Impact Of Repopulation Research Articles

In vivo efficacy of the CD40 agonist antibody CP-870,893 against a broad range of tumor types: Impact of tumor CD40 expression, dendritic cells, and chemotherapy

2514 Background: CP-870,893 is a fully human IgG2 CD40 agonist antibody currently in early clinical trials. In vitro studies demonstrate its ability to bind human CD40 and enhance dendritic cell costimulatory molecule expression and cytokine production. Methods: In order to assess its potential for cancer therapy, we evaluated the anti-tumor efficacy of CP-870,893 against several CD40pos and CD40neg human tumors in SCIDbeige mice. We specifically addressed the role of tumor CD40 expression, the impact of re-population with human dendritic and T cells on efficacy, and it’s potential to act in synergy with chemotherapeutic agents. Results: We demonstrate that a single i.p. injection of CP-870,893 (T1/2 ∼ 7 days) prevented the growth of several subcutaneous CD40pos tumors including two B cell lymphomas, the breast carcinoma BT-474, and the prostate tumor PC-3 (ED50 = 0.02 mg/kg; Ceff ∼100 ng/mL). Efficacy was demonstrated when CP-870,893 was administered at the time of tumor challenge, but was also observed when treatment was delayed until tumors were well established. Although efficacious against CD40pos tumors, CP-870,893 had no effect on the growth of CD40neg/low tumors unless mice were repopulated at the tumor site with both naïve human dendritic cells and T cells. In these repopulated animals, i.p. administration of CP-870,893 inhibited the growth of a CD40low colon carcinoma and a CD40neg erythroleukemic tumor (ED50 = 0.005 mg/kg). The presence of human T cells and dendritic cells at the tumor site also improved the activity of CP-870,893 against CD40pos tumors, reducing the ED50 and Ceff >10-fold as compared to its effects in the absence of these cells, suggesting a synergy between direct CD40 mediated tumor killing and immune activation. Further, when administered as part of a combination treatment with a sub-optimal dose of cisplatin, improved activity was observed which resulted in tumor regression. Conclusions: These studies demonstrate the potent, broad-spectrum anti-tumor activity of CP-870,893 through both direct and immune mediated effects, its increased efficacy when co-administered with chemotherapeutic agents, and suggest its potential utility as a therapy for human cancer. [Table: see text]

Assessment of tumor cell repopulation after chemotherapy for advanced ovarian cancer: pilot study.

Repopulation of clonogenic tumor cells appears to increase during fractionated radiation treatment and is recognized as an important factor affecting local control. Given the longer intervals between cycles and longer total duration of treatment, the impact of repopulation is likely to be greater after chemotherapy. We assessed tumor cell repopulation with the proliferative marker Ki-67 in 21 patients with ovarian carcinoma who received initial chemotherapy. Paraffin slides were evaluated from the diagnostic biopsy and from tumor obtained at debulking surgery after chemotherapy. Immunohistochemistry using the MIB-1 antibody was performed on the paired samples and analyzed with a digital imaging device linked to a color camera mounted on a transmitted-light microscope. The ratio of Ki-67 positive to all nuclei was used as a proliferative index and compared for pre- and postchemotherapy specimens. All patients received platinum-based chemotherapy and most showed a response to treatment. The median duration between last chemotherapy and debulking surgery was 33 days (range, 22-50 days). Four (19%) of 21 patients showed an increased proliferative index after chemotherapy, and the remainder showed a decrease (n = 12) or no significant change (n = 5). Our results did not suggest an increase in proliferation of tumor cells after this type of chemotherapy in the majority of patients with ovarian cancer.