Adenovirus-mediated intratumoral expression of immunostimulatory proteins in combination with systemic Treg inactivation induces tumor-destructive immune responses in mouse models

Abstract

Tumor-associated antigens (TAAs) include overexpressed self-antigens (e.g. Her2/neu) and tumor-virus antigens (e.g. HPV-16 E6/E7). Although in cancer patients, TAA-specific CD4+ and CD8+ cells are often present, they are not able to control tumor growth. In recent studies it became apparent that tumor-site located immune-evasion mechanisms contribute to this phenomenon and that regulatory T-cells play a major role. We tested in Her2/neu+ breast cancer and HPV-16 E6/E7+ cervical cancer mouse models, whether intratumoral expression of immunostimulatory proteins (ISPs), e.g. recombinant antibodies (αCTLA-4, αCD137, αCD3), cyto/chemokines (IL-15, LIGHT, mda-7), and costimulatory ligands (CD80), via adenovirus(Ad)-mediated gene transfer would overcome resistance. In both the breast and cervical cancer model, none of the Ad.ISP vectors displayed a significant therapeutic effect when compared with an Ad vector that lacked a transgene (Ad.zero). However, the combination of Ad.ISP vectors with systemic Treg depletion, using anti-CD25 mAb (breast cancer model) or low-dose cyclophosphamide (cervical cancer model) resulted in a significant delay of tumor growth in mice treated with Ad.αCTLA4. In the cervical cancer model we also demonstrated the induction of a systemic anti-tumor immune response that was able to delay the growth of distant tumors. Ad.αCTLA4 mediated tumor-destructive immune responses involved NKT- and CD8+ T-cells. In both models no auto-immune reactions were observed. The study shows that Ad.αCTLA4 in combination with systemic Treg depletion has potentials in the immunotherapy of cancer.

Th2 type inflammation promotes the gradual progression of HPV-infected cervical cells to cervical carcinoma

“…It is associated with tumor-infiltrating lymphocytes which express the FoxP3 marker of Treg cells [42, 43], and agents counteracting Treg cells can partially counteract the growth of mouse TC1 tumors which express E6 and E7 [44-47]. We have applied IHC to analyze archived cervical tissue samples representing several stages during the progression from hr-HPV infected cervical epithelial cells to ICC, and have focused on cellular markers that have been associated with a Th2 type inflammation, hypothesizing that such inflammation contributes to the local, tumor-related immunosuppression.…”

EMMPRIN reduction via scFv-M6-1B9 intrabody affects α3β1-integrin and MCT1 functions and results in suppression of progressive phenotype in the colorectal cancer cell line Caco-2

“…However, the application of an adenoviral gene transfer system should include several precautions for the inflammatory response and immune response in preexisting patients with immune system problems. [54][55][56] We suggest that this method is proper for solid cancer or local treatment, transplants of colon tumors into a mouse could be utilized as an experimental model in the future for studying the efficacy of scFv-M6-1B9 intrabodies.…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…Viral vector vaccine strategies using adenovirus vectors [257][258][259][260], alphavirus vectors [212,213,261], vaccinia virus vectors (NCT00485277 and NCT01152398), vesicular stomatitis virus [262] and polyoma virus systems [263,264] have all been used to elicit anti-HER2/neu immune responses. The intracellular bacteria Listeria monocytogenes has also been adapted as an immunotherapeutic vector system and studied in strategies to elicit anti-HER2/neu immune responses [215,265].…”