Repeated intratumoral administration of ONCOS-102 leads to systemic antitumor CD8<sup>+</sup>T-cell response and robust cellular and transcriptional immune activation at tumor site in a patient with ovarian cancer

Vassilev, Lotta; Ranki, Tuuli; Joensuu, Timo; Jäger, Elke; Karbach, Julia; Wahle, Claudia; Partanen, Kaarina; Kairemo, Kalevi; Alanko, Tuomo; Turkki, Riku; Linder, Nina; Lundin, Johan; Ristimäki, Ari; Kankainen, Matti; Hemminki, Akseli; Backman, Charlotta; Dienel, Kasper; Euler, Mikael von; Haavisto, Elina; Hakonen, Tiina; Juhila, Juuso; Jäderberg, Magnus; Priha, Petri; Vuolanto, Antti; Pesonen, Sari

doi:10.1080/2162402x.2015.1017702

Cited by 47 publications

(55 citation statements)

References 25 publications

(21 reference statements)

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“…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. [38][39][40] In addition to antitumor efficacy in vivo, increased tumor cell killing activity of combination treatment-derived splenocytes ex vivo suggest the presence of active antitumor T cells on a systemic level.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 d were adoptively transferred into tumorbearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target (E/T) assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8 C T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic antitumor immunity was induced. For the first time, TIL of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Recent results have suggested that OV likely functions through the induction of anti-tumor T-cell responses (3). Unfortunately, while the initial induction of these responses can be observed in both preclinical models (4–7) and human trials (8–12), they frequently result in only modest long-term efficacy. Identifying mechanisms and/or pathways which restrict the efficacy of OV is therefore highly significant.…”

Section: Introductionmentioning

confidence: 99%

Tumor-Localized Secretion of Soluble PD1 Enhances Oncolytic Virotherapy

2017

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Oncolytic virotherapy represents an attractive option for the treatment of a variety of aggressive or refractory tumors. While this therapy is effective at rapidly debulking directly injected tumor masses, achieving complete eradication of established disease has proven difficult. One method to overcome this challenge is to use oncolytic viruses to induce secondary anti-tumor immune responses. Unfortunately, while the initial induction of these immune responses is typically robust, their subsequent efficacy is often inhibited through a variety of immunoregulatory mechanisms, including the PD1/PDL1 T-cell checkpoint pathway. To overcome this inhibition, we generated a novel recombinant myxoma virus (vPD1) which inhibits the PD1/PDL1 pathway specifically within the tumor microenvironment by secreting a soluble form of PD1 from infected cells. This virus both induced and maintained anti-tumor CD8+ T-cell responses within directly treated tumors and proved safer and more effective than combination therapy using unmodified myxoma and systemic αPD1 antibodies. Localized vPD1 treatment combined with systemic elimination of regulatory T cells had potent synergistic effects against metastatic disease that was already established in secondary solid organs. These results demonstrate that tumor-localized inhibition of the PD1/PDL1 pathway can significantly improve outcomes during oncolytic virotherapy. Furthermore, they establish a feasible path to translate these findings against clinically relevant disease.

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“…The treatment, called ONCOS-102, has been clinically evaluated in a phase I studies [31] [32]. Repeated intratumoral administration of ONCOS-102, in combination with cyclophosphamide, mediated infiltration of CD8+ and CD4+ T-cells to the treated tumor site, concomitant with an increase in tumor-specific activation of CD8+ cells in the peripheral blood [33]. Evaluation of patients receiving ONCOS-102 revealed that tumor cells up-regulated PD-L1 expression, leading to the possibility that combining ONCOS-102 with PD-L1 checkpoint blockade could further enhance the anti-tumor effects of this immunotherapy [32].…”

Section: Immunologic Barriers To Effective Oncad Anti-tumor Effect Imentioning

confidence: 99%

Recent advances in oncolytic adenovirus therapies for cancer

Shaw

Suzuki

2016

Current Opinion in Virology

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Oncolytic adenoviruses (Onc.Ads) selectively replicate in and lyse cancer cells and are therefore commonly used vectors in clinical trials for cancer gene therapy. Building upon the well-characterized adenoviral natural tropism, genetic modification of Onc.Ad can enhance/regulate their transduction and replication within specific cancer cell types. However, Onc.Ad-mediated tumor cell lysis cannot fully eliminate tumors. The hostile tumor microenvironment provides many barriers to efficient oncolytic virotherapy, as tumors develop structure and immune-evasion mechanisms in order to grow and ultimately spread. For these reasons, Onc.Ads modified to deliver structural or immune modulatory molecules (Armed Onc.Ads) have been developed to overcome the physical and immunological barriers of solid tumors. The combination of oncolysis with tumor microenvironment modulation/destruction may provide a promising platform for Ad-based cancer gene therapy.

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Repeated intratumoral administration of ONCOS-102 leads to systemic antitumor CD8⁺T-cell response and robust cellular and transcriptional immune activation at tumor site in a patient with ovarian cancer

Cited by 47 publications

References 25 publications

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

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

Tumor-Localized Secretion of Soluble PD1 Enhances Oncolytic Virotherapy

Recent advances in oncolytic adenovirus therapies for cancer

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Repeated intratumoral administration of ONCOS-102 leads to systemic antitumor CD8+T-cell response and robust cellular and transcriptional immune activation at tumor site in a patient with ovarian cancer

Cited by 47 publications

References 25 publications

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

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

Tumor-Localized Secretion of Soluble PD1 Enhances Oncolytic Virotherapy

Recent advances in oncolytic adenovirus therapies for cancer

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Repeated intratumoral administration of ONCOS-102 leads to systemic antitumor CD8⁺T-cell response and robust cellular and transcriptional immune activation at tumor site in a patient with ovarian cancer