Abstract PR09: Intratumoral delivery of engineered modified vaccinia virus Ankara expressing Flt3L and OX40L for "in situ" therapeutic cancer vaccination
Bibliographic record
Abstract
Abstract Modified vaccinia virus Ankara (MVA) is a highly attenuated, effective, and safe vaccinia strain that is an important vaccine vector for infectious diseases and cancers. We have previously shown that intratumoral (IT) injection of inactivated MVA elicits stronger antitumor immunity compared with live MVA in murine B16-F10 melanoma and MC38 colon cancer models, indicating that viral immune inhibitory factors might be involved in attenuating antitumor effects. Here we provide evidence that vaccinia virulence factor C7 interacts with transcription factors IRF3 and STAT2, which attenuates both type I IFN production and IFN receptor signaling. Infection of conventional dendritic cells (cDCs) with MVAΔC7L in which C7L gene is deleted results in higher levels of IFNB gene induction and IRF3 phosphorylation compared with MVA. IT MVAΔC7L also induced stronger antitumor responses compared with MVA, which correlates with higher levels of tumor infiltrating activated CD4+ and CD8+ T-cells in both injected and noninjected tumors in a bilateral B16-F10 tumor implantation model. We engineered a recombinant MVA in which the C7L gene was replaced with human Flt3L (hFlt3L) and the J2R gene (a.k.a. TK gene) was replaced with murine OX40L (mOX40L) or human OX40L (hOX40L). Using B16-F10 and MC38 tumor models, we show that IT MVAΔC7L-hFlt3L-ΔJ2R-mOX40L is more effective than MVAΔC7L-hFlt3L, or MVAΔC7L, or heat-inactivated MVAΔC7L in eradicating injected tumors, delaying the growth of the noninjected tumors, and prolonging mice survival. ELISPOT analysis demonstrate that IT MVAΔC7L-hFlt3L-ΔJ2R-mOX40L generates the most tumor-specific CD8+ and CD4+ T-cells compared with the other viruses mentioned above. The combination of IT MVAΔC7L-hFlt3L-ΔJ2R-mOX40L with systemic delivery of anti-CTLA-4 or anti-PD-L1 antibodies results in more efficient eradication of injected tumors, higher survival rate compared with IT virus alone in both bilateral tumor implantation and unilateral large established tumor models. MVAΔC7L-hFlt3L-ΔJ2R-hOX40L has been generated and will be investigated in clinical trials for patients with metastatic cancers in the near future. Taken together, we provide proof-of-concept results for the development of immune activating recombinant MVA to alter tumor immunosuppressive microenvironment through the induction of type I IFN via the cytosolic DNA-sensing pathway, activation of CD103+ dendritic cells, as well as direct activation of both CD4 and CD8 T-cells. This approach enhances tumor antigen presentation and T-cell activation through "in situ" therapeutic vaccination effects, either used as monotherapy or in combination with anti-CTLA-4 or anti-PD-L1 antibody therapy. Citation Format: Liang Deng, Ning Yang, Yi Wang, Wei Yan, Jiahu Wang, John Choi, Stewart Shuman, Taha D. Merghoub, Jedd D. Wolchok. Intratumoral delivery of engineered modified vaccinia virus Ankara expressing Flt3L and OX40L for "in situ" therapeutic cancer vaccination [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR09.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".