Pilot Studies of Breast Cancer Immunophototherapy

Institution: University of California, Irvine
Investigator(s): Edward Nelson, M.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9IB-0119 Award: $99,834
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2003)
Many patients treated for breast cancer will have their cancer recur, often after a long remission period. This suggests there are a small number of tumor cells that remain alive after treatment. Our goal is to explore ways to harness the immune system to find and destroy tumor cells. However, early attempts to increase anti-breast tumor immunity have been sub-optimal, so achieving significant clinical benefit has been elusive. Using the most potent antigen-presenting cell in the immune system, the dendritic cell (DC), we might be able to increase the immune response. Recently, techniques have been developed for studying these very potent cells in both human and animal model systems. DCs can engulf, or "feed on", dead cells and can make the immune system “see” portions of the surviving tumor. Tumor cells can die in two different ways, either apoptosis or necrosis. DCs respond differently to cells that die in these alternate ways, and we do not know which type of cell death is best for the DC function in promoting tumor immunity.

The aim of this project is to combine DC-based immunotherapy with photodynamic therapy (PDT), which is a treatment method that involves administering a drug, which is harmless by itself, but when exposed to light causes cell damage and death. This cell death occurs only in the area exposed to the light and for the period that the light is on. Different light doses in PDT cause either apoptotic or necrotic cell death. PDT has been used for the treatment of pre-malignant conditions, skin disorders, and palliation of several tumors. Although this treatment provides very good local effects, it does not treat metastatic disease. We will establish tumors in animals (rats), then treat the tumors with 5-ALA (5-aminolevulinic acid), which is converted to ”photosensitive” protoporpyrin IX in tissues. We can then illuminate tumors with 630 nm laser light for various times and intensities to achieve either necrotic or apoptotic cell death. In parallel studies, we will harvest bone marrow DCs, stimulate them using in vitro culture conditions, and re-inject them into tumors after PDT treatment. Because activation of DCs is associated with migration to lymph nodes, we will evaluate DC ”trafficking” from PDT-treated tumors to the local, draining lymph nodes. We will also assess whether the combined immunophototherapy is more effective than PDT alone in treating established tumors.

Combining PDT with DC-based immunotherapy is a new and previously unexplored concept that adapts two distinct approaches to develop a potentially more effective therapy for breast cancer.


Final Report (2006)
Note: This grant was extended 1-yr to complete the aims and funding.

Many patients treated for breast cancer will have their cancer come back, often after long periods of time suggesting that there are a small number of tumor cells that remain alive even after our best treatment. It is this "recurrence" that generally leads to the patient's death. If we can harness the immune system to find and destroy tumor cells we will have another, potentially highly beneficial therapy for breast cancer patients. Early attempts to increase anti-tumor immunity have been sub-optimal, so clinical benefit has been elusive. Using the most potent antigen-presenting cell in the immune system, the dendritic cell (DC), we might be able to increase this sub-optimal immune response.

Recently, techniques have been developed for studying DCs in both human and animal model systems. DCs can engulf, "feed on", dead cells and can make the immune system “see” parts of the tumor contained within those dead cells. Cells can die in two different ways, one called apoptosis and the other called necrosis. DCs respond differently to cells that die in each way and we do not know which type of cell death is best for DCs to use.

By causing tumor cell death of a particular type, a treatment could provide a "feeding ground" for DCs to gather parts of the tumor and stimulate the immune system to "see" the tumor much better. Photodynamic therapy (PDT) is a treatment method that involves administering a drug, which is harmless by itself, but when exposed to light causes cell damage and death. This cell death occurs only in the area exposed to the light and for the period of light exposure. Different light doses in PDT cause either apoptotic or necrotic cell death. PDT has been used for the treatment of pre-malignant conditions, skin disorders, and palliation of several tumors. Although this treatment provides very good local effects, it does not treat all the sites of the tumors, i.e. metastatic disease. We believe that PDT could be combined with DCs to make the anti-tumor immune response larger and potentially use the immune system to treat disease distributed throughout the whole body.

We sought to answer the question of whether the use of PDT to induce preferential necrotic or apoptotic cell death combined with local administration of bone marrow-derived DCs at the same site would lead to better DC trafficking and anti-tumor immunity in our established animal breast cancer model. In our studies we demonstrated that: 1) tumors rapidly and preferentially accumulated the PDT-sensitizer, protoporphorin IX, after 5-ALA (5-aminolevulinic acid) administration. However, there was substantial anatomic variation of PDT sensitizer within the tumor mass. 2) photodynamic therapy (PDT) treatment of breast tumors enhanced the trafficking of adoptively transferred DCs to draining lymph nodes and that the use of PDT did not result in production of DC toxins, and 3) the combination of immunophototherapy was superior to photodynamic therapy alone as measured in survival of animals with breast cancer. These studies support the continued development of this combination treatment method.

Immunophototherapy Using PDT Combined with Rapid Intratumoral Dendritic Cell Injection.
Periodical:Photochemistry and Photobiology
Index Medicus: Photochem Photobiol
Authors: Sur BW, Nguyen P, Sun CH, Tromberg BJ, Nelson EL
Yr: 2008 Vol: 84 Nbr: Abs: Pg:1257-1284