LOAd703 and chemotherapy combination in pancreatic cancer: insights from the LOKON001 study

Pancreatic cancer is one of the most aggressive and lethal malignancies. It is one of the top 10 malignancies diagnosed in both males and females and the third leading cause of cancer death in the United States (1). In 2024, the number of new cases and deaths of pancreatic cancer are estimated to be 66,440 and 51,750, respectively in the United States (1). Despite notable progress in systemic therapies, the median overall survival for patients with metastatic disease remains under 12 months. Current first-line treatments remain chemotherapy regimens such as FOLFIRINOX (a combination of fluorouracil, leucovorin, oxaliplatin, and irinotecan), NALIRIFOX (liposomal irinotecan, oxaliplatin, fluorouracil, and leucovorin), gemcitabine plus nab-paclitaxel, or in limited cases gemcitabine monotherapy (2-4). While immunotherapy has revolutionized treatment for many cancers, its impact on pancreatic ductal adenocarcinoma has been minimal. A major barrier to achieving therapeutic success from immunotherapy in pancreatic ductal adenocarcinoma is the tumor’s highly complex and immunosuppressive tumor microenvironment (5,6).

Oncolytic virus therapy is a form of immunotherapy with genetically modified viruses to infect and lyse tumor cells. In addition to tumor cell lysis, oncolytic viruses may modify tumor immune microenvironment by activation of innate and adaptive immune system through danger signals and immunogenic cell death pathways (7). To further enhance anticancer immunity and remodel immunosuppressive tumor microenvironment, engineered oncolytic viruses encoding costimulatory molecules, cytokines and chemokines have been extensively studied (8).

LOAd703 is an oncolytic adenovirus encoding immunostimulatory molecules CD40L (CD40 ligand) and 4-1BBL (4-1BB ligand) (9). CD40/CD40L and 4-1BB/4-1BBL are promising costimulatory targets for cancer immunotherapy. CD40, a member of the tumor necrosis factor receptor family, is expressed by antigen-presenting cells, and ligation of CD40 by CD40L induces dendritic cell maturation to effectively trigger T cell activation and differentiation (10). 4-1BB is also a member of the tumor necrosis factor receptor family and is expressed on activated T cells (11). Upon binding to 4-1BBL, 4-1BB signaling sustains T cells survival, induces T cells proliferation and enhances effector function of T cells (11). Previous in vitro data showed LOAd703 virus infected dendritic cells promoted T and natural killer (NK) cell expansion, and LOAd703 virus infected endothelial cells enhanced expression of VACM-I, ICAM-I and E-selection which are essential for lymphocyte attachment and transmigration (12). In addition, intra-tumoral injection of LOAd703 could control tumor growth in a transgenic pancreatic cancer mouse model (12). Based on the preclinical results, Benjamin L. Musher et al. conducted a phase 1/2 study (LOKON001) of LOAd703 combined with gemcitabine plus nab-paclitaxel in patients with locally advanced unresectable or metastatic pancreatic cancer (13). The primary endpoints were safety and immune response. Toxicity of the combination was well manageable, and the only dose limiting toxicity was a transient grade 3 alanine aminotransferase elevation. The maximum tolerated dose was not reached in the study. LOAd703 treatment increased adenovirus-specific T cells and effector memory CD8 T cells in over 90% of eligible 16 patients. Objective response rate was 44%. The median overall survival and median progression free survival were 9.3 and 5.4 months, respectively. While these results are encouraging, further exploration is needed. Due to the facts that patients with relatively low disease burden were selected, heterogenous patient population including locally advanced disease and metastatic disease was enrolled, and three of 21 patients were excluded for evaluation of clinical outcome, the efficacy of LOAd703 should be further evaluated in a randomized study. Although preclinical data have demonstrated LOAd703 can enhance the immunogenic profile by upregulation of costimulatory molecules and adhesion molecules (12,14), evaluation of tumor microenvironment after LOAd703 treatment is necessary for deeper and better understanding of mechanisms of action and pancreatic cancer immune microenvironment. Given increased adenovirus-specific T cells and effector memory CD8 T cells after LOAd703 treatment, it would be a reasonable approach to combine LOAd703 and immune checkpoint inhibitors for synergistic effects. Currently, another study which combines LOAd703, gemcitabine/nab-paclitaxel and atezolizumab is ongoing (NCT02705196).

The combination of LOAd703 and chemotherapy demonstrated promising anticancer activity in pancreatic cancer. However, further evaluation of LOAd703 and pancreatic tumor immune microenvironment is needed to improve our understanding and clinical outcome of this aggressive and lethal disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-139/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-139/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74:12-49. [Crossref] [PubMed]
2. Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol 2013;31:23-9. [Crossref] [PubMed]
3. Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet 2023;402:1272-81. [Crossref] [PubMed]
4. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703. [Crossref] [PubMed]
5. Basso D, Fogar P, Falconi M, et al. Pancreatic tumors and immature immunosuppressive myeloid cells in blood and spleen: role of inhibitory co-stimulatory molecules PDL1 and CTLA4. An in vivo and in vitro study. PLoS One 2013;8:e54824. [Crossref] [PubMed]
6. Clark CE, Hingorani SR, Mick R, et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 2007;67:9518-27. [Crossref] [PubMed]
7. Malfitano AM, Di Somma S, Iannuzzi CA, et al. Virotherapy: From single agents to combinatorial treatments. Biochem Pharmacol 2020;177:113986. [Crossref] [PubMed]
8. Tian Y, Xie D, Yang L. Engineering strategies to enhance oncolytic viruses in cancer immunotherapy. Signal Transduct Target Ther 2022;7:117. [Crossref] [PubMed]
9. Rojas JJ, Guedan S, Searle PF, et al. Minimal RB-responsive E1A promoter modification to attain potency, selectivity, and transgene-arming capacity in oncolytic adenoviruses. Mol Ther 2010;18:1960-71. [Crossref] [PubMed]
10. Elgueta R, Benson MJ, de Vries VC, et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 2009;229:152-72. [Crossref] [PubMed]
11. Singh R, Kim YH, Lee SJ, et al. 4-1BB immunotherapy: advances and hurdles. Exp Mol Med 2024;56:32-9. [Crossref] [PubMed]
12. Eriksson E, Milenova I, Wenthe J, et al. Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus. Clin Cancer Res 2017;23:5846-57. [Crossref] [PubMed]
13. Musher BL, Rowinsky EK, Smaglo BG, et al. LOAd703, an oncolytic virus-based immunostimulatory gene therapy, combined with chemotherapy for unresectable or metastatic pancreatic cancer (LOKON001): results from arm 1 of a non-randomised, single-centre, phase 1/2 study. Lancet Oncol 2024;25:488-500. [Crossref] [PubMed]
14. Wenthe J, Naseri S, Labani-Motlagh A, et al. Boosting CAR T-cell responses in lymphoma by simultaneous targeting of CD40/4-1BB using oncolytic viral gene therapy. Cancer Immunol Immunother 2021;70:2851-65. [Crossref] [PubMed]