Armed Oncolytic Virus Enhances Immune Functions of Chimeric Antigen Receptor–Modified T Cells in Solid Tumors

Abstract

The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared to leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus (OV) armed with the chemokine RANTES and the cytokine IL-15, reasoning that the modified OV will have both a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma (NB) as a tumor model we found that the adenovirus Ad5Δ24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, while CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, while the intratumoral release of both RANTES and IL-15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor bearing mice. These preclinical data support the use of this innovative biological platform of immunotherapy for solid tumors.

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

“…19,21,22 To overcome this barrier, a number of groups have combined CAR T cells with other therapies designed to modulate the tumor microenvironment including checkpoint inhibitors and oncolytic viruses. 36 Additionally, CAR T cells themselves have been modified by the incorporation of co-stimulatory endodomains such as CD28, 4-1BB, and OX40, 37,38 though our results suggest that this is likely insufficient to provide long term in vivo benefit at the tumor site ( Figure S1). Other modifications include the transgenic expression of Th1 cytokines to promote autocrine growth 36,[39][40][41] or the incorporation of a dominant-negative TGF-b receptor, which sequesters this tumor-produced immunosuppressive cytokine.…”

“…36 Additionally, CAR T cells themselves have been modified by the incorporation of co-stimulatory endodomains such as CD28, 4-1BB, and OX40, 37,38 though our results suggest that this is likely insufficient to provide long term in vivo benefit at the tumor site ( Figure S1). Other modifications include the transgenic expression of Th1 cytokines to promote autocrine growth 36,[39][40][41] or the incorporation of a dominant-negative TGF-b receptor, which sequesters this tumor-produced immunosuppressive cytokine. 42,43 Our approach extends upon the dominant-negative receptor concept by inverting a soluble immunosuppressive signal present in the tumor microenvironment into one that is immunostimulatory (4/7 ICR).…”

Syngeneic Syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting

“…Superior tumor cell killing with the combination of CAR T-cells and Ad5-D24 was recently reported to be associated with accelerated caspase pathways in human tumor cells. 30 However, upregulation of death receptors or costimulatory molecules on infected tumor cells (rendering tumor cells more sensitive to lymphocyte-mediated killing) was not observed. Speculatively, these mechanisms may play a role in hamster tumor cells, warranting further investigation of the in vitro setting, if the appropriate reagents can be generated.…”

Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

“…In a recent study, Nishio and colleagues reported that adoptive T-cell therapy can be enhanced by oncolytic adenovirus armed with chemokine RANTES and cytokine IL15, thus improving the trafficking and survival of CAR T cells in an immunodeficient mouse model (33). Although the results from these authors are valuable, the lack of an immune system overlooks many key attributes of ACT.…”