competitive renewal, we request support to continue this translational research program with three specific aims:
Aim 1. AFP Peptide Clinical Trial. In this phase I/II trial, AFP/A2.1-positive HCC patients are immunized with four immunodominant AFP peptides [hAFP137-145, hAFP158-166, hAFP325-334 and hAFP542-550] emulsified in incomplete Freund's adjuvant. Peripheral T cell responses will be measured by ELISPOT and tetramer assays. This study will allow us to determine if AFP-derived peptides are immunogenic in vivo.
Aim 2. AFP-Engineered Dendritic Cell Trial. In this phase I/II trial, patients will be immunized with autologous dendritic cells (DC) transduced with a recombinant adenovirus vector expressing human AFP. T cell responses to immunodominant and subdominant epitopes will be measured. In this clinical trial, we will determine whether tumor antigen-engineered DC can generate polyclonal responses in vivo.
Aim 3. Construction and Preclinical Testing of AFP DNA Vaccines. Plasmid-based DNA vaccines are capable of generating strong T cell responses and protective immunity. We propose to modify our first generation AFP DNA vaccine to improve these responses and test them in both protection and hepatocarcinogenesis models. In summary, we propose a largely clinically-directed research program that translates this original work into novel, evidence-based immunotherapy trials for hepatocellular carcinoma.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077623-06
Application #
6633311
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wu, Roy S
Project Start
1998-04-01
Project End
2005-03-31
Budget Start
2003-07-28
Budget End
2004-03-31
Support Year
6
Fiscal Year
2003
Total Cost
$308,729
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Butterfield, Lisa H; Ribas, Antoni; Potter, Douglas M et al. (2007) Spontaneous and vaccine induced AFP-specific T cell phenotypes in subjects with AFP-positive hepatocellular cancer. Cancer Immunol Immunother 56:1931-43
Schumacher, Lana Y; Vo, Dan D; Garban, Hermes J et al. (2006) Immunosensitization of tumor cells to dendritic cell-activated immune responses with the proteasome inhibitor bortezomib (PS-341, Velcade). J Immunol 176:4757-65
Butterfield, Lisa H; Ribas, Antoni; Dissette, Vivian B et al. (2006) A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res 12:2817-25
Ribas, Antoni; Vo, Dan D; Weeks, David L et al. (2006) Broad antitumor protection by dendritic cells administered to CD8alpha knock out mice. Cancer Immunol Immunother 55:663-71
Wargo, Jennifer A; Schumacher, Lana Y; Comin-Anduix, Begonya et al. (2005) Natural killer cells play a critical role in the immune response following immunization with melanoma-antigen-engineered dendritic cells. Cancer Gene Ther 12:516-27
Ribas, Antoni; Wargo, Jennifer A; Comin-Anduix, Begonya et al. (2004) Enhanced tumor responses to dendritic cells in the absence of CD8-positive cells. J Immunol 172:4762-9
Mehrotra, Shikhar; Chhabra, Arvind; Chakraborty, Abolokita et al. (2004) Antigen presentation by MART-1 adenovirus-transduced interleukin-10-polarized human monocyte-derived dendritic cells. Immunology 113:472-81
Ribas, Antoni; Glaspy, John A; Lee, Yohan et al. (2004) Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy. J Immunother 27:354-67
Schumacher, Lana; Ribas, Antoni; Dissette, Vivian B et al. (2004) Human dendritic cell maturation by adenovirus transduction enhances tumor antigen-specific T-cell responses. J Immunother 27:191-200
Butterfield, Lisa H; Ribas, Antoni; Dissette, Vivian B et al. (2003) Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. Clin Cancer Res 9:998-1008

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