Oncolytic adenovirus-mediated intratumoral expression of TRAIL and CD40L enhances immunotherapy by modulating the tumor microenvironment in immunocompetent mouse models

Liu, Wenmo; Wang, Xupu; Feng, Xinyao; Yu, Jiahao; Liu, Xinyao; Jia, Xiaoxu; Zhang, Haihong; Wu, Hui; Wang, Chu; Wu, Jiaxin; Yu, Bin; Yu, Xianghui

doi:10.1016/j.canlet.2022.215661

Cited by 14 publications

(9 citation statements)

References 43 publications

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“…For example, several murine models were reported to be semi-permissive for the adenoviruses and support the transgenes expression in the tumor microenvironment. 43 , 44 Thus, using fully immunocompetent mice might be a reasonable solution to collect the data from B cells, NK cell, T regs and other suppressive cells, such as myeloid-derived suppressive cells and M2 macrophages. Of critical importance is to evaluate effector and central memory cells and, therefore, the generation of immunological memory and, as a result, better survival, and reduced probability of tumor relapse.…”

Section: Discussionmentioning

confidence: 99%

Local delivery of interleukin 7 with an oncolytic adenovirus activates tumor-infiltrating lymphocytes and causes tumor regression

et al. 2022

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Cytokines have proven to be effective for cancer therapy, however whilst low-dose monotherapy with cytokines provides limited therapeutic benefit, high-dose treatment can lead to a number of adverse events. Interleukin 7 has shown promising results in clinical trials, but anti-cancer effect was limited, in part due to a low concentration of the cytokine within the tumor. We hypothesized that arming an oncolytic adenovirus with Interleukin 7, enabling high expression localized to the tumor microenvironment, would overcome systemic delivery issues and improve therapeutic efficacy. We evaluated the effects of Ad5/3-E2F-d24-hIL7 (TILT-517) on tumor growth, immune cell activation and cytokine profiles in the tumor microenvironment using three clinically relevant animal models and ex vivo tumor cultures. Our data showed that local treatment of tumor bearing animals with Ad5/3- E2F-d24-hIL7 significantly decreased cancer growth and increased frequency of tumor-infiltrating cells. Ad5/3-E2F-d24-hIL7 promoted notable upregulation of pro-inflammatory cytokines, and concomitant activation and migration of CD4+ and CD8 + T cells. Interleukin 7 expression within the tumor was positively correlated with increased number of cytotoxic CD4+ cells and IFNg-producing CD4+ and CD8+ cells. These findings offer an approach to overcome the current limitations of conventional IL7 therapy and could therefore be translated to the clinic.

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Section: Discussionmentioning

confidence: 99%

Local delivery of interleukin 7 with an oncolytic adenovirus activates tumor-infiltrating lymphocytes and causes tumor regression

et al. 2022

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“…OVs could also remodel the immunosuppressive TME through several mechanisms and thus indirectly enhances the activation and function of immune cells in solid tumors [ 40 ]. It is worth noting that OVs can also be the effective vectors to delivery the immune modulators into tumors for further modification of TME [ 41 ]. OVs carrying genes encoding inflammatory cytokines are expected to enhance antitumor immune responses in TME, and a number of OVs have been evaluated for several cancers [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Recombinant oncolytic adenovirus armed with CCL5, IL-12, and IFN-γ promotes CAR-T infiltration and proliferation in vivo to eradicate local and distal tumors

Fang,

Yuan,

Wang

et al. 2023

Cell Death Discov.

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The efficacy of chimeric antigen receptor T (CAR-T) cells for solid tumors remains unsatisfactory due to the limited tumor infiltration and immunosuppressive microenvironment. To overcome these limitations, the genetically engineered recombinant oncolytic adenoviruses (OAVs) that conditionally replicate in tumor cells were developed to modify the tumor microenvironment (TME) to facilitate CAR-T-mediated tumor eradication. Here in the present study, a novel recombinant OAV carrying CCL5, IL12, and IFN-γ controlled by Ki67 promoter was constructed (named AdKi67-C3). The antitumor activity of AdKi67-C3 was tested in vitro and in vivo by using mono administration or combing with CAR-T cells targeting B7H3. It proved that CCL5 expressed by AdKi67-C3 indeed induced more CAR-T migration in vitro and CAR-T infiltration in tumor mass in vivo. Meanwhile, cytokines of IFN-γ and IL12 secreted by AdKi67-C3-infected tumor cells significantly promoted proliferation and persistence of CAR-T cells in vitro and in vivo. In tumor-bearing xenograft mouse models of kidney, prostate or pancreatic cancer, local pretreatment with AdKi67-C3 dramatically enhanced CAR-T cell efficacy and eliminated local and distant tumors. More importantly, mice achieving complete tumor regression resisted to re-challenge with the same tumor cells, suggesting establishment of long-term antitumor immune response. Therefore, OAVs armored with cytokines could be developed as a bioenhancer to defeat the immunosuppressive microenvironment and improve therapeutic efficacy of CAR-T in solid tumors.

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“…While rAd can effectively deliver therapeutic payloads to tumors, transient expression of these viruses necessitates repeated high-titer injections to maintain effective local concentrations [ 185 , 186 ]. This strategy, combined with other therapies, is anticipated to significantly boost antitumor immunity (Fig.…”

Section: Rad-based Immunostimulatory Therapymentioning

confidence: 99%

Harnessing adenovirus in cancer immunotherapy: evoking cellular immunity and targeting delivery in cell-specific manner

Zeng,

Zhang,

et al. 2024

Biomark Res

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Recombinant adenovirus (rAd) regimens, including replication-competent oncolytic adenovirus (OAV) and replication-deficient adenovirus, have been identified as potential cancer therapeutics. OAV presents advantages such as selective replication, oncolytic efficacy, and tumor microenvironment (TME) remodeling. In this perspective, the principles and advancements in developing OAV toolkits are reviewed. The burgeoning rAd may dictate efficacy of conventional cancer therapies as well as cancer immunotherapies, including cancer vaccines, synergy with adoptive cell therapy (ACT), and TME reshaping. Concurrently, we explored the potential of rAd hitchhiking to adoptive immune cells or stem cells, highlighting how this approach facilitates synergistic interactions between rAd and cellular therapeutics at tumor sites. Results from preclinical and clinical trials in which immune and stem cells were infected with rAd have been used to address significant oncological challenges, such as postsurgical residual tumor tissue and metastatic tissue. Briefly, rAd can eradicate tumors through various mechanisms, resulting from tumor immunogenicity, reprogramming of the TME, enhancement of cellular immunity, and effective tumor targeting. In this context, we argue that rAd holds immense potential for enhancing cellular immunity and synergistically improving antitumor effects in combination with novel cancer immunotherapies.

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Oncolytic adenovirus-mediated intratumoral expression of TRAIL and CD40L enhances immunotherapy by modulating the tumor microenvironment in immunocompetent mouse models

Cited by 14 publications

References 43 publications

Local delivery of interleukin 7 with an oncolytic adenovirus activates tumor-infiltrating lymphocytes and causes tumor regression

Local delivery of interleukin 7 with an oncolytic adenovirus activates tumor-infiltrating lymphocytes and causes tumor regression

Recombinant oncolytic adenovirus armed with CCL5, IL-12, and IFN-γ promotes CAR-T infiltration and proliferation in vivo to eradicate local and distal tumors

Harnessing adenovirus in cancer immunotherapy: evoking cellular immunity and targeting delivery in cell-specific manner

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