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Dendritic Cell Therapy

Dendritic cells (DCs) represent unique antigen-producing cells capable of sensitizing T cells to both new and recall antigens. In fact, these cells are the most potent antigen-producing cells. The goal of DC based cancer immunotherapy is to use the cells to prime specific antitumor immunity through the generation of effector cells that attack and lyse tumors.

DCs as Cancer Vaccines

 Key Researchers
Edgar Engleman
Ronald Levy
George Fisher
   

The first attempt to use DCs as cancer vaccines in humans was made by Edgar Engleman and Ronald Levy (Program 6) here at Stanford, who isolated DCs from patients with non-Hodgkin's lymphoma who had failed conventional chemotherapy, loaded the cells with immunoglobulin idiotype obtained from the patient's tumor, and reinjected the antigen-loaded cells back into the patients. Remarkably, most of the treated patients developed T cell mediated immune responses to their tumor-specific antigen and of the first six patients, two had complete remissions.

Since then, a larger number of patients with non-Hodgkin's lymphoma have been treated at Stanford with idiotype-pulsed DCs and the efficacy confirmed. In addition, pilot clinical trials of antigen-pulsed DCs have been conducted at Stanford in various types of cancer, including prostate cancer, colorectal cancer, multiple myeloma, and non-small cell lung cancer. These studies, and other studies carried out elsewhere, show that antigen-loaded DC vaccinations represent a safe and promising form of immunotherapy for a wide range of malignancies.

DC Loading and Activation

However, the current approaches are far from optimal in that many patients treated with DC vaccines have failed to respond. Moreover, ex vivo manipulation of DCs is time consuming and costly, requires the use of numerous cytokines and exposes the patient to increased risk of infection. To avoid manipulation of DCs in vitro and increase the potency of DC vaccination, Dr. Engleman's group has been working on approaches to load and activate DCs in vivo.

By administering a DC growth factor, Fms like tyrosine kinase 3 Ligand ( Flt3L ), to tumor bearing mice, followed by subcutaneous injection of oligodeoxynucleotides containing unmethylated CG motifs (CpG) together with a defined tumor Ag, they were able to induce significant anti-tumor responses in mice challenged with B16 melanoma.

The induction of a strong and durable immune response was dependent on the accumulation in skin of high numbers of Flt3L -mobilized DCs which facilitated their loading and activation with a local injection of a mixture of tumor antigen and CpG. These results suggested that access of DCs to tumor antigens, as well as the ability of these cells to mature, are critical for the induction of an efficient immune response.

Uptake of Tumor Antigens

More recently the Engleman lab has attempted to increase the uptake of tumor antigens by DCs, in vivo, by directing circulating DCs to tumors rather than delivering exogenous tumor antigens to Flt3L mobilized DCs. CCL20/macrophage inflammatory protein-3 a (MIP-3 chemokine, a potent chemo-attractant for a subset of DCs in both humans and mice, was used alone or in combination with CpG to activate tumoral DCs in mice.

Expression of CCL20 in the tumo r site attracted large numbers of circulating DCs into the tumor mass, and in the case of CT26 (colorectal) tumors led to complete tumor regression. Intratumoral CpG injections, in addition to CCL20, were required to induce therapeutic immunity against B16 melanoma tumors.

In this model CpG overcame tumor mediated inhibition of DC activation and enabled tumoral DCs to cross present tumor antigens to naïve CD8 T cells. CpG activation of tumoral DCs alone was not sufficient to induce tumor regression in either tumor model, nor was systemic delivery of Flt3 ligand, which dramatically increased the number of circulating DCs but not the number of tumoral DCs.

These results indicate that the number of tumoral DCs as well as the tumor milieu determines the ability of tumor bearing hosts to mount an effective anti-tumor immune response. The results also suggest that DCs can be manipulated in vivo without delivery of defined tumor antigens to induce a specific T cell mediated anti-tumor response and provide the basis for the use of chemokines in DC-targeted clinical strategies.

Intratumoral Injections of Naïve DCs

An additional approach under investigation by the Engleman lab involves intratumoral injections of naïve DCs into tumors that have been treated with either radiofrequency ablation or photodynamic therapy. The latter therapies are effective locally but not systemically, and importantly, in tumor bearing mice the combination of either treatment with intratumoral DCs can be curative.

These observations formed the basis of two recently approved INDs for clinical trials that are being undertaken by Drs. Engleman, George Fisher (Program 9), and Wenru Song (Program 6) for the treatment of pancreatic cancer and metastatic colorectal cancer, respectively.

 

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