Comparison of Clinically Relevant Oncolytic Virus Platforms for Enhancing T Cell Therapy of Solid Tumors

Victor Cervera-Carrascon, Dafne C A Quixabeira, Riikka Havunen, Joao M Santos, Emma Kutvonen, James H A Clubb, Mikko Siurala, Camilla Heiniö, Sadia Zafar, Teija Koivula, Dave Lumen, Marjo Vaha, Arturo Garcia-Horsman, Anu J Airaksinen, Suvi Sorsa, Marjukka Anttila, Veijo Hukkanen, Anna Kanerva, Akseli Hemminki, Victor Cervera-Carrascon, Dafne C A Quixabeira, Riikka Havunen, Joao M Santos, Emma Kutvonen, James H A Clubb, Mikko Siurala, Camilla Heiniö, Sadia Zafar, Teija Koivula, Dave Lumen, Marjo Vaha, Arturo Garcia-Horsman, Anu J Airaksinen, Suvi Sorsa, Marjukka Anttila, Veijo Hukkanen, Anna Kanerva, Akseli Hemminki

Abstract

Despite some promising results, the majority of patients do not benefit from T cell therapies, as tumors prevent T cells from entering the tumor, shut down their activity, or downregulate key antigens. Due to their nature and mechanism of action, oncolytic viruses have features that can help overcome many of the barriers currently facing T cell therapies of solid tumors. This study aims to understand how four different oncolytic viruses (adenovirus, vaccinia virus, herpes simplex virus, and reovirus) perform in that task. For that purpose, an immunocompetent in vivo tumor model featuring adoptive tumor-infiltrating lymphocyte (TIL) therapy was used. Tumor growth control (p < 0.001) and survival analyses suggest that adenovirus was most effective in enabling T cell therapy. The complete response rate was 62% for TILs + adenovirus versus 17.5% for TILs + PBS. Of note, TIL biodistribution did not explain efficacy differences between viruses. Instead, immunostimulatory shifts in the tumor microenvironment mirrored efficacy results. Overall, the use of oncolytic viruses can improve the utility of T cell therapies, and additional virus engineering by arming with transgenes can provide further antitumor effects. This phenomenon was seen when an unarmed oncolytic adenovirus was compared to Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (TILT-123). A clinical trial is ongoing, where patients receiving TIL treatment also receive TILT-123 (ClinicalTrials.gov: NCT04217473).

Keywords: T cell therapy; adenovirus; gene therapy; herpes simplex virus; immunotherapy; oncolytic virus; reovirus; solid tumor; tumor microenvironment; vaccinia virus.

© 2020 The Authors.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Antitumor Efficacy after the Use of Different Oncolytic Viruses to Enable T Cell Therapy (A) Experimental design: forty-one Syrian hamsters carrying subcutaneous HapT1 tumors were randomized into groups and treated with TILs intraperitoneally and PBS or one of the studied viruses intratumorally. After the treatment period, the animals were followed up to day 250. (B) Individual normalized tumor volume lines for PBS group (n = 9). (C) Individual normalized tumor volume lines for Adenovirus group (n = 8). (D) Individual normalized tumor volume lines for Vaccinia group (n = 8). (E) Individual normalized tumor volume lines for Herpes simplex group (n = 8). (F) Individual normalized tumor volume lines for Reovirus group (n = 8).
Figure 2
Figure 2
Study of Antitumor Memory in Complete Responders (A) Experimental design: animals treated with ACT and different oncolytic viruses (or PBS) experiencing complete responses were rechallenged with HapT1 and challenged with DDT1-MF2 to study antitumor-specific memory (no additional treatments given). In addition, naive animals were simultaneously engrafted with HapT1 and DDT1-MF2 tumors. (B) Groups included in the experiment: naive animals group (n = 3), PBS + TILs group (n = 1), adenovirus + TILs group (n = 5), vaccinia + TILs (n = 1), and reovirus + TILs (n = 1). The number of animals depended on how many had been cured in the first part of the experiment. (C) Mean (and SEM) tumor volumes for the HapT1 tumors. (D) Mean (and SEM) tumor volumes for the DDT1-MF2 tumors.
Figure 3
Figure 3
Tracking of Systemically Administered TILs after Oncolytic Virus Intratumoral Injection (A) Experimental design: thirty-four Syrian hamsters carrying subcutaneous HapT1 tumors were randomized into groups and treated with 111indium-labeled TILs intraperitoneally and PBS or one of the studied viruses intratumorally. During the experiment, animals were imaged with SPECT/CT to quantify the biodistribution of the injected TILs. At the end of the experiment, animals were euthanized, and different organs were harvested for ex vivo111indium measurement or in the case of tumors, also for multiplexed RNA sequencing. (B) Normalized tumor volumes for the different groups (n = 6–8). (C) Correlation between tumor volumes measured using CT and the weight of those tumors after they were harvested. (D) Correlation between the in vivo radiation signal measured with SPEC/CT and the ex vivo samples measured by gamma counting. (E) TIL-associated radiation of tumors measured in vivo with SPECT/CT on days 1, 3, and 6. (F) TIL-associated radiation measured ex vivo on different tissues by gamma counting on day 6 (∗p < 0.05; ∗∗p < 0.01). All error bars are SEM; ∗p < 0.05; ∗∗p < 0.01.
Figure 4
Figure 4
Impact of Different Oncolytic Viruses in the Tumor Microenvironment Comparisons were made between RNA expression profiles from the different virally treated groups versus PBS-treated group. (A–D) Viral treatment used in the group compared to PBS-treated animals: (A) adenovirus, (B) vaccinia virus, (C) herpes simplex virus, and (D) reovirus. The plots indicate the names of those genes for which there is a statistically significant difference (adjusted p value  log2 fold change > 1).
Figure 5
Figure 5
Antitumor and Immunological Effects of Arming an Adenovirus with Immunostimulatory Cytokines (A) Summary of unarmed and armed virus constructs. (B) Grouped-normalized tumor volume values for the different groups (n = 6–9 per group) after receiving TIL therapy (intraperitoneally) and virotherapy or PBS (intratumorally). Treatment schedule is presented in Figure 1A. (C) Overall survival data. Gray dashed line marks discontinuation of the treatments. (D) Mean tumor volume at day 19 after HapT1 rechallenge in complete responders from HapT1 tumors. (E) Mean tumor volume at day 19 after DDT1-MF2 challenge in complete responders from HapT1 tumors (naive, n = 3; PBS + TILs, n = 1; adenovirus + TILs, n = 5; TILT-123 + TILs, n = 2). (F) 13 Syrian hamsters carrying subcutaneous HapT1 tumors were randomized into groups and treated with 111indium-labeled TILs intraperitoneally and with PBS (n = 4), unarmed adenovirus (n = 5), or armed adenovirus (n = 4). At day 6 of the experiment, tumors were harvested for ex vivo111indium measurement by a gamma counter (∗p < 0.05). Comparisons were made between the RNA expression profiles from each of the two adenovirus-treated groups versus the PBS-treated group. Animals carrying these tumors were treated as described in Figure 3A. Viral treatment used in the group compared to PBS-treated animals: (G) adenovirus and (H) TILT-123. The plots indicate the names of those genes for which there is a statistically significant difference (adjusted p value < 0.05) and an expression change over double or below half to those in the reference group (−1 > log2 fold change > 1). All error bars are SEM.

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