CTLA-4 Blockade Enhances Antitumor Immunity of Intratumoral Injection of Immature Dendritic Cells into Irradiated Tumor in a Mouse Colon Cancer Model

Abstract

Dendritic cells (DCs)-based cancer immunotherapy has been used various strategies to inhibit immune suppressive mechanisms. CD25 antibodies and cyclophosphamide are well-studied immunomodulators through inhibition of regulatory T cells (Treg) and a blockade the immune-checkpoint molecule, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) was recently targeted for immunomodulation. We used anti-CTLA-4 antibody, which is known to induce effective antitumor immunity by facilitating tumor-specific T-cell activation and suppressing Treg cells, as useful immunomodulator to provide a potentiating effect in the intratumoral injection of immature DCs (iDCs) into the irradiated tumor (IR/iDC). Ionizing radiation (IR) was applied at a dose of 10 Gy to the tumor on the right thigh of mice. Then, iDCs were intratumorally injected into the irradiated tumor. Anti-CTLA-4 antibody (100 µg/mouse) was administered intraperitoneally to mice on the same day with every iDCs injection. The growth of distant tumors was inhibited by IR/iDC and this effect was significantly augmented by combination treatment of anti-CTLA-4 antibody. Furthermore, the survival rate of tumor-bearing mice improved more by the combination treatment of anti-CTLA-4 antibody and IR/iDC compared with other groups. It was related to the increased tumor-specific interferon-γ-secreting T cells and CTL activity. Therefore, our results demonstrated that immunomodulator such as anti-CTLA-4 antibody enhances antitumor immunity of intratumoral injection of iDCs into irradiated tumor and suggested a new strategy to get more clinical benefits for cancer treatment.

Coinhibitory Pathways in Immunotherapy for Cancer

“…Results from additional retrospective studies are consistent with these findings (213). In preclinical approaches with dendritic cell-based vaccines, CTLA-4 blockade enhanced efficacy compared to either therapy alone (214,215). When combined with appropriate adjuvants, long-peptide vaccines have induced clinical responses and T cell immunity (216,217).…”

Immune Checkpoint Inhibitor Combinations in Solid Tumors: Opportunities and Challenges

“…In animal models, vaccination with peptideantigen-loaded DCs, in combination with systemic CTLA-4 blockade, demonstrated increased efficacy than either treatment alone [81][82][83]. Another study explored a different strategy, where immature DCs were used for in situ vaccination by injection directly into irradiated tumor, in combination with systemic CTLA-4 blockade [88], resulting in the inhibition of distant tumor growth and improved animal survival. A Phase I trial of combination of MART-1 peptidepulsed DC and tremelimumab has shown objective and durable tumor responses at the higher range of the expected response rate with either agent alone [89].…”

Radiotherapy combined with immune checkpoint blockade immunotherapy: Achievements and challenges

“…It is reasonable to hypothesize that radiotherapy combined with immunotherapy will lead to enhanced antitumor immune responses and improved clinical outcomes. Based on this theory, since the term "abscopal" has been proposed, dozens of preclinical studies and reviews have discussed this phenomenon and demonstrated the priming clinical outcomes of combinatorial treatment from radiotherapy and immunotherapy [5,[8][9][10].…”