TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade
V Cervera-Carrascon1,2, M Siurala1,2, J M Santos1,2
1TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland.
Abstract:
Releasing the patient's immune system against their own malignancy by the use of checkpoint inhibitors is delivering promising results. However, only a subset of patients currently benefit from them. One major limitation of these therapies relates to the inability of T cells to detect or penetrate into the tumor resulting in unresponsiveness to checkpoint inhibition. Virotherapy is an attractive tool for enabling checkpoint inhibitors as viruses are naturally recognized by innate defense elements which draws the attention of the immune system. Besides their intrinsic immune stimulating properties, the adenoviruses used here are armed to express tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2). These cytokines result in immunological danger signaling and multiple appealing T-cell effects, including trafficking, activation and propagation. When these viruses were injected into B16.OVA melanoma tumors in animals concomitantly receiving programmed cell-death protein 1 (PD-1) blocking antibodies both tumor growth control (p < 0.0001) and overall survival (p < 0.01) were improved. In this set-up, the addition of adoptive cell therapy with OT-I lymphocytes did not increase efficacy further. When virus injections were initiated before antibody treatment in a prime-boost approach, 100% of tumors regressed completely and all mice survived. Viral expression of IL2 and TNFa altered the cytokine balance in the tumor microenvironment towards Th1 and increased the intratumoral proportion of CD8+ and conventional CD4+ T cells. These preclinical studies provide the rationale and schedule for a clinical trial where oncolytic adenovirus coding for TNFa and IL-2 (TILT-123) is used in melanoma patients receiving an anti-PD-1 antibody.
Insights
Virotherapy combined with checkpoint inhibitors enhances anti-tumor immunity. Oncolytic adenovirus expressing tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2) significantly improved tumor control and survival in preclinical models.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Immune checkpoint inhibitors show promise but benefit only a subset of patients.
- Tumor-infiltrating T cells are crucial for effective anti-cancer immunity.
- Limited T cell infiltration and recognition hinder checkpoint inhibitor efficacy.
Purpose of the Study:
- To evaluate the efficacy of oncolytic adenovirus therapy combined with immune checkpoint blockade.
- To investigate the potential of armed adenoviruses expressing tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2) in enhancing anti-tumor responses.
- To establish a prime-boost strategy for maximizing therapeutic outcomes in melanoma models.
Main Methods:
- Preclinical studies using B16.OVA melanoma tumor model in animals.
- Administration of armed oncolytic adenoviruses (expressing TNFa and IL-2) and programmed cell-death protein 1 (PD-1) blocking antibodies.
- Evaluation of tumor growth control, overall survival, and immune cell infiltration.
- Implementation of a prime-boost vaccination schedule.
Main Results:
- Concomitant administration of armed adenovirus and PD-1 blockade significantly improved tumor growth control (p < 0.0001) and survival (p < 0.01).
- A prime-boost approach with virus injections preceding antibody treatment led to complete tumor regression and 100% survival.
- Viral expression of IL-2 and TNFa shifted the tumor microenvironment towards Th1 immunity and increased intratumoral CD8+ and CD4+ T cells.
Conclusions:
- Oncolytic adenovirus armed with TNFa and IL-2 enhances the efficacy of PD-1 blockade in melanoma.
- A prime-boost strategy with this oncolytic adenovirus offers a highly effective therapeutic approach.
- These findings support the clinical translation of armed oncolytic adenoviruses in combination with checkpoint inhibitors for melanoma treatment.
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