T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy

We have previously shown that intratumoral injection of CpG oligodeoxynucleotide plus systemic chemotherapy can induce a T-cell immune response against lymphoma and serve as a therapeutic vaccine to cure tumors in a murine model. Here, we demonstrate that antibody-mediated modulation of T cells increases the efficacy of CpG vaccination, thereby eliminating the need for chemotherapy. T-cell modulation was accomplished by targeting both effector and regulatory T-cell populations using systemic administration of monoclonal antibodies against OX40, CTLA4, GITR, and folate receptor 4 (FR4). Each of these antibodies enhanced the effect of intratumoral CpG. Some pair-wise combinations of these antibodies potentiated T-cell modulation and further enhanced the efficacy of CpG vaccination. Specifically, the combination of anti-OX40 and anti-CTLA4 which enhance activation and block cell-intrinsic negative regulatory circuits in T cells, respectively, was especially potent. When combined with intratumoral CpG, it induced antitumor CD4 and CD8 T-cell immunity, cured large and systemic lymphoma tumors without chemotherapy, and provided long-lasting immunity against tumor rechallenge. Our results show that the combination of intratumoral CpG and immunomodulatory T-cell antibodies has promise for therapeutic vaccination against lymphoma. These reagents are becoming available for human clinical trials. (Blood. 2009; 113: 3546-3552)