Perspectives for cancer immunotherapy mediated by p19Arf plus interferon-beta gene transfer

Abstract

While cancer immunotherapy has gained much deserved attention in recent years, many areas regarding the optimization of such modalities remain unexplored, including the development of novel approaches and the strategic combination of therapies that target multiple aspects of the cancer-immunity cycle. Our own work involves the use of gene transfer technology to promote cell death and immune stimulation. Such immunogenic cell death, mediated by the combined transfer of the alternate reading frame (p14ARF in humans and p19Arf in mice) and the interferon-β cDNA in our case, was shown to promote an antitumor immune response in mouse models of melanoma and lung carcinoma. With these encouraging results, we are now setting out on the road toward translational and preclinical development of our novel immunotherapeutic approach. Here, we outline the perspectives and challenges that we face, including the use of human tumor and immune cells to verify the response seen in mouse models and the incorporation of clinically relevant models, such as patient-derived xenografts and spontaneous tumors in animals. In addition, we seek to combine our immunotherapeutic approach with other treatments, such as chemotherapy or checkpoint blockade, with the goal of reducing dosage and increasing efficacy. The success of any translational research requires the cooperation of a multidisciplinary team of professionals involved in laboratory and clinical research, a relationship that is fostered at the Cancer Institute of Sao Paulo.

Gene-based Interventions for Cancer Immunotherapy

“…Together these studies show that our gene transfer approach is an effective immunotherapy [114,115]. The results to date are promising and research will continue to evolve, with critical development using clinically relevant models, such as testing with patient-derived tumor samples as well as alternative animal models, including canines [116].…”

Combined p14ARF and Interferon-β Gene Transfer to the Human Melanoma Cell Line SK-MEL-147 Promotes Oncolysis and Immune Activation

“…Although the results were encouraging, the use of human cells in animal models brings an important limitation, the use of immunocompromised animals. Our previous data using the B16 cell line in immunocompetent mice pointed out that the contribution of the immune system to the control of tumors treated with the mouse transgenes (p19Arf + mIFNb) is crucial (18,20,52). One of our main motivations for the use of gene transfer to promote oncolysis was precisely the potential to modulate the tumor microenvironment, release tumor antigens, and DAMPs to stimulate the immune response.…”

“…Our group has been working on the development of nonreplicating adenoviral vectors that induce oncolysis due to the combined activity of the p14ARF and IFNb transgenes as well as antiviral response (18). While p14ARF (alternate reading frame of the CDKN2a locus, p19Arf in mice, p14ARF in humans) acts as the functional partner of p53, IFNb is a critical cytokine that contributes to innate and adaptive anti-tumor responses (19).…”

“…Peculiarities in the melanoma genotype shaped the rationale of the adenoviral strategy used in this work. Since 80% of melanomas preserve p53 in its wild-type form (26), we have incorporated a p53responsive promoter (PG) to drive transgene expression (18). The p14ARF transgene is expected to activate endogenous p53, in turn providing both tumor suppressor function and transactivation from the PG promoter (27).…”

p19Arf sensitizes B16 melanoma cells to interferon-β delivered via mesenchymal stem cells in vitro

“…In particular, the MSC approach is expected to be transient when applied in vivo, since cells may migrate out of the tumor, differentiate, or die (9,10). The adenovirus that they carry cannot replicate and is not integrated in the host genome, therefore this approach is incompatible with stable, long term exogenous gene expression (23,24). The transient nature of the technology should be sufficient to bring about cell killing and stimulation of an anti-tumor immune response.…”