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A translational approach evaluating novel strategies using chemotherapy to enhance immune-mediated anti-tumor activity

Final Report Summary - CHEMO-IMMUNE THERAPY (A translational approach evaluating novel strategies using chemotherapy to enhance immune-mediated anti-tumor activity)


Executive Summary:

The immune system is important in targeting cancer cells and prevents tumor spread. Several studies have demonstrated that intratumoral infiltration of lymphocytes, namely T and natural killer (NK) cells correlate with favorable prognosis in patients with cancer. Although infusion of T cells can result in clinically meaningful responses, the number of patients that respond to this therapy is limited. T cells can exert an immunological pressure on the tumor cells leading to down-regulation of the tissue antigen MHC class I. As a consequence, individual tumor cells within a growing tumor mass have varying expression of MHC class I. Tumor cells with a high expression of MHC class I are targeted by T cells, whereas tumor cells with a low or absent expression of MHC class I are targeted by NK cells. It may therefore be of interest to treat cancer patients with a combined infusion of both T and NK cells.

NK and T cells can kill tumor cells through binding of death receptors expressed on the surface of tumor cells. Previous studies have showed that chemotherapy agents have immune-sensitizing effects on tumors through up-regulation of death receptors. In order to increase the tumor immunogenicity to improve targeting of immune escape variants with differential expression of MHC class I, we studied whether conventional chemotherapeutic drugs sensitize tumors to combined NK and T cell therapy.

NK cells and T cells were isolated from patients with melanoma and tested for their capacity to kill tumor cell lines of various origins in vitro. We screened more than a dozen chemotherapy agents for their ability to sensitize tumor cells to killing by NK and T cell in vitro. While most chemotherapy agents were able to sensitize tumor cells of various origin to NK and T cell -mediated killing, we found that the anthracyclin, doxorubicin, and the proteasome inhibitor, b-AP15, consistently augmented sensitivity by tumor cells to killing by NK and T cells in the majority of tumor cell lines tested.

Exposure to either the doxorubicin or b-AP15 resulted in significantly increased expression of death receptors on the surface of tumor cells as well as reduced expression of anti-apoptotic molecules. As a consequence, these pre-treated tumors were more sensitive to killing by NK and T cell in vitro. Importantly, treatment with doxorubicin or b-AP15 did not sensitize normal fibroblasts to NK or T cell -mediated killing. We further found that following treatment with either doxorubicin or b-AP15, combined infusion of NK and T cells resulted in significantly reduced tumor progression and prolonged survival in tumor bearing mice compared with untreated mice or mice treated with chemotherapy alone or chemotherapy with either NK or T cell infusion. Our findings present a novel use of doxorubicin or b-AP15 as a pre-treatment of adoptive infusion of expanded NK cells and T cells. Since a combination approach increases the chances of targeting immune escape variants of tumor cells, with variable expression of MHC class I, doxorubicin or b-AP15 pre-treatment coupled with infusion of autologous NK and T cells may be a therapeutic option for the treatment of cancer.