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Boosting CAR T cell functionality with oncolytic viruses for the treatment of pediatric diffuse midline gliomas
Konstantinos Vazaios1, Antonio C Tallon-Cobos1, Louisa P J van Oosterhout1
1Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands.
Abstract:
Despite the success of CAR (chimeric antigen receptor) T cells in hematological malignancies, their effectiveness against solid or brain tumors, such as pediatric diffuse midline gliomas (DMGs), is limited. CAR T cell success is hampered by factors including immunosuppression from DMGs and their surrounding tumor microenvironment (TME). Oncolytic viruses (OVs) can reverse this immunosuppression, suggesting a potential combination with CAR T cells. Here, we show that infection with Goravir adenovirus and R124 reovirus induced DMG cell lysis (n = 6 cultures), with minimal effect on the viability of B7H3- or GD2-targeted CAR T cells, even at high virus concentrations. In addition, RNA sequencing of infected tumor cells revealed altered gene expression in cell cycle and antiviral response pathways. Furthermore, co-cultures of CAR T cells with OV-infected DMGs enhanced CAR T-specific anti-tumor killing in 14 out of 24 cases. The successful combinations exhibited enhanced cytokine and chemokine release, coupled with an increased cytotoxic phenotype. These findings highlight the benefit of DMG pre-infection with OVs to boost CAR T cell activity and suggest that immune stimulation is a key driver of enhanced combination responses.
Insights
Combining oncolytic viruses (OVs) with chimeric antigen receptor (CAR) T cells can overcome tumor immunosuppression in pediatric diffuse midline gliomas (DMGs). Pre-infecting DMGs with OVs enhances CAR T cell anti-tumor activity and immune responses.
Area of Science:
- Immunotherapy
- Oncology
- Virology
Background:
- Chimeric antigen receptor (CAR) T cells show limited efficacy against solid tumors like pediatric diffuse midline gliomas (DMGs).
- Tumor microenvironment (TME) and immunosuppression in DMGs hinder CAR T cell effectiveness.
- Oncolytic viruses (OVs) have the potential to reverse tumor-induced immunosuppression.
Purpose of the Study:
- To investigate the combination of OVs and CAR T cells for treating pediatric diffuse midline gliomas (DMGs).
- To assess if OV infection can enhance CAR T cell anti-tumor activity in DMGs.
- To explore the mechanisms behind enhanced combination therapy responses.
Main Methods:
- Infection of DMG cells with Goravir adenovirus and R124 reovirus.
- Assessment of DMG cell lysis and CAR T cell viability post-infection.
- RNA sequencing of infected tumor cells to analyze gene expression changes.
- Co-culture experiments of CAR T cells with OV-infected DMGs.
Main Results:
- OV infection induced DMG cell lysis with minimal impact on CAR T cell viability.
- Gene expression analysis revealed altered cell cycle and antiviral response pathways in infected tumor cells.
- Co-culturing with OV-infected DMGs enhanced CAR T cell anti-tumor killing in a significant portion of cases (14/24).
- Successful combinations showed increased cytokine/chemokine release and enhanced cytotoxic phenotype.
Conclusions:
- Pre-infection of DMGs with OVs can boost CAR T cell activity.
- Immune stimulation is a key factor driving enhanced responses in OV-CAR T cell combination therapy.
- This combination strategy holds promise for treating pediatric diffuse midline gliomas.
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