Nontoxic radioactive Listeria ^at is a highly effective therapy against metastatic pancreatic cancer

Abstract

No significant improvement in therapy of pancreatic cancer has been reported over the last 25 y, underscoring the urgent need for new alternative therapies. Here, we coupled a radioisotope, 188 Rhenium, to an attenuated (at) live Listeria monocytogenes (Listeria at ) using Listeria-binding antibodies, thus creating a unique radioactive Listeria at (RL). We then demonstrated in a highly metastatic pancreatic mouse tumor model (Panc-02) that RL delivered radioactivity to the metastases and less abundantly to primary tumors in vivo, without harming normal cells. This result was possible because Listeria at was efficiently cleared by the immune system in normal tissues but not in the heavily immune-suppressed microenvironment of metastases and primary tumor. Multiple treatments with low doses of the RL resulted in a dramatic decrease in the number of metastases (∼90%) compared with control groups in the Panc-02 model. This is the first report of using live attenuated bacteria delivering a highly radioactive payload to the metastases, resulting in killing tumor cells in vivo without harming normal cells. The nontoxic RL treatment is attractive for clinical development as a therapy to prevent pancreatic cancer recurrence and metastases. P ancreatic ductal adenocarcinoma, synonymous to pancreatic cancer, is the fourth leading cause of cancer deaths. The socalled silent killer is characterized by its metastatic behavior before the primary tumor can be detected, resulting in a 5-y survival rate of only 4%. Current cancer treatments-i.e., surgery followed by radiation and/or chemotherapy-are ineffective, particularly against liver metastases. Gemcitabine and erlotinib, Food and Drug Administration-approved drugs for pancreatic cancer treatment, improve median survival by ∼6 mo in patients with advanced-stage disease (1-3), emphasizing the need for new alternative therapies for metastatic pancreatic cancer.For any anticancer approach to be effective, it needs to target metastases and/or remaining tumor cells after primary therapeutic intervention. Indeed, in most cases, cancer therapy is now highly effective in eradicating primary tumors through combinations of surgery, radiation, and adjuvant therapy. The reason that cancer remains such a formidable health problem is its capacity to recur in the form of widespread metastases, often with a fatal consequence. In a previous study, we found that a highly attenuated bacterium, Listeria monocytogenes (Listeria at ), which was originally used to deliver tumor-associated antigens into antigen-presenting cells, also infected tumor cells in vitro and in vivo (4). Although Listeria at was efficiently cleared by the immune system in the normal tissues within 3-5 d, immune suppression in the tumor microenvironment allowed these bacteria to accumulate in metastases and primary tumors and to kill tumor cells through high levels of reactive oxygen species (ROS) (4). Based on these results we hypothesized that Listeria at could be used to deliver anticancer agents, such as therapeutic ...

Single-agent combinatorial cancer therapy

“…Quispe-Tintaya et al (6) suggest the following mechanisms of action for the unique therapeutic strategy (Fig. 1): Based on their results and previous publications (9-11), the authors hypothesize that direct cytotoxicity caused by 188 Re radiation, especially in highly proliferating metastases, resulted in cancer cell death.…”

“…Quispe-Tintaya et al, as reported in PNAS, have taken a major next step in this emerging field of biological therapy (6). The authors report a unique combinatorial strategy against cancer using radiolabeled antibodies bound to tumor-colonizing bacteria, thereby enhancing therapeutic efficacy in a model of metastatic pancreatic cancer in mice.…”

“…Although during replication the amount of radiolabeled antibody per bacterium will diminish, reactive oxygen species in infected tumor cells will increase, leading to their further destruction. However, Quispe-Tintaya et al (6) attributed the major cytocidal effect to 188 Re radiation (red arrow), which leads to DNA damage and cell death, especially in quickly dividing metastatic cancer antibodies bound to L. monocytogenes resulted in reduction of the primary tumor by more than 60%, and remarkably, the number of detectable metastases was reduced by more than 90%. Metastases had greater 188 Re concentrations and the antibodybound bacteria were found to replicate to a greater degree in metastases than the solid tumors.…”

“…Metastases had greater 188 Re concentrations and the antibodybound bacteria were found to replicate to a greater degree in metastases than the solid tumors. Additionally, Quispe-Tintaya et al (6) found that myeloid-derived suppressor cells (MDSCs), particularly monocytic MDSCs, were infected by the bacteria.…”

“…In contrast to earlier approaches that combine radiotherapy with bacterial tumor therapy, here 188 Rhenium ( 188 Re)-labeled antibodies were directly linked to the bacterium before injection. Therefore, Quispe-Tintaya et al (6) injected a single agent (live bacteria with bound antibodies) rather than administering the radiotherapeutic and the bacterial tumor therapy independently.…”