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

Abstract

Despite the rapid progress in the development of novel adoptive T-cell therapies, the clinical benefits in treatment of established tumors have remained modest. Several immune evasion mechanisms hinder T-cell entry into tumors and their activity within the tumor. Of note, oncolytic adenoviruses are intrinsically immunogenic due to inherent pathogen-associated molecular patterns. Here, we studied the capacity of adenovirus to overcome resistance of chicken ovalbumin-expressing B16.OVA murine melanoma tumors to adoptive ovalbumin-specific CD8 antigens TRP-2 and gp100 was detected in combination-treated mice, indicating epitope spreading. Moreover, the majority of virus/T-cell-treated mice rejected the challenge of parental B16. F10 tumors, suggesting that systemic antitumor immunity was induced. In summary, we provide proof-of-mechanism data on combining adoptive T-cell therapy and adenovirotherapy for the treatment of cancer.

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

“…Instead, other mechanisms such as the activation status of T cells are suggested and discussed below. 36 In contrast to mouse studies, the available human evidence suggest that accumulation of T cells does correlate with efficacy endpoints. 37 Further, for most tumor types there is a large body of data indicating that the concentration of T cells in tumors (TIL) correlates with favorable outcome.…”

“…36 Unfortunately, these hypotheses cannot be studied in the hamster model due to lack of hamster-specific (or acceptably cross-reactive) reagents for the aforementioned markers. In addition, the actual mechanism-of-action might differ from mouse studies due to active oncolysis of hamster tumor cells, a scenario that cannot be studied in murine models but is much closer to the clinical situation in human patients.…”

Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy

“…Previously, we have not detected significant differences in CD8 C T cells specific for the xenoantigen chicken ovalbumin expressed by the B16.OVA cells. 6,36 Instead, we have seen responses in T-cell clones against "natural epitopes" such as gp100 and TRP-2 36 suggesting that the "more natural" B16.F10 model without OVA may be more appropriate in many cases. Therefore, immunocompetent mice-bearing B16.F10 melanoma tumors were injected intratumorally with PBS, Ad5/3-CMVmCD40L, antigen-pulsed DCs, or with both Ad5/3-CMVmCD40L and antigen-pulsed DCs.…”

“…Enrichment of CD8a splenocytes was performed as previously reported. 36 Briefly, spleen from C57BL/6-Tg (TcraTcrb) 1100Mjb/J (OT-1) mice were mashed and treated with lysis buffer (ACK). Mouse CD8 C (Ly-2) microbeads (Miltenyi Biotech) were used to enrich CD8a C T cells, which were then expanded in supplemented growth media for 1 week.…”

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

“…But these drugs only work on B-raf mutated tumors, and side effects usually occur during treatment, both of which limit their applications (Boussemart et al, 2013). Some viral vectors, such as adenovirus, have been shown to enhance lymphocyte infiltration and improve efficacy of adoptive T cell therapy (Tähtinen et al, 2015). Previous studies in our lab have used adenovirus expressing LIGHT for tumor immunotherapy (Lee et al, 2009;Yu et al, 2007).…”