The field of T-cell therapy of cancer holds great promise, as demonstrated by the results obtained in Chimeric Antigen Receptor (CAR) modified T-cell therapy of CD19+ leukemia. However, the approach has not yielded similar results in the treatment of solid tumors with the exception of tumor infiltrating lymphocyte (TIL) therapy of melanoma. Recent work has identified key obstacles which has limited the efficacy of the approach: i) lack of recruitment of transferred T-cells to the tumor due to lack of trafficking signals ii) anergy of transferred cells at the tumor due to tumor immunosuppression iii) lack of propagation of transferred T-cells at the tumor. Previously, we have identified interleukin 2 (IL-2) and Tumor Necrosis Factor alpha (TNFα) as the most promising factors to stimulate the graft used in adoptive T-cell therapy. Both cytokines are important activators of immune cells and also known for their direct anti-tumor properties. Notably, these cytokines can cause severe side effects when administered systemically. Previously, we and others have achieved long lasting, high level cytokine expression locally but low level systemically when using armed oncolytic viruses in vivo. Oncolytic viruses armed with immunostimulatory molecules constitute a potent form of immunotherapy. In essence, the danger signal caused by virus replication, coupled with the actions of the transgene, and effective presentation of tumor epitopes by lysis of the cells, results in a personalized cancer vaccine. One attractive aspect of this approach is the ease of combinations with standard therapies including chemotherapy, radiation and immune checkpoint inhibiting antibodies for example. Therefore, we developed oncolytic adenoviruses expressing one or both above mentioned human cytokines. For more detailed immunological studies in immune competent mouse models, we constructed non-replicative adenoviruses with murine cytokines (Ad5-CMV-mIL2 and Ad5-CMV-mTNFα). These viruses were studied in combination with adoptive transfer of OT-1 TCR transgenic T-cells to treat C57BL/6 mice bearing B16-OVA melanoma tumors. The animals were administered intraperitoneally with CD8+-enriched OT-1 cells with or without intratumoral injections of cytokine-coding viruses. Combination treatment with Ad5-CMV-mIL2 and OT-1 resulted in statistically significant antitumor efficacy when compared with either monotherapy or untreated control. In further experiments a triple combination of Ad5-CMV-mIL2 + Ad5-CMV-mTNFa and OT-1 T-cells improved antitumor efficacy was observed over dual agent therapies. Furthermore, in Syrian hamster model, oncolytic virus successfully improved the efficacy of TIL therapy. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes.
### O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1,
Abstract Checkpoint inhibitors (CPI) started a new golden era of immunotherapy for cancer treatment. Since approval of the first product in 2011, a number of these antibodies are now available for different indications. Hundreds of trials are ongoing, which could predict many further approvals soon. Unfortunately, only a minority of patients currently benefit from CPI treatment. One of the biggest limitations appears to be poor immune infiltration of many tumors, known as immune desert or excluded tumors. Oncolytic viruses are an interesting tool to use together with CPI to increase the frequency and the quality of patients’ responses. Besides their inherent ability to raise the immune alarm towards the tumor, resulting in recruitment of lymphocytes and other cells, they can be armed with transgenes to potentiate these effects. In a data-driven approach, adenoviruses expressing Tumor Necrosis Factor Alpha and Interleukin 2 were identified as the optimal approach for recruiting and activating T cells in tumors. In this approach, the regimen of administration must be considered as it can affect the outcome of the treatment. We used an aggressive and immunosuppressive solid tumor model (B16.OVA melanoma) to study the interaction between the above-mentioned viruses and anti-PD-1 and anti-PD-L1. After optimizing treatment regimes, control of every tumor led to complete responses in 100% of the animals when the viral platform and anti-PD-1 (or anti-PD-L1) were used together. This was a significant improvement when compared to them used as monotherapies (p-value <0.01), but the optimal regimens of administration were different for anti-PD-1 and for anti-PD-L1. Full data, including tumor growth control, survival and extensive immunologic characterization, revealing the mechanism of action, will be presented. Checkpoint inhibitors and oncolytic adenovirus are an attractive approach for increasing the proportion of patients benefiting from CPI therapy. It is of critical relevance to understand how to best use them to maximize their therapeutic effect. Our study underlines the importance of scheduling of the agents with each other, and the differences between CPI targets. Citation Format: Victor Cervera-Carrascon, Dafne Quixabeira, Eleonora Munaro, Joao M. Santos, Riikka Havunen, Mikko Siurala, Akseli Hemminki. Enabling checkpoint inhibitors with oncolytic viruses to deliver complete responses: A matter of timing [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B16.
Vaccination with dendritic cells (DCs), the most potent professional antigen-presenting cells in the body, is a promising approach in cancer immunotherapy. However, tumors induce immunosuppression in their microenvironment that suppresses and impairs the function of DCs. Therefore, human clinical trials with DC therapy have often been disappointing. To improve the therapeutic efficacy and to overcome the major obstacles of DC therapy, we generated a novel adenovirus, Ad3-hTERT-CMV-hCD40L, which is fully serotype 3 and expresses hCD40L for induction of antitumor immune response. The specific aim is to enhance DCs function. Data from a human cancer patient indicated that this capsid allows effective transduction of distant tumors through the intravenous route. Moreover, patient data suggested that virally produced hCD40L can activate DCs in situ. The virus was efficient in vitro and had potent antitumor activity in vivo. In a syngeneic model, tumors treated with Ad5/3-CMV-mCD40L virus plus DCs elicited greater antitumor effect as compared with either treatment alone. Moreover, virally coded CD40L induced activation of DCs, which in turn, lead to the induction of a Th1 immune response and increased tumor-specific T cells. In conclusion, Ad3-hTERT-CMV-hCD40L is promising for translation into human trials. In particular, this virus could enable successful dendritic cell therapy in cancer patients.
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